Key information

Title
Radiopharmaceutical MOFs for medical imaging
Application number
20221181
Case type
National
Status
25.08.2025 Patent meddelt (B1)
Filed
02.11.2022
Effective date
02.11.2022
Publicly available
03.05.2024
Next annual fee due
30.11.2026
Applicant
Node Pharma AS (NO)
Owner
Node Pharma AS (NO)
Inventor
Erik Mjåland (NO) et al.
Agent
BRYN AARFLOT AS (NO)
Granted
25.08.2025
Patent number
349016
Expiry date
02.11.2042

Abstract and drawing

Disclaimer: This text has been machine-scanned and may contain errors – please refer to "Publications" for legally binding content.
The present invention relates to MOFs for use in imaging and as radiolabeled tracers. More particularly, the invention provides a particle comprising a MOF, optionally at least one targeting moiety and at least one short-lived radionuclide; a composition comprising said particle; said particle or composition for use as an imaging agent; said particle or composition for use in a method for the diagnosis of a proliferative disease; said particle or composition for use in a method for the diagnosis of a chronic inflammatory disease; and a kit comprising a particle comprising a MOF, an optional targeting moiety, and a short-lived radionuclide cation.

Publications

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 Date Doc. No. Process Case number In/Out Journal description To/from
 28.08.2025 19-01 Saksbehandling 20221181(349016) UT PT Registreringsbrev nasjonal patent (15) (PT20221181)
26.05.2025 18-01 Saksbehandling 20221181 UT Intention to grant BRYN AARFLOT AS
 10.02.2025 17-07 Saksbehandling 20221181 INN Letter to NIPO patent BRYN AARFLOT AS
 10.02.2025 17-06 Saksbehandling 20221181 INN Claim set Amended February 2025 clean BRYN AARFLOT AS
 10.02.2025 17-05 Saksbehandling 20221181 INN Claim set Amended February 2025 annotated BRYN AARFLOT AS
 10.02.2025 17-04 Saksbehandling 20221181 INN Approved claim set - NO translation BRYN AARFLOT AS
 10.02.2025 17-03 Saksbehandling 20221181 INN 141284 Description Amended February 2025 clean BRYN AARFLOT AS
 10.02.2025 17-02 Saksbehandling 20221181 INN 141284 Description Amended February 2025 annotated BRYN AARFLOT AS
 10.02.2025 17-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 22.11.2024 16-01 Saksbehandling 20221181 UT Substantive Examination BRYN AARFLOT AS
 02.10.2024 15-01 Saksbehandling 20221181 UT PT Varsel om betaling av første årsavgift (3317) (PT20221181) BRYN AARFLOT AS
 30.09.2024 14-07 Saksbehandling 20221181 INN Re OA3 final BRYN AARFLOT AS
 30.09.2024 14-06 Saksbehandling 20221181 INN Claim set Amended September 2024_Main Request marked BRYN AARFLOT AS
 30.09.2024 14-05 Saksbehandling 20221181 INN Claim set Amended September 2024_Main Request clean BRYN AARFLOT AS
 30.09.2024 14-04 Saksbehandling 20221181 INN Claim set Amended September 2024_Auxiliary Request marked BRYN AARFLOT AS
 30.09.2024 14-03 Saksbehandling 20221181 INN Claim set Amended September 2024_Auxiliary Request clean BRYN AARFLOT AS
 30.09.2024 14-02 Saksbehandling 20221181 INN 141284 PCT experimental data to include re OA3 BRYN AARFLOT AS
 30.09.2024 14-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 01.07.2024 13-01 Saksbehandling 20221181 UT Substantive Examination BRYN AARFLOT AS
 11.04.2024 12-04 Saksbehandling 20221181 INN Le to NIPO OA2 response BRYN AARFLOT AS
 11.04.2024 12-03 Saksbehandling 20221181 INN Claim set Amended April 2024 marked BRYN AARFLOT AS
 11.04.2024 12-02 Saksbehandling 20221181 INN Claim set Amended April 2024 clean BRYN AARFLOT AS
 11.04.2024 12-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 12.12.2023 11-02 Saksbehandling 20221181 UT PT report 08:32:30
12.12.2023 11-01 Saksbehandling 20221181 UT 20221181_1789032_PT 08 Eng BRYN AARFLOT AS
 04.10.2023 10-04 Saksbehandling 20221181 INN Letter to NIPO patent BRYN AARFLOT AS
 04.10.2023 10-03 Saksbehandling 20221181 INN 141284 Claims as amended 4 Oct 2023 Marked BRYN AARFLOT AS
 04.10.2023 10-02 Saksbehandling 20221181 INN 141284 Claims as amended 4 Oct 2023 Clean BRYN AARFLOT AS
 04.10.2023 10-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 01.06.2023 09-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 30.05.2023 08-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 16.05.2023 07-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 08.05.2023 06-02 Saksbehandling 20221181 UT PT report 08:04:42
08.05.2023 06-01 Saksbehandling 20221181 UT 20221181_1707503_PT 08 Eng BRYN AARFLOT AS
 15.11.2022 05-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 15.11.2022 04-03 Saksbehandling 20221181 INN Power of Attorney Node Pharma AS_signed BRYN AARFLOT AS
 15.11.2022 04-02 Saksbehandling 20221181 INN Declaration of rights to invention Node Pharma AS_signed BRYN AARFLOT AS
 15.11.2022 04-01 Saksbehandling 20221181 INN Korrespondanse (Hovedbrev inn) BRYN AARFLOT AS
 15.11.2022 01-01 Endring av søker/innehaver 2022/17713 INN Generell henvendelse BRYN AARFLOT AS
 03.11.2022 03-01 Saksbehandling 20221181 UT Formal Examination 1 BRYN AARFLOT AS
 03.11.2022 02-01 Saksbehandling 20221181 UT Informasjon til oppfinner Sigurd ØIEN-ØDEGAARD
 02.11.2022 01-03 Saksbehandling 20221181 INN 141284 Patent application Final BRYN AARFLOT AS
 02.11.2022 01-02 Saksbehandling 20221181 INN 141284 Figures BRYN AARFLOT AS
 02.11.2022 01-01 Saksbehandling 20221181 INN Søknadsskjema Patent BRYN AARFLOT AS

Description, claims and drawings

Disclaimer: This text has been machine-scanned and may contain errors – please refer to "Publications" for legally binding content. Description
3490161Field of the invention5 The present invention relates to MOFs for use in imaging and as radiolabeled tracers.More particularly, the invention provides a particle comprising a MOF and at least one short-lived radionuclide; a particle comprising a MOF, at least one targeting moiety and at least one short-lived radionuclide; a composition comprising said particle; said particle or composition for use as an imaging agent; said particle or composition for use in a method 10 for the diagnosis of a proliferative disease; and a kit comprising a particle comprising a MOF and optionally a targeting moiety, and a short-lived radionuclide cation.Background of the inventionCancer is a widespread group of diseases that affect millions of people, either directly or 15 indirectly. WHO estimated 19.3 million new cases of cancer in 2020, and 50.6 million individuals living with a 5-year life expectancy. Despite decades of improvement in treatments, the American Cancer Society expects the number of new incidents of cancer to grow to 27.5 million per year by 2040, and the number of annual deaths from cancer to increase to 16.2 million. Common methods of cancer treatment include surgery,20 chemotherapy and external beam irradiation. However, there is a significant unmet medical need for new and more effective cancer treatment options.One treatment option, with the potential of high specificity and efficiency, is so-called theranostic which combines the use of diagnostic and cancer killing radioisotope (e.g 25 gamma emitter and alpha emitter). Theranostic treatment uses the same delivery compound, only altering the radioisotope. This allows for assessing biodistribution of the diagnostic compound prior to administrating the cancer killing radiopharmaceutical such as radioimmunotherapy (RIT) or targeted alpha therapy (TAT). RIT drugs are based on tissue targeting moieties linked to a carrier that can bind and hold on to radioisotopes. The 30 tissue targeting moieties, which frequently are antibodies, are used to bring the radioisotopes into close proximity of the unwanted cell types, such as cancer cells, resulting in local delivery of high energy and highly cytotoxic radiation - killing the unwanted cells and not the healthy surrounding tissue. This type of specific cell killing can be essential not only for the treatment of cancerous diseases such as sarcomas and 35 carcinomas, but also hyperplastic and neoplastic diseases and chronic inflammatory 3490162141284/mwwdiseases. Further, systemic treatment using RIT can be extremely effective for patients with metastatic tumours, otherwise difficult to reach without detrimental side effects.Successful delivery of the radiation to the unwanted cells depends on a stable5 radioisotope-carrier interaction to prevent unanticipated side effects due to radioisotope leakage, in particular the alpha-emitting radium isotopes including radium-223 and radium-224, and new radiopharmaceuticals for treatment are being developed. One type of new radioisotope-carriers being explored, are crystalline porous coordination polymers (PCP), also referred to as metal-organic frameworks (MOF), constructed of alternating 10 inorganic and organic monomers in a three-dimensional network with pores. The interior pores of the MOF particles may have strong binding sites where cationic radioisotopes can be strongly bound by e.g. chelation.Various small-scale carriers are being explored as payload carriers for a range of15 applications. For example, ultra-small PEGylated polyvinylpyrrolidone particles (PVP) enable incorporation of iron-gallic acid in the PVP matrix forming dense particles (Jin Q et. al, Ultra-small iron-gallic acid coordination polymer nanoparticles for chelator-free labelling of 64Cu and multimodal imaging-guided photothermal therapy. Nanoscale, 2017, vol 9., no. 34, p.12609-12617). A study demonstrated in situ polymerization on nanoscale MOFs 20 for enhanced physiological stability and stimulus-responsive intracellular drug delivery (Liu, Y. et al. In situ polymerization on nanoscale metal-organic frameworks for enhanced physiological stability and stimulus-responsive intracellular drug delivery. Biomaterials, 2019, vol.218, 119365.) US10272157 B2 discloses that the outer surfaces of MOFs may be coated with polymers and used as carriers for a range of active principles, such as 25 traditional therapeutic molecules. Zeng et al. discloses PEGylated nanoscale MOFs, without functional groups, coupled to targeting ligands such as the F3 peptide (Zeng, Y. et al. PEGylated Nanoscale Metal-Organic Frameworks for Targeted Cancer Imaging and Drug Delivery. Bioconjugate Chem., 2021, vol.32, p.2195-2204.) CN114806546 A describes a surface-modified organic framework material based on fluorescent molecules.30 Tao et al. discloses that PEG-modified nMOFs can be labelled with a subset of radionuclides (Tao Y. et al, Versatile labelling of multiple radionuclides onto a nanoscale metal-organic framework for tumor imaging and radioisotope therapy, Biomater. Sci., 2021, vol.9, p.2947-2954).35 RIT drugs are antibody drug conjugates using a targeting unit (the antibody), to transport radioisotopes by the blood to the tumours, where emitted radiation then eradicate the 3490163141284/mwwcancer cells. Controlled administration of radionuclides is an emerging form of targeted therapy of metastatic cancers: radionuclides emitting high-energy particles upon decay enable precise micro-irradiation of small cell-clusters without harming neighbouring healthy cells. However, unfortunately not all patients or cancer forms may respond to such 5 therapy due to lack of co-localisation of the drug and cancer cells.To identify and monitor disease, medical imaging is typically performed. By using imaging modalities like scintigraphy or positron emission tomography (PET) and radionuclidecontaining imaging agents, also functional assessments of metabolism can be achieved.10 When a radiopharmaceutical imaging agent is administered to a patient it is monitored by a specific imaging device such as a gamma camera. These systems may include SPECT, PET, PET/MRI or PET/CT imaging. The radiopharmaceuticals which are used for diagnostic purposes are short-lived radiotracers, that emit gamma rays or are positron emitting, used to produce a 2-D picture, or alternatively a 3-D image by the application of 15 tomography.However, it is still difficult to predict how a patient and the indication of the patient will respond to planned treatment with radiopharmaceuticals.Hence, there is a need for improved radiotracers, imaging agents and methods for 20 selecting patients that are likely to respond to a treatment with radiopharmaceuticals, particularly to treatment with radiopharmaceuticals wherein the radioisotopes are comprised in MOF particles.Brief description of the drawings25 Figure 1 shows a schematic illustration of an embodiment of the invention.Figure 2 shows a schematic representation of a network structure with fcu topology, Figure 3 illustrates the pores in fcu MOFs.Figure 4 shows an example of a coordinating site in a tetrahedral cage corner.Figure 5 shows an example of a coordinating site in an octahedral pore corner.30 Figure 6 shows an example of a coordinating site in an octahedral pore corner.Figure 7 shows an example of a coordinating site in an octahedral cage corner.Figure 8 shows an example of a pore where several free functional groups are extending into the pore.Figure 9 illustrates the MOF UiO-66.35 Figure 10 illustrates the MOF MIL-53. 3490164141284/mwwFigure 11 illustrates a MOF having a zeolitic imidazolate framework and a so-called sod topology.Figure 12 shows a BCA assay of antibody (IgG) conjugated UIO-66(COOH)2.Figure 13 shows that anti-CD37-conjugated MOFs (NP1) bind CD37 positive cells (Duadi 5 cells).Figure 14 shows that anti-EpCAM or anti-HER-conjugated UiO-66-(COOH) 2 bind colorectal cancer cells (HTC116 and HT29) expressing both antigens.Figure 15 shows anti-HER2-conjugated UiO-66-(COOH)2 binds HER2 positive cancer cells (JIMT1 cells).10 Figures 16 A and B show in vitro cell viability of HT29 or HCT116 respectively, after exposing them to UiO-66-(COOH)2 for 24 and 48 hours.Brief summary of the invention15 The inventors have discovered that particular metal-organic-framework (MOF) structures comprising certain free functional groups can adsorb and act as stable carriers for selected radionuclides in clinically relevant environments. Furthermore, these MOFs, in the form of particles, can be linked to targeting moieties, enabling targeted delivery of the particles, and thus radionuclides, in vivo. These particles, comprising short-lived20 radionuclides, or comprising both targeting moieties and short-lived radionuclides, thus represent promising radiotracer candidates. The radiotracers of the invention, comprising MOFs as carriers for short-lived radionuclides, can e.g. be used in medical imaging such as in pre-screening of patients diagnosed with a proliferative disease, to predict the response to therapy with alpha-emitting radionuclides. The invention is set out in the 25 appended set of claims.In one aspect, the present invention relates to a particle, said particle comprising- a MOF, wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic 30 monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof;35 - at least one short-lived radionuclide, wherein the radionuclide is a radionuclide cation with a half-life in the range of 0.5 hours to 60 days; 3490165141284/mwwand wherein the at least one radionuclide is adsorbed within at least one of the pores by the at least one free functional group that extends into the pore.The present invention also relates to a targeting particle, said particle comprising5 - a MOF, wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, 10 carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof;- at least one targeting moiety connected to the particle on an external surface of the particle; and- at least one short-lived radionuclide, wherein the radionuclide is a radionuclide 15 cation with a half-life in the range of 0.5 hours to 60 days:and wherein the at least one radionuclide is adsorbed within at least one of the pores by the at least one free functional group that extends into the pore.In a second aspect, the invention relates to a kit, wherein the kit comprises20 in a first container,a particle comprising- a MOF, wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and25 - at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof;- optionally at least one targeting moiety connected to the particle on an external 30 surface of the particle;and in a second container,a short-lived radionuclide, wherein the radionuclide is a radionuclide cation with a half-life in the range of 0.5 hours to 60 days;and wherein the at least one radionuclide is adsorbed within at least one of the pores by 35 the at least one free functional group that extends into the pore. 3490166141284/mwwIn a third aspect, the invention relates to a contrast media composition as further disclosed, said composition comprising at least one particle as defined above with at least one pharmaceutically acceptable carrier, diluent, and/or excipient.5 In a fourth aspect, the invention relates to said particle or said composition for use as an imaging agent, as further disclosed herein.In a fifth aspect, the invention relates to said particle or said composition for use in a method for the diagnosis of a proliferative disease, as further disclosed herein.10Detailed description of the inventionUnless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains. In some cases, terms with15 commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.Metal-organic frameworks (MOF), also referred to as porous coordination polymers 20 (PCP), are solid compounds, usually in the form of powders, that belong to the substance class of coordination polymers. Chemically, MOFs comprise repeating networks of polytopic inorganic monomers in the form of metal ions or clusters, and organic monomers, also referred to as bridging ligands or linkers. The inorganic and organic monomers are bound by coordinate covalent bonds or ionic bonds between a Lewis acidic 25 metal cation and a Lewis basic organic functional group (e.g. carboxylate, amine, imine).The structures of MOFs are well-tuneable by selection of the organic and inorganic monomers. The organic monomers of a MOF may all be identical, or the MOF may comprise two or more different organic monomers with near-identical geometry of the framework-coordinating functional groups. The latter is referred to as a “mixed-linker 30 MOF”. Analogously, the inorganic monomers of a MOF may also be identical, or they may differ, resulting in a “mixed-metal MOF”.MOFs may be crystalline, amorphous, or have a deformable structure. MOFs that are made of structurally rigid monomers tend to form repeating three-dimensional networks 35 that feature permanent porosity, i.e. they are crystalline. Such crystalline MOFs feature a number of pores. As used herein, the term “pore” refers to any type of aperture, cavity, 3490167141284/mwwchannel, hole in the MOF network. A MOF may comprise pores of different shapes in different ratios, based on the crystal structure of the MOF. However, the pores of a particular MOF are generally quite similar to each other in respect to size and chemical environment.5The organic monomer of a MOF may contain functional groups that are not interacting directly with the inorganic monomers to form the MOF network. In the present disclosure, such functional groups are referred to as “free” functional groups. If such functional groups are present in a crystalline MOF, these may be directed into the pores of the MOF, 10 creating a site for adsorption, coordination and/or chelation of a guest ion or molecule.The precise nature of such a site depends on the network topology (geometry) of the MOF and the type and number of functional groups directed into the pore. By selecting the appropriate MOF in terms of e.g. free functional groups, specific chelating sites, such as in the pores, can be constructed for strong, selective adsorption, coordination and/or 15 chelation, of particular compounds. As used herein, the terms “chelating” and “chelation” refer to the coordination to, complexing of and/or binding of a metal, such as a radionuclide cation, by at least two ligands. The term “ligand” refers to a moiety, such as a molecule, a part of a molecule, a functional group, capable of coordinating to, complexing and/or binding a metal.20Different functional groups can be used to modify the geometry and charge balance of the chelating site. Since MOFs are built from coordination bonds between the organic and inorganic monomers, additional functional groups which may act as coordinating groups can produce undesired and/or unexpected products in the preparation of the MOF.25 Therefore, the introduction of free functional groups in a MOF requires careful design.In the present invention, particles of specific types of MOFs are used as carriers for particular radionuclides suitable for use in imaging, providing new radiolabeled tracers. As further disclosed below, suitable radionuclides are short-lived radionuclides that emit 30 gamma rays or are positron-emitting radionuclides. The MOFs used in the present invention are crystalline MOFs comprising potentially metal-coordinating free functional groups extending into pores of the MOF in such a manner that said free functional groups can coordinate to and/or bind the short-lived radionuclide, such as a radionuclide cation. Hence, each pore of these MOFs has the ability of functioning as a chelating macro ligand 35 for a radionuclide. The MOF particles represent a new class of carriers and may have the ability to contain radioisotopes, with little or no leakage. Thus, MOFs suitable for carrying 3490168141284/mwwpotent radioisotopes, typically alpha-emitters, for use in treatment, have now also been found useful as carriers for short-lived radionuclides for use in imaging. Using the same MOF carrier for different radioisotopes for imaging and therapy, ensures close to identical biodistribution of the MOF carrier containing imaging agent (e.g. gamma emitters) and a 5 therapeutic agent (e.g. radium223), and this approach allows for a pre-treatment screening of the patients to predict the response to the therapy and prevent unnecessary treatment of non-responders.Thus, in one aspect, the invention relates to a particle comprising a MOF, wherein the 10 MOF comprises a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, wherein the pores are designed for chelating a shortlived radionuclide, and wherein the particle comprises a short-lived radionuclide located in at least one of the pores. Optionally, the particle comprises at least one targeting moiety. Hence, in one embodiment, the particle comprises at least one targeting moiety15 connected to the particle on an external surface of the particle.In some embodiments, the invention relates to a particle comprising- a MOF, wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic 20 monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof; and25 - optionally at least one targeting moiety connected to the particle on an external surface of the particle; and- at least one short-lived radionuclide, wherein the radionuclide is a radionuclide cation with a half-life in the range of 0.5 hours to 60 days;and wherein the at least one radionuclide is adsorbed within at least one of the pores by 30 the at least one free functional group that extends into the pore.In one embodiment, at least one targeting moiety is connected to the particle on an external surface of the particle.35 Figure 1 illustrates schematically a non-limiting embodiment of a particle 1 of the invention, comprising a MOF 2 forming pores 3, and having functional groups 4 extending 3490169141284/mwwinto pores 3, wherein the particle 1 comprises targeting moieties 5, here shown as antibodies, and wherein a radionuclide 6 is located in a pore 3.The MOF particle of the invention comprises at least one short-lived radionuclide. As used 5 herein, the term “radionuclide”, which may also be referred to as a radioactive nuclide, radioisotope or radioactive isotope, is an atom that has excess nuclear energy, making it unstable. Generally, this excess energy can be used in one of three ways: emitted from the nucleus as gamma radiation; transferred to one of its electrons to release it as a conversion electron; or used to create and emit a new particle (alpha particle or beta 10 particle) from the nucleus. During those processes, the radionuclide is said to undergo radioactive decay. The resulting nuclide is referred to as a daughter or as progeny. The radionuclides in the particles of the invention, are short-lived radionuclides suitable for use as radiotracers, i.e. as imaging agents. In some embodiments, the at least one radionuclide is a radionuclide that emits gamma rays, or it is a radionuclide that emits 15 positrons. Positron emitters interact with nearby electrons resulting in the simultaneous emission of two gamma rays in opposite directions. In one embodiment, the at least one radionuclide of the invention is a gamma emitter, wherein gamma emitter as used herein also may include positron emitters. The diagnostic radioisotope must be able to emit gamma rays and contain enough energy to escape from the body. Ideally, the rate of 20 decay of the radioisotope must be completed quite soon after the imaging, i.e. it is shortlived. The radionuclide has a half-life of 0.5h to 60 days, e.g. of 5 hours to 60 days, such as 1 to 20 days, such as 1 to 5 days, e.g.3 to 5 days.The at least one radionuclide is located in a pore, such as present in a pore, such as 25 enclosed by a pore, preferably coordinated to and/or chelated by the at least one free functional group extending into said pore.Preferably, the radionuclide is a radionuclide cation. More preferably, the radionuclide is a radionuclide selected from the group comprising Ga-68, Ti-45, Tc-99m, Ba-133m, In-111, 30 Ga-67, Zr-89, Ba-131, Yb-169 and Sc-43. In some embodiments, the radionuclide is selected from the group comprising Zr-89, and Ga-67. If using F-18, which is not according to the present invention but is present for illustration purposes only, the isotope is not cationic per se, but may rather form part of a cationic complexion, e.g. as an aluminium-[18F]fluoride ([18F]AlF) complex. The AlF(18) will hence bind to the MOF as a 35 cation. If using Tc-99m, the isotope is not easily obtainable as a cation in aqueous solution per se, but may rather form part of a cationic complexion, e.g. [Tc(H2O)3(CO)3]+. 34901610141284/mwwSuitable radionuclides have a relatively short half-life, compatible with imaging procedures and clinical administration, and thus have a great diagnostic potential, described below for each isotope (see Table 1). These radionuclide cations listed above may bind strongly to 5 negatively charged chelating groups of the MOFs, such that radioisotope leakage, which otherwise occurs due to competition with salts and other components in vivo, may be limited. Daughter isotopes of these radioisotopes may also be captured and retained in these MOFs. The half-life of the radionuclides must be long enough to allow purification, transport, drug synthesis and administration before too much of the activity is lost. A too 10 long a half-life may, however, lead to a substantial dosage increase to obtain effect. In that case, there is an increased risk of chemical toxicity and accumulation of radioactivity in the tissue.Table 1: List of examples of isotopes (radionuclides) that may be used in the particles of 15 the invention. Symbols legend: β+: Beta plus decay (positrons are emitted), β-: Beta minus decay (emitting electons), ε: Electron capture (with associated gamma radiation emitted), IT: Isomeric transition (rearrangement of nucleus with associated gamma emission), γ: Gamma emission. F-18 is not part of the present invention.Isotopes Half-life Example ion in Decay mode aqueous solutionGa-68 1.13 hours Ga3+ ε / β+Ti-45 3.08 hours Ti4+ ε / β+Tc-99m 6.0 hours [Tc(H2O)3(CO)3]+ IT / γBa-133m 1.62 days Ba2+ IT / γF-18 1.83 hours 18F-[AlF2]+ β+In-111 2.80 days In3+ εGa-67 3.26 days Ga3+ εZr-89 3.27 days Zr4+ β+Ba-131 11.5 days Ba2+ ε / β+ Yb-169 32.0 days Yb3+ Ε Sc-43 3.891 h Sc3+ β+ 20In some embodiments, the particle comprises one radionuclide. In other embodiments, the particle comprises more than one radionuclide, such as two, such as three, such as five radionuclides, independently selected from the group comprising the short-lived 34901611141284/mwwradionuclides listed above. If the particle comprises more than one radionuclide, the radionuclides will typically be located in separate pores, although the presence of two radionuclides in the same pore may also be possible. It should be noted that in all embodiments, complete control of the number of radionuclides per particle cannot be 5 expected; during a chelation process wherein particles are contacted with a solution containing radionuclides, a statistical distribution of radionuclides per particle will result.The MOFs of the invention comprise a repeating three-dimensional network of inorganic monomers and organic monomers, i.e. they are crystalline. The organisation of the 10 inorganic monomers and organic monomers in a repeating three-dimensional network leads to the formation of pores; i.e. the rigidity and set geometry of the inorganic and organic monomers leads to a set spatial separation between certain monomers such that pores are formed. MOFs with free functional groups can be seen as having a somewhat dynamic pore size due to the freedom of orientation of the free functional groups. Pore 15 size may e.g. be measured by “inclusion sphere”, i.e. the largest sphere that can be placed in a pore without the sphere contacting the van der Waals surface of the MOF. The size of pore openings, also referred to as “window size”, may be measured by “diffusion sphere”, i.e. the smallest sphere that can move through the structure. A MOF for use in the invention advantageously has a pore size of 0.3-3 nm inclusion sphere, preferably 0.5-20 1.5 nm inclusion sphere. Further, the MOFs of the invention have a pore window of a certain size to allow the adsorption of radionuclides, preferably a diffusion sphere with diameter of at least 3 Å. The pore size may be controlled by the size, structure and bonding of the inorganic monomers and the organic monomers. The pores may be of any shape, including, but not limited to, tetrahedral, octahedral, hexagonal.25Among the about 100000+ reported MOF structures, only a limited selection can be utilized in the invention. Useful MOFs are naturally limited by pore topology and the MOFs' ability to accommodate functional groups on their linkers (or by post-synthetic incorporation on either linker or inorganic cluster), that point into the pores instead of 30 binding to the inorganic monomers. The MOF pore topology must allow for diffusion of the radioactive ion into the pores from the exterior, and the pore must be of a size that allows the presence of functional groups and the adsorbed radioactive cation. Examples of MOF structures fitting this description include the list of MOFs provided herein. Appropriate pore sizes and pore window sizes are described above.35 34901612141284/mwwSince the radioactive cations are to be adsorbed into negatively charged pockets in a MOF, the aforementioned functional groups should have negative or partially negative poles in aqueous environment at physiological pH. A list of such functional groups is described herein. In some cases, such functional groups are available directly following 5 MOF synthesis, such as UiO-66-(COOH)2 and UiO-66-NH2, in which carboxylate and amine groups, respectively, point into the pores. In some cases, the functional groups are made available through post-synthetic modification, for example the case of ZIF-90 which contains aldehyde groups pointing into suitable pores, that can be converted to ZIF-8-COOH by a reaction with hydrogen peroxide. In other examples, the functional groups are 10 incorporated onto the inorganic monomer, such as the introduction of free imidazolate groups in MOF-808 through a reaction with histidine.MOFs based on Zr(IV), Hf(IV), Ce(IV), Fe(III), Al(III), Ti(IV), Cr(III) with carboxylate organic monomers, and Zn(II) imidazolates, are known to be stable in aqueous media, and may 15 therefore be particularly useful in the invention.Examples of preferred MOFs are the zirconium-based UiO-66, which comprises terephthalate (C6H4(COO)22-) organic monomers and cationic hexanuclear zirconium oxide clusters Zr6O4(OH)412+ as inorganic monomers, each carboxylate group of the20 terephthalates coordinated to two cations of the inorganic monomer, and the corresponding hafnium and cerium derivatives of UiO-66, Hf-UiO-66 and Ce-UiO-66, which have Hf6O4(OH)412+ and Ce6O4(OH)412+ oxide cluster inorganic monomers, respectively, and terephthalate organic monomers. Another example of a zirconium-based MOF is MOF-808, C24H16O32Zr6, comprising benzene-1,3,5-tricarboxylic acid linkers.25 UiO-66, Hf-UiO-66, and MOFs having the same topology (network geometry), known as fcu network topology, comprise tetrahedral and octahedral pores, in a dynamic 2:1 ratio between the former and the latter. Each tetrahedral pore contains four corners where three organic linkers “meet”, i.e. extend towards the same spatial volume, and each octahedral pore contains six corners where four organic linkers “meet”. Free functional 30 groups point toward the corner of the octahedral pore in the most stable conformation, but due to the dynamic rotation of the linker about its axis of connectivity and steric repulsion between neighbouring carboxylate groups, free functional groups may also frequently be directed into tetrahedral pores.35 Figure 2 shows a schematic representation of a network structure with fcu topology, where the inorganic monomers are shown as spheres with cuboctahedral coordination 34901613141284/mwwgeometry, and the organic monomers are shown as bridging rods. Pores are illustrated in Figure 3, which illustrates the octahedral (O) and tetrahedral pores (T) in fcu MOFs. The large transparent spheres illustrate the size of each of the pores.5 M(IV)-based MOFs wherein M = Zr and/or Hf, i.e. MOFs wherein the inorganic monomers are based on metals Zr and/or Hf in their 4 (M(IV)) oxidation state, having carboxylatebased organic monomers, such as UiO-66, Hf-UiO-66, and derivatives thereof, may be particularly well-suited for in vivo applications for several reasons: (1) The monomers may have an advantageously low toxicity in vivo, (2) said MOFs may show an exceptional 10 stability in aqueous solutions such as human serum, as shown in Experiments 2 and 3, owing to the stability of the M(IV)-carboxylate bond towards hydrolysis, and (3) the M(IV) oxocluster inorganic monomers may have a high connectivity, i.e. a high number of organic monomers connected to it such that free functional groups of several organic monomers may be spatially close to each other, which may allow the formation of highly 15 coordinated chelating sites neighbouring the clusters. As a consequence, the MOF particles of the invention represent particularly stable and efficient carriers for radionuclides, which may have exceptionally high adsorption capacity enabling specific imaging with negligible leakage to other organs.20 Mixed-metal and/or mixed-linker derivatives of UiO-66 can also be expected to show similarly advantageous properties as UiO-66. Relevant mixed-metal derivatives include derivatives comprising in the inorganic monomers two or more metals from the group comprising or consisting of Zr(IV), Ce(IV) and Hf(IV). Relevant mixed-linker derivatives include derivatives having monomers known by the skilled person to have a coordinating 25 geometry similar to terephthalate, such as monomers selected from the group comprising or consisting of aminoterephthalate, hydroxyterephthalate, mellitate, pyromellitate, sulfoterephthalate, muconate, and combinations thereof. Suitable mixed-linker MOFs can be obtained through synthesis where multiple linkers are present, or through linker exchange, which both are well-known to the person skilled in the art.30Further, MOFs having inorganic monomers based on Fe(III), Al(III), Ti(IV), and/or Cr(III) may also be particularly useful in the invention. Organic monomers may e.g. be selected from the group comprising or consisting of terephthalate, aminoterephthalate, hydroxyterephthalate, mellitate, pyromellitate, sulfoterephthalate, muconate, and35 combinations thereof. While said MOFs cannot form the same topology as UiO-66, they may form other interesting topologies that may function in the same manner. 34901614141284/mwwThe MOF of the invention comprises at least one free functional group that extends into a pore. Preferably, the MOF comprises a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and at least one free functional group 5 that extends into each pore, i.e. each pore has at least one free functional group extending into it. In some embodiments, only a certain amount of the pores has at least one free functional group extending into it, such as 50% of the pores, such as 80% of the pores, such as 95%, such as 100% of the pores.10 The term “extending into a pore” as used herein means that the functional group is directed into, points into, and/or is present in one of the pores formed by the repeating three-dimensional network of inorganic monomers and organic monomers. Hence, the free functional group is available for coordinating to, binding and/or reacting with a compound, an ion, or the like, within the pore. In particular, the functional group is 15 available for coordinating to, complexing, and/or binding a radionuclide, such as a radionuclide cation.The at least one free functional group is connected to an inorganic monomer and/or to an organic monomer. When the at least one free functional group is connected to an organic 20 monomer, it is preferably covalently bonded to the organic monomer. In some embodiments, each organic monomer of the MOF has at least one free functional group connected to it. In other embodiments, a predetermined amount of the organic monomers each has at least one free functional group connected to it. In some embodiments, each inorganic monomer of the MOF has at least one free functional group connected to it. In 25 other embodiments, a predetermined amount of the inorganic monomers each has at least one free functional group connected to it.The free functional group is preferably Lewis basic, and is preferably selected from the group comprising or consisting of carboxylic acid, carboxylate, hydroxyl, sulfonic acid, 30 sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof. The secondary amines are selected from the group comprising or consisting of amines of the general structure -NHR, wherein R is selected from the group comprising or consisting of C1-C8 alkyl, alkenyl, and alkynyl with at least one Lewis basic functional group (e.g. carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid, sulfonate, primary amines, 35 secondary amines, and combinations thereof), such as C1-C4 straight chain and branched alkyl, alkenyl, and alkynyl, with at least one Lewis basic functional group (e.g. carboxylic 34901615141284/mwwacid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof). Such functionality can for example be obtained by performing a peptide condensation of N-protected natural amino acids with free primary amino groups of the organic monomer of the MOF.5The free functional group or groups may advantageously be selected based on the choice of radionuclide. For example, if the radionuclide is known by the skilled person to be oxophilic, or "hard" within the HSAB theory (hard and soft (Lewis) acids and bases), the pores may advantageously comprise at least one oxygen-containing functional group, i.e.10 carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid, and/or sulfonate.Correspondingly, if the radionuclide is “soft” within the HSAB theory, the pores may advantageously comprise at least one amine group.Hence, in some embodiments, the MOF comprises as least one free functional group 15 selected from the group comprising or consisting of carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof. In other embodiments, the MOF comprises as least one free functional group selected from the group comprising or consisting of carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfhydryl, sulfonate, and combinations thereof. In yet other embodiments, 20 the MOF comprises as least one free functional group selected from the group comprising or consisting of primary amines and secondary amines and combinations thereof.Preferably, the MOF comprises 1-4 free functional groups, such as 1-2 functional groups, such as at least three, such as at least four free functional groups. In some embodiments, 25 the MOF comprises as least two free functional groups, and the free functional groups are identical, or at least two, such as at least three, such as all, of the free functional groups are different from each other. In some embodiments, the MOF comprises as least three free functional groups, and the free functional groups are identical, or at least two, such as at least three, such as all, of the free functional groups are different from each other. In 30 some embodiments, the MOF comprises as least four free functional groups, and the free functional groups are identical, or at least two, such as at least three, such as all, of the free functional groups are different from each other.The MOF may be selected such that when the MOF comprises as least two free functional 35 groups as disclosed above, the structure of the MOF allows some or all of the at least two free functional groups to point towards a common spatial volume, such as a common 34901616141284/mwwpoint or volume within the pore. The MOF may be selected such that when the MOF comprises as least two free functional groups as disclosed above, the structure of the MOF allows some or all of the at least two free functional groups to orient in a manner that, in the presence of a radionuclide cation, enables favourable interaction with the 5 radionuclide cation, e.g. by aligning with outer orbitals of the radionuclide cation. In some embodiments, each free functional group has a distance of 4-15 Å from at least one, such as all, of the other free functional groups extending into the same pore, such as 4-12 Å, such as 5-10 Å.10 Further, the choice and placement of the at least one free functional group may be used to modify the geometry of a coordinating, such as binding, such as chelating, site in a pore. Such site may be formed by the presence of one or more free functional groups, but may also result from the size and/or geometry of a pore. In some embodiments, such site is defined as comprising all free functional groups extending into the same pore. In some 15 embodiments, such site is defined as comprising free functional groups extending into the same pore and that have a maximum distance from at least one other free functional group in the same pore that does not exceed 15 Å, such as 10 Å. In some embodiments, such a site is present in a corner of a pore. This placement may entail that the site is accessible from one direction only, thus limiting competitive absorption. Further, when 20 such site is present in a corner of a pore, or in another way inside the pore as opposed to at the opening of the pore, other compounds, such as other cations, such as a competing cation, may be present in the pore and sterically block the radionuclide from leaving the pore. Such sites present in corners may in principle be constructed in all MOFs that can contain free functional groups. Examples include the MOFs Cr-MIL-100, Fe-MIL-100, and 25 Al-MIL-100, Cr-MIL-53, Fe-MIL-53, and Al-MIL-53, Zr-MIL-140, Hf-MIL-140, Zr-MOF-711, Hf-MOF-711, ZIF-8, Ti-MIL-125 and MOF-808.Examples of coordinating, binding and/or chelating sites are shown in Figures 4-7. Figure 4 shows an example of a coordinating, binding and/or chelating site in a tetrahedral cage 30 corner, provided by three free carboxylate groups directed into said pore. Figure 5 shows an example of such a site in an octahedral pore corner, provided by four free carboxylate groups directed into said pore. Figure 6 shows such a site in an octahedral pore corner, provided by two free carboxylate groups, and two free amido-groups directed into said pore. The latter can e.g. be obtained by post-synthetic peptide condensation on free 35 primary amino groups. Post-synthetic modifications are discussed below. Figure 7 shows such a site in an octahedral cage corner, provided by two free carboxylate groups, and 34901617141284/mwwtwo free amido-groups directed into said pore, where one amido-group is bearing a DOTA chelator. Figure 8 shows a pore where several free functional groups are extending into the pore.5 Further, the at least one functional group directed into the pores may be used to modify the charge balance of a pore and/or of a coordinating, such as binding, such as chelating, site in a pore. Advantageously, the MOFs of the invention comprise a free functional group, or a combination of functional groups, that result in a net negative charge in a pore. This net negative charge may facilitate strong, selective adsorption of cations.10The introduction of substituents on the phenyl ring of the terephthalate monomers of UiO-66 and the UiO-66-type MOFs gives easy access to crystalline MOFs comprising at least one free functional group extending into a pore, wherein the at least one free functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, 15 sulfonic acid, sulfonate, sulfhydryl, primary amine, secondary amines, and combinations thereof. For example, UiO-66-COOH, UiO-66-(COOH)2 and UiO-66-NH2 are all commercially available. UiO-66-COOH, UiO-66-(COOH)2, Hf-UiO-66-COOH, and Hf-UiO-66-(COOH)2 represent preferred MOFs having 6-12 free carboxylic acid functional groups extending into their pores, whereof three or four free functional groups form a coordinating 20 site in a pore, and that may thus chelate radionuclide cations in an efficient and/or stable manner.Two main approaches exist for so-called pore engineering, i.e. introduction of free functional groups that extend into a pore. The synthesis of MOFs using “preintegrated 25 organic monomers” in which two different coordinating sites coexist for framework construction and for other use, and “post-synthetic modification”, such as sequential attachment of further functional groups on preconstructed MOFs. Free functional groups in a MOF can be modified through chemical reactions, colloquially known as “postsynthetic modification”. In principle, all chemical reactions that can be performed by 30 standard wet-chemical methods can also be performed on the same functional group in a MOF. For example, an amino acid can be reacted with a free primary amine group in a MOF by a peptide condensation reaction. Molecules that have specific properties can be grafted onto the MOF, such as within pores of the MOF, using this approach. Hence, MOFs having particular structures and particular free functional groups are available both 35 by designing and synthesising new MOFs, and by modifying existing MOFs. Derivatives of various MOFs having the UiO-66 structure, as well as MOFs having other structures, and 34901618141284/mwwcomprising various free functional groups, are thus readily available. In some embodiments, at least one radionuclide chelator known to the skilled person, such as EDTA, such as DOTA, is grafted onto a group extending into a pore, such that at least one free functional group is a known chelator.5Further, most MOFs can tolerate a certain fraction of linker vacancy defects, i.e. a site where an organic linker is missing from the structure, leaving coordinatively unsaturated sites on the adjacent inorganic monomer. These unsaturated sites can be modified with coordinating molecules, such as a molecule that can coordinate the inorganic monomer 10 with at least one functional group and that has a free functional group for extending into a pore, e.g. an amino acid, that can contribute to the functional properties of the MOF.Preferably, the MOF of the invention comprises a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and at least one free 15 carboxylic acid or carboxylate functional group that extends into each pore.Figures 9, 10, and 11 show schematic representations of preferred MOFs.Figures 9 and 10 show partial crystal structures of M(IV) and M(III) based terephthalate 20 MOFs. Figure 9 illustrates UiO-66 (organic monomer shown as sticks where each C/O atom is situated on the corners, inorganic monomer as polyhedra). Figure 10 illustrates MIL-53, where in addition to lines and polyhedra, the available pore space is illustrated by large spheres.25 The preferred MOFs shown in Figures 9 and 10 may have M(IV) inorganic monomers.Suitable organic monomers are shown below (structures I, II, III, IV, V, and VI): 34901619(I) (II) (III)(IV) (V)5 (VI)Structure I represents a terephthalic acid/terephtalate organic monomer, which may form MOFs with M(III) and M(IV) based inorganic monomers through metal-carboxylate bonds. R11, R12, R13, and R14 may each independently be selected from the group comprising or 10 consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, 34901620141284/mwwsulfhydryl, primary amines, and secondary amines, i.e. each of the R groups may be hydrogen or a free functional group.Structure II represents a biphenyl-4,4'-dicarboxylic acid organic monomer, which may form 5 MOFs with M(III) and M(IV) based inorganic monomers through metal-carboxylate bonds.R21, R22, R23, R24, R25, R26, R27, and R28 may each independently be selected from the group comprising or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, and secondary amines, i.e. each of the R groups may be hydrogen or a free functional group.10Structure III represents a trimesic acid (1,3,5-benzenetricarboxylic acid) organic monomer, which may form MOFs with M(III) and M(IV) based inorganic monomers through metalcarboxylate bonds. R31, R32, and R33 may each independently be selected from the group comprising or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, 15 sulfonate, sulfhydryl, primary amines, and secondary amines, i.e. each of the R groups may be hydrogen or a free functional group.Structure IV represents an adipic acid organic monomer, which may form MOFs with M(III) and M(IV) based inorganic monomers through metal-carboxylate bonds.20 R41, R42, R43, and R44 may each independently be selected from the group comprising or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, and secondary amines, i.e. each of the R groups may be hydrogen or a free functional group.25 Structure V represents a 1,4-cyclohexyldicarboxylic acid organic monomer, which may form MOFs with M(III) and M(IV) based inorganic monomers through metal-carboxylate bonds. R61, R62, R63, R64, R65, R66, R67, R68, R69, and R70 may each independently be selected from the group comprising or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, and secondary 30 amines, i.e. each of the R groups may be hydrogen or a free functional group.Structure VI represents a naphthyl organic monomer, which may form MOFs with M(III) and M(IV) based inorganic monomers through metal-carboxylate bonds.R71, R72, R73, R74, R75, and R76 may each independently be selected from the group 35 comprising or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, 34901621141284/mwwsulfonate, sulfhydryl, primary amines, and secondary amines, i.e. each of the R groups may be hydrogen or a free functional group.In each of structures I-VI, the secondary amines may be selected from the group 5 comprising or consisting of amines of the general structure -NHR, wherein R is selected from the group comprising or consisting of C1-C8 alkyl, alkenyl, and alkynyl with at least one Lewis basic functional group (e.g. carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof), such as C1-C4 straight chain and branched alkyl, alkenyl, and alkynyl, with at 10 least one Lewis basic functional group (e.g. carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof).Figure 11 illustrates MOFs having a zeolitic imidazolate framework and a so-called sod 15 topology. The organic monomer is shown as balls and sticks to represent atoms and bonds, and Zn atoms are shown as tetrahedra.The preferred MOFs shown in Figure 11 may have M(II) inorganic monomers. Suitable organic monomers are shown below (structure VII):20(VII)Structure VII represents a imidazole organic monomer, which may form MOFs (also known as ZIFs) with M(II) based inorganic monomers through metal-imide bonds.25 R51, R52, and R53 may each independently be selected from the group comprising or consisting of hydrogen, carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, and secondary amines, i.e. each of the R groups may be hydrogen or a free functional group. The secondary amines may be selected from the group comprising or consisting of amines of the general structure -NHR, wherein R is 30 selected from the group comprising or consisting of C1-C8 alkyl, alkenyl, and alkynyl with 34901622141284/mwwat least one Lewis basic functional group (e.g. carboxylic acid, carboxylate, hydroxyl, sulfhydryl, sulfonic acid, sulfonate, primary amines, secondary amines, and combinations thereof), such as C1-C4 straight chain and branched alkyl, alkenyl, and alkynyl, with at least one Lewis basic functional group (e.g. carboxylic acid, carboxylate, hydroxyl, 5 sulfhydryl, sulfonic acid, sulfonate, primary amines, secondary amines, and combinations thereof).In the invention disclosed herein, the MOF is present in the form of a particle, such as a microparticle or a nanoparticle. Preferably, the particle is a nanoparticle. As used herein, 10 the term “nanoparticle” refers to any particle having a diameter of less than 1000 nm, such as from 1 to 1000 nm. Similarly, the term “nanoparticles” refers to a plurality of particles having an average diameter of between about 1 and 1000 nm. Reference to the “size” of a nanoparticle is a reference to the length of the largest straight dimension of the nanoparticle. For example, the size of a perfectly spherical nanoparticle is its diameter. 15 The size may e.g. refer to the hydrodynamic radius of the particle characterized by dynamic light scattering. In some embodiments, the nanoparticles of the invention have a particle size of 1-200 nm. Correspondingly, the term “microparticle” refers to any particle having a diameter of less than 1000 µm, such as from 1 to 1000 µm.20 Micro and nanoparticles have found some use in radiopharmaceuticals. An important factor when such particles are to be used is their stability, both in the sense that the particles themselves should be completely stable or slowly degradable, in order to reduce the risk of system toxicity, and in the sense that the radionuclide should strongly associated to the particle to avoid leakage of the radionuclide. The MOFs of the invention 25 are very stable, as discovered by the inventors and illustrated in Examples 2 and 3.Further, the presence of the free functional groups, along with the confining effect of the pores themselves, ensure a strong chelation of a radionuclide to the particle as illustrated in example 7. The choice of free functional groups may also lead to a high level of selectivity, e.g. in that cations rather than anions, and/or hard rather than soft ions, are 30 preferably chelated. Hence, the invention provides particularly stable carriers for radionuclides, useful as imaging agents.Throughout a MOF particle of the invention, 10^3 to 10^5 pores exist, with the possibility of trapping a radionuclide cation in a fraction of them, i.e. the fraction accessible from the 35 outside of the particle. Should a radionuclide cation be released from one pore, it may be caught by a neighbouring pore, preventing leakage from the particle. This ability of “re 34901623141284/mwwadsorbtion” of desorbed radionuclide cations indicates that the MOF particles of the invention may more efficiently hold on to the radionuclide cations compared to conventional chelators. Further, the number of cations per particle can be tuned, thus tuning the level of radioactivity of the particle.5Due to the presence of pores having a suitable diffusion sphere and the free functional groups extending into the pores, if a particle according to the invention is exposed to a solution comprising radionuclide cations, these cations will be readily adsorbed and chelated within the pores. An additional advantage of using a MOF particle according to 10 the invention is that any competitive species, such as any other cations present in the solution, may occupy vacant pores rather than evicting the radionuclide cation.When used in imaging, the signal to noise ratio of the particles of the invention greatly surpass conventional molecular contrast agents limited to one or few gamma emitters. 15 The particles have a high density of strong bonding sites compatible with a wide range of alpha, beta and gamma emitters, and may by highly loaded with radiotracers. For use in therapy, MOFs, such as the MOFs disclosed herein for use in imaging, may be loaded with alpha- or beta-emitters (as a “MOF-drug”), and for use in imaging the MOFs may be loaded with gamma-emitters or positron-emitters (as a “MOF-radiotracer”). The universal 20 loading concept and process enables the use of one single particle platform for both imaging and treatment omitting the need for separate development of particles for each purpose. Hence, the MOFs disclosed herein have been found useful as carrier for radionuclides, either for use in therapy, or for use in imaging.25 The nanoparticle approach, as opposed to the conventional molecular chelator approach, provides several key advantages. (1) Each particle can be loaded with the desired number of radioisotopes, which allows flexible radiation density/dosage. (2) Its external surface can be functionalized with multiple targeting antibodies, which offers flexibility in respect to avidity, and unlocks the possibility to use different antibodies on the same particle to 30 ensure multi-specificity. (3) The radioisotopes occupy a negligible number of the uniform binding pores of the particle. Thus, it accepts cations from its environment without competitive desorption of the radioisotopes, and if a radioisotope should detach from its binding site, it’s likely to be recaptured by a neighbouring pore. (4) The lattice structure of the particle provides a barrier that inhibits the release of daughter isotopes to the35 environment (Figure 1). 34901624141284/mwwThe applicant hence plans to use the same MOF carrier for different types of radioisotopes, for imaging and therapy respectively, which will ensure identical biodistribution of the imaging agent (e.g. comprising a gamma emitter) and therapeutic agent (e.g. comprising radium-223). This approach allows for a pre-treatment screening of 5 the patients using a MOF-radiotracer according to the invention to predict the response to a subsequent therapy using a MOF-drug, and/or prevent unnecessary treatment of nonresponders. The major challenge with targeted radiotherapy, as RITs, is to achieve the ideal biodistribution where the drug and tumour co-localise, ensuring specific radiation of cancer cells. Every patient and cancer are unique and cannot necessarily be treated using 10 the same approach despite common disease characteristics. Using the particles and methods of the invention, including the use of the MOF-radiotracers as imaging agents in pre-screening of subjects, is expected to improve the selection of subjects that will respond to a treatment comprising a MOF-drug. Patients that do not meet set selection criteria during diagnostic screening will not undergo treatment, which otherwise could lead 15 to unnecessary side effects and loss of an opportunity to enter alternative treatment options. The patients that pass the selection criteria may obtain therapy comprising treatment with an alpha emitter, i.e. treatment with a MOF-drug, and are likely to respond well to the treatment. The selection criteria may e.g. be based on sufficient co-localisation of the MOF-radiotracers and tumours, predicting irradiation of cancer cells or cancer 20 supporting cells with the therapeutic MOF.The MOFs of the invention, as well as the particles thereof, may be obtained by any manner known to the skilled person, such as obtained commercially, such as synthesised using any synthetic protocol available to the skilled person.25In some embodiments, the particle of the invention comprises at least one targeting moiety connected to the particle on an external surface of the particle. The term “external surface” as used herein with respect to a particle, refers to the surfaces at its exterior, as opposed to the surface of a pore within the particle. Where pores permeate a particle and 30 are visible within it, the external surface is defined to include all surfaces at the outermost faces of the particle, but not surfaces that define the pores.As used herein, the term “targeting moiety” refers to a moiety, such as a molecule, such as a part of a molecule, which is “tissue targeting”, i.e. that serves to localise itself, and 35 any moiety, such as a particle, to which it is connected – preferentially to at least one tissue site at which its presence, e.g. to deliver a radioactive decay, is desired. The term 34901625141284/mww“targeting moiety” can also refer to a functional group that serves to target or direct a particle to a particular location, cell type, diseased tissue, or association. The targeting moiety may, for example, be a moiety known by the skilled person to bind to or complex with a biomarker, such as a cell-surface marker, e.g. a receptor, transport protein, cell 5 adhesion molecule, present on a cell affected by a disease, or cells in the vicinity of such cells. Such cell-surface markers include, but are not limited to, proteins more heavily expressed on diseased cell surfaces than on healthy cell surfaces or those more heavily expressed on cell surfaces during periods of growth or replication of cells than during dormant phases. Components present in the vicinity of target cells or tissues or10 associated therewith may also be utilised at the target for therapy in accordance with any aspect of the invention. For example, components present in or released into the matrix around targeted cells or tissues may be used for targeting if the presence, form or concentration allows the region to be distinguished from healthy tissue.15 Non-limiting examples of targeting moieties include- small molecule targeting moieties, such as folic acid; folate; carbohydrates;monosaccharides such as glucose, mannose, galactose; urea derivatives; lipids; streptavidin; albumin; biotin; steroidal and non-steroidal hormones;- aptamers, i.e. single-stranded oligonucleotides that recognise specific binding 20 domains of a receptor;- macromolecules, such as biomacromolecules, such as antibodies; peptides, such as biomimetic peptides, such as phage display peptides; proteins; nucleic acid; and- cells, such as natural cells, such as genetically engineered cells.25Preferred targeting moieties include antibodies, antibody fragments, antibody constructs, constructs of antibody fragments, minibodies, nanobodies, intrabodies, unibodies, affibodies, and diabodies. As used herein, the term “antibody” refers to an immunoglobulin, derivatives thereof which maintain specific binding ability, and proteins 30 having a binding domain which is homologous or largely homologous to an immunoglobulin binding domain. These proteins may be derived from natural sources, or partly or wholly synthetically produced. The term “antibody” encompasses e.g. monoclonal, polyclonal, recombinant, humanized, and/or chimeric antibodies. The antibody may be a member of any immunoglobulin class, including any of the human 35 classes: IgG, IgM, IgA, IgD, and IgE. Examples of useful antibodies are conventional full length antibodies (e.g IgG) and camelid heavy chain antibodies (VHH). 34901626141284/mwwAs used herein, the term “antibody fragment” refers to any derivative of an antibody which is less than full-length. In exemplary embodiments, the antibody fragment retains at least a significant portion of the full-length antibody's specific binding ability. Examples of 5 antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, scFv, Fv, dsFv diabody, and Fd fragments.In some embodiments, the targeting moiety is one of two or more components collectively having the effect of targeting the particle of the invention to the desired tissue(s). This may 10 be, for example, where one component binds to a particular tissue, tumour, or cell-type (a tissue-binding agent) and a second or further component, the targeting moiety, binds to the tissue-binding agent. Suitable specific binding pairs for providing the tissue binding agent and targeting moiety with mutual affinity are known in the art (e.g. biotin with avidin or streptavidin).15The targeting moiety may be obtained by any manner known to the skilled person, such as obtained commercially, such as synthesised using any synthetic protocol available to the skilled person, such as enzymatically, synthetically and/or chemically produced.20 In some embodiments, the particle comprises only one targeting moiety. In other embodiments, the particle comprises two or more targeting moieties, such as five, such as ten targeting moieties. The number of targeting moieties may be selected based on the size of the particle. The targeting moieties may be the same or different from each other. The mass ratio of targeting moiety and particle may depend on the molecular weight of 25 the targeting moiety and the diameter of the particle.The use of two or more different targeting moieties may have the advantage of improved binding to tissue or cells expressing a profile of antigens associated with the target (e.g M2 tumour associated macrophages expressing CD163 and CD206), since more than 30 one antigen can be targeted. An additional advantage may be the ability to target vessels that accumulate at the tumour site (e.g. VCAM1) as well as a tumour specific antigen.The at least one targeting moiety may be linked directly to the particle, such as via a covalent bond, or the at least one targeting moiety may be linked to the particle via a 35 linking group. Target moiety can also be linked to the particles covalently conjugated to streptavidin which strongly bind biotin/biotin derivates. Streptavidin may then function as a 34901627141284/mwwlinker, but also as a binding moiety for biotinylated moieties. Thus, streptavidin conjugated particles can be combined with one or more biotinylated targeting moieties. Methods for linking a targeting moiety to a surface are well-known in the art; standard organic and/or inorganic chemistry may be used, such as carbodiimide coupling. Suitable linking groups 5 may readily be determined by the person skilled in the art; for example, a range of linking groups are known from the field of antibody-drug-conjugates. Non-limiting examples of linking groups include poly(ethylene glycol) (PEG), 2-(maleimidomethyl)-1,3-dioxanes (MD), and maleimidocaproyl succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate) (SMCC). The external surface of a MOF particle may comprise the same 10 organic functional groups as the interior of the pores, which may be subject to the same reactions. However, size discrimination may be used in order to perform reactions on the external surface and not in the pores by using reagents that are sterically prohibited from entering the pores of the MOF, thus enabling selective attachment of targeting moieties to the external surface of the particle.15The at least one targeting moiety may be a targeting moiety for targeting a cell affected by a proliferative disease, such as tumour cell, a cancer cell, a cell affected by a hyperplastic disease, a cell affected by a neoplastic disease. In preferred embodiments, the targeting moiety is a targeting moiety for targeting a cancer cell. As used herein, the terms “cancer 20 cell” and “tumour cell” refer to cells that divide at an abnormal, increased rate. Cancer cells include, but are not limited to, carcinomas, such as squamous cell carcinoma, nonsmall cell carcinoma (e.g., non-small cell lung carcinoma), small cell carcinoma (e.g., small cell lung carcinoma), basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, 25 cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchogenic carcinoma, melanoma, renal cell carcinoma, hepatoma-liver cell carcinoma, bile duct carcinoma, cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, choriocarcinoma, semonoma, embryonal carcinoma, mammary carcinomas, gastrointestinal carcinoma, colonic carcinomas, bladder carcinoma, prostate carcinoma, 30 and squamous cell carcinoma of the neck and head region; sarcomas, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synoviosarcoma and mesotheliosarcoma; hematologic cancers, such as myelomas, leukemias (e.g., acute myelogenous leukemia, chronic lymphocytic leukemia, granulocytic 35 leukemia, monocytic leukemia, lymphocytic leukemia), lymphomas (e.g., follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, malignant lymphoma, 34901628141284/mwwplasmocytoma, reticulum cell sarcoma, or Hodgkin's disease), and tumours of the nervous system including glioma, glioblastoma multiform, meningoma, medulloblastoma, schwannoma and epidymoma. The person skilled in the art is knowledgeable about targeting moieties that may be used for targeting specific types of cells affected by 5 proliferative diseases, in particular cancer cells.In another embodiment, the particle of the invention comprises no targeting moiety.Whether a drug substance is administered into the human body through the oral, intravenous or parenteral route, they will be metabolized by the hepatic portal system 10 (liver) which is the site for most metabolism, by metabolizing enzymes, which will degrade the substances delivered for easy removal from the body. Accordingly, the particles of the invention, where no targeting moiety is included, will after having been administrated to a subject be transported to the liver, and could be well suited for imaging of the liver.Furthermore, the natural biodistribution of the particle can also be used to obtain15 radioisotopes to the given site and radiate the tissue in situ.The particle disclosed herein, i.e. a particle comprising a MOF,wherein the MOF comprises a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and at least one free functional group 20 that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof, wherein the particle optionally further comprises at least one targeting moiety connected to the particle on an external surface of the particle, and at least one radionuclide, wherein the at least one 25 radionuclide is selected from the group short-lived radionuclides as disclosed, and wherein the at least one radionuclide is located in at least one of the pores, may have at least the following advantages compared to the state of the art:- (a) In contrast to existing small-molecule chelators, the MOF particle contains 30 numerous chelating sites, which may enable dose control by loading the particles with a predetermined number of radionuclides.- (b) The network structure of the MOF may positively affect the ability of the particle to contain the radiation, such as by the following mechanisms:- (1) In contrast to state-of-the-art molecular chelators, the MOF may be 35 able, through physisorption, to contain daughter isotopes that appear 34901629through the decay chains of a radionuclide, thus keeping also the daughters close to the tumour cells,- (2) In contrast to state-of-the-art molecular chelators, adsorbed radionuclides in MOFs may be less susceptible to competitive adsorption 5 by other ions because these may be adsorbed by vacant pores, and- (3) desorbed radionuclides may be re-adsorbed by adjacent, vacant pores.In summary, the invention may thus provide an improved method of imaging.10 Regarding (b)(2), competitive adsorption may be relevant not only during preparation and storage of the particles and during adsorption of the radionuclide cation, but also when the particle is used as an imaging agent.The particle of the invention may further comprise one or more molecules for modifying 15 the external surface of the particle. Such one or more molecules may be connected to, such as covalently bound to, such as coordinated to, the particle on an external surface of the particle. Again, size discrimination may be used in order to perform reactions on the external surface and not in the pores. For example, the exterior surface of a MOF comprising free carboxyl or amino groups can be functionalised with one or more20 compounds selected from the group comprising or consisting of PEG derivatives, N-hydroxysuccinimide (NHS), N-hydroxysulfosuccinimide (sulfo-NHS), MD linker, Mal-PAB, albumin, to facilitate transport, prevent agglomeration and/or provide targeting functionality by increasing the targeting flexibility and spatial distance between a MOF and its target. Albumin can be used to prevent agglomeration and to increase the blood half-25 life of the particles.The particle of the invention may further comprise one or more further compounds, such as a molecule, such as an ion, located in at least one of the pores. Non-limiting examples include buffers and/or particular ions, such as ions for limiting leakage of radionuclide by 30 steric blockage.The MOF particles are typically produced by an aqueous synthesis at 20-100 C° where a solution of a suitable inorganic precursor for the inorganic monomer and a solution of the organic monomer are mixed. In some cases, the organic monomer is dissolved directly in 35 the solution of the inorganic precursor or vice versa. In some cases, a growth controlling factor (also known as growth modulator) is added to affect the particle growth rate. The 34901630141284/mwwMOF particles precipitate from the solution as the structure is formed. Published procedures for the production of MOFs may be followed.Targeting moieties may be attached, linked, bonded – generally referred to as conjugated 5 – to the MOF particles directly, or via a linker. As an example: carboxyl MOFs can be conjugated to amine groups (present on the targeting unit) by carbodiimid (EDC, NHS/Sulfo-NHS) based cross linking.Radiolabelling may be performed by mixing a solution or a suspension of the radionuclide 10 cation homogeneously with a suspension of the particles for >1 minutes, and then separating residual unbound radionuclide cation from the labelled particles, such as by centrifugation or column purification. The radiolabelling procedure may be more convenient, such as in terms of time used, purification of the product, etc., if the targeting moiety is present on the particle before radiolabelling takes place.15Hence, the particle of the invention may be prepared by providing a particle, such as a nanoparticle, comprising a MOF,wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic 20 monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof,25 wherein the particle optionally comprises- optionally at least one targeting moiety connected to the particle on an external surface of the particle,and contacting the particle with a short-lived radionuclide.30 The radionuclide cation may, for example, be present in composition comprising a liquid.In another aspect, the invention relates to a kit comprising,in a first container,a particle comprising35 - a MOF, wherein the MOF comprises 34901631- a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, 5 carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof;- optionally at least one targeting moiety connected to the particle on an external surface of the particle; andand in a second container,10 a short-lived radionuclide, wherein the radionuclide is a radionuclide cation with a half-life in the range of 0.5 to 60 days;and wherein the at least one radionuclide is adsorbed within the at least one of the pores by the at least one free functional group that extends into the pore.15 Suitable radionuclides for use in this aspect are as disclosed for the first aspect.The skilled person will appreciate that the first and the second container may further comprise liquids, such as solvents, such as for dissolving or suspending any component, as well as further components such as at least one carrier, diluent, and/or excipient. 20The particles of the invention comprising at least one short-lived radionuclide, are for use in suitable imaging modalities such as scintigraphy or positron emission tomography (PET). Scintigraphy and PET imaging with suitable radiotracers enable functional or molecular-based imaging of disease. Such imaging may provide information on tumour 25 metabolism, demonstrating which tumours are metabolically active and malignant or indicating which tumours have reoccurred. In some embodiments, the imaging modality is selected from the group comprising SPECT, PET and PET/CT imaging. In some embodiments, the imaging of the invention using a particle comprising MOFs loaded with short-lived radionuclides provide assessments of metabolic function, and this may be 30 combined with other imaging modalities such as x-ray, MR or ultrasound e.g. to image pathology.The particle disclosed herein may be present as an active ingredient in a desired dosage unit formulation, such as a pharmaceutically acceptable composition containing a 35 conventional pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable" means that compound must be physiologically acceptable 34901632141284/mwwto the recipient as well as, if part of a composition, compatible with other ingredients of the composition. The term “composition” refers to a mixture, in any formulation, of one or more compounds according to the invention with one or more additional chemical component.5Thus, in another aspect, the invention relates to a composition comprising at least one particle, wherein the at least one particle comprises a MOF,wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic 10 monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof,15 wherein the particle comprises- optionally at least one targeting moiety connected to the particle on an external surface of the particle, and- at least one short-lived radionuclide wherein the radionuclide is a radionuclide cation with a half-life in the range of 0.5 hours to 60 days,20 and wherein the at least one radionuclide is adsorbed within at least one of the pores by the at least one free functional group that extends into the pore,together with at least one pharmaceutically acceptable carrier, diluent, and/or excipient.The particle is defined as disclosed above. It may be a microparticle or a nanoparticle. 25 Preferably, the particle is a nanoparticle.The composition may be considered to be a pharmaceutical contrast agent composition, as it comprises an active agent, i.e. the particle, combined with at least one pharmaceutically acceptable carrier, diluent, and/or excipient, making the composition 30 especially suitable for diagnostic use, such as in imaging procedures.The composition preferably comprises a multitude of the particles of the invention. The particles can be the same of different, i.e. with regards to type and number of radionuclides and/or targeting moieties. In some embodiments, the composition is a 35 particle suspension comprising monodisperse or polydisperse particles labelled with a radionuclide cation. 141284/mwwThe composition may further include one or more of any conventional, pharmaceutically acceptable excipients and/or carriers, e.g. solvents, fillers, diluents, binders, lubricants, glidants, viscosity modifiers, surfactants, dispersing agents, disintegration agents, 5 emulsifying agents, wetting agents, suspending agents, thickeners, buffers, pH modifiers, absorption-delaying agents, stabilisers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, aromas, and colouring agents. Conventional formulation techniques known in the art, e.g., conventional mixing, dissolving, suspending, granulating, drageemaking, levigating, 10 emulsifying, encapsulating, entrapping or compressing processes, may be used to formulate the composition.In some embodiments, the composition is formulated for a particular method of administration to a subject.15The amount of particles according to the invention present in the composition can vary. In some embodiments, the amount of particles according to the invention present in the composition is 0.1-50% by weight, such as 1-30%, such as 50-20%. In other embodiments, the amount of the particles according to the invention present in the 20 composition is 30-70% by weight, such as 40-60%. In yet other embodiments, the amount of the particles according to the invention present in the composition is 50-100% by weight, such as 50-70%, such as 50-80%, such as 60-98%, such as 70-95%.The composition may also comprise MOF particles that do not comprise a radionuclide 25 cation, such as particles comprising a MOF, wherein the MOF comprises a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations 30 thereof, wherein the particle comprises at least one targeting moiety connected to the particle on an external surface of the particle. Such particles may be the same as the particles of the invention except for the absence of the radionuclide cation, or they may be different. The ratio between particles that comprise a radionuclide cation and particles that do not comprise a radionuclide cation may vary. In preferred embodiments, at least 90 % 35 of the particles comprise a radionuclide cation. The activity per mg particles may typically range from 10 kBq to about 900000 MBq, e.g. from 100 kBq to 900000 MBq, or from 100 141284/mwwkBq to 1000 MBq. This corresponds to a maximum of 5% mass ratio (percentage radioisotope per MOF) using Zirconium-89 as an example (specifically 831450 MBq).Further, the composition is substantially free of contaminants or impurities. In some 5 embodiments, the level of contaminants or impurities other than residual solvent in the composition is below about 5% relative to the combined weight of the particles according to the invention and the intended other ingredients. In certain embodiments, the level of contaminants or impurities other than residual solvent in the composition is no more than about 2% or 1% relative to the combined weight of the particles according to the invention 10 and the intended other ingredients.In certain embodiments, the particle or composition according to the invention is sterile. Sterilisation can be achieved by any suitable method, including but not limited to by applying heat, chemicals, irradiation, high pressure, filtration, or combinations thereof. 15The particle of the invention may be included in a composition and may be used as a contrast agent. Accordingly, in another aspect, the invention relates to a particle comprising- a MOF, wherein the MOF comprises20 - a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and 25 combinations thereof; and- optionally at least one targeting moiety connected to the particle on an external surface of the particle; and- at least one short-lived radionuclide;and wherein the at least one radionuclide is located in at least one of the pores,30 or a composition comprising said particle together with at least one pharmaceutically acceptable carrier, diluent, and/or excipient,for use as a contrast agent.The particles of the invention, and compositions comprising said particles, may be used 35 diagnostically, such as for targeted delivery of radioactive decay to one or more particular sites in vivo, such as a particular cell, tissue, organ, etc. The targeting moieties target the 141284/mwwparticle to a particular site where radioactive decay, such as emission of gamma rays, is desired, and the MOF serves as a chelating agent with the advantageous properties discussed above. When the particles do not comprise a targeting moiety, the particles will be transported to other organs for example the liver depending on the nanoparticles 5 biodistribution properties, wherein the radioactivity will decay. Hence in one embodiment, the particles may be used diagnostically for indications where the nanoparticles naturally transport, particularly liver cancer.For the various aspects of the invention as described herein that relate to use as an 10 imaging agent and/or imaging or diagnosis of disease, particularly for the selective targeting of diseased tissue, the diseased tissue may in all embodiments reside at a single site in the body (for example in the case of a localised solid tumour) or may reside at a plurality of sites (for example in the case of a distributed or metastasised cancerous disease).15The particles and the compositions of the invention may be particularly useful in imaging procedures, in diagnostic procedures and particularly for imaging of proliferative diseases. Thus, in a further aspect, the invention relates to a particle comprising- a MOF, wherein the MOF comprises20 - a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, 25 secondary amines, and combinations thereof;- optionally, at least one targeting moiety connected to the particle on an external surface of the particle; and- at least one short-lived radionuclide, wherein the radionuclide is a radionuclide cation with a half-life in the range of 0.5hours to 60 days;30 and wherein the at least one radionuclide is adsorbed within at least one of the pores by the at least one free functional group that extends into the pore,or a composition comprising said particle together with at least one pharmaceutically acceptable carrier, diluent, and/or excipient,for use in a method of diagnosis. 141284/mwwParticularly, in one embodiment, the particles or composition comprising said particle is for use in a method for the diagnosis of a proliferative disease of a subject. Such method for diagnosis may comprise imaging screening and biodistribution control. Particularly, the diagnostic method comprises a step of assessing information about biodistribution and 5 uptake of the MOF in relevant tissue of a subject, particularly of proliferative tissue. The method may provide powerful insights into the distribution, binding and other biological effects of the particles comprising the MOFs. This approach allows for a pre-treatment screening of subjects using particles according to the invention as imaging agents to predict the response to a subsequent therapy, e.g. using a MOF-drug, and/or prevent 10 unnecessary treatment of non-responders.In one embodiment, the method of diagnosis is followed by a subsequent treatment step with particles comprising the same MOF as used in the diagnosis, but carrying a therapeutic radionuclide. Hence, the method of diagnosis may be followed by a15 subsequent treatment with a particle comprising- a MOF, wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the 20 functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof;- optionally, at least one targeting moiety connected to the particle on an external surface of the particle; and25 - at least one radionuclide, wherein the at least one radionuclide is selected from the group comprising radium-223, radium-224, radium-225, bismuth-212, bismuth-213, lead-212, actinium-225, thorium-227, terbium-149 and terbium-161;and wherein the at least one radionuclide is located in at least one of the pores.30 Hence, the diagnostic method using a MOF-radiotracer is followed by a treatment with a MOF-drug. The carrier MOF is preferably the same in the two steps, while the carried nucleotide is different, and is respectively a gamma-emitter or positron emitter, and an alpha-emitter.35 The particle is defined as disclosed herein, and may be a nanoparticle or a microparticle, preferably a nanoparticle. 34901637141284/mwwAs used herein, the terms “administer”, “administration”, and “administering” refer to (1) providing, giving, dosing and/or prescribing by either a health practitioner or their authorised agent or under their direction, or by self-administration, a formulation,5 preparation or composition according to the present disclosure, and (2) putting into, taking or consuming by the subject themselves, a formulation, preparation or composition according to the present disclosure.As used herein, “subject” means any human or non-human animal selected for treatment 10 or therapy, and encompasses, and may be limited to, “patient”. None of the terms should be construed as requiring the supervision (constant or otherwise) of a medical professional (e.g., physician, nurse, nurse practitioner, physician's assistant, orderly, clinical research associate, etc.) or a scientific researcher.The subject is preferably a human subject. The subject may be male or female. In some 15 embodiments, the subject is an adult (i.e.18 years of age or older). In certain embodiments, the subject is geriatric. In certain embodiments, the subject is not geriatric. The subject is preferably a subject that has been diagnosed with a proliferative disease, such as a cancer.20 The diseased tissue to be targeted may be at a soft tissue site, at a calcified tissue site or a plurality of sites which may all be in soft tissue, all in calcified tissue or may include at least one soft tissue site and/or at least one calcified tissue site. In one embodiment, at least one soft tissue site is targeted. The sites of targeting and the sites of origin of the disease may be the same, but alternatively may be different. Where more than one site is 25 involved, this may include the site of origin or may be a plurality of secondary sites.The term "soft tissue" is used herein to indicate tissues which do not have a "hard" mineralised matrix. In particular, soft tissues as used herein may be any tissues that are not skeletal tissues. Correspondingly, "soft tissue disease" as used herein indicates a disease occurring in a "soft tissue" as used herein. The invention is particularly suitable for 30 the treatment of cancers and "soft tissue disease" thus encompasses carcinomas, sarcomas, myelomas, lukemias, lymphomas and mixed type cancers occurring in any "soft" (i.e. non-mineralised) tissue, as well as other non-cancerous diseases of such tissue. Cancerous "soft tissue disease" includes solid tumours occurring in soft tissues as well as metastatic and micro-metastatic tumours. Indeed, the soft tissue disease may 35 comprise a primary solid tumour of soft tissue and at least one metastatic tumour of soft 34901638141284/mwwtissue in the same patient. Alternatively, the "soft tissue disease" may consist of only a solid tumour or only metastases with the primary tumour being a skeletal disease.When the particles or composition of the invention is used as an imaging agent and/or in a 5 method of diagnosis according to the invention, the targeting moiety may be selected based on specific biomarkers, such as antigens, expressed by or near tissue, cells or organs affected by the proliferative disease.In some embodiments, said proliferative disease is a cancer, a non-cancerous tumour, a 10 neoplastic disease, or a hyperplastic disease.In some preferred embodiments, said proliferative disease is a cancer. As used herein, the terms “cancer” and “tumour” refer to any neoplastic growth in a subject, including an initial tumour and any metastases. The cancer can be of the liquid or solid tumour type.15 Liquid tumours include tumours of hematological origin, including, e.g., myelomas (e.g., multiple myeloma), leukemias (e.g., Waldenstrom's syndrome, chronic lymphocytic leukemia, other leukemias), and lymphomas (e.g., B-cell lymphomas, non-Hodgkin's lymphoma). Solid tumours can originate in organs and include, but are not limited to, cancers of the lungs, brain, breasts, prostate, ovaries, colon, kidneys and liver.20In some embodiments, the cancer is selected from the list comprising or consisting of lung cancer, pancreatic cancer, colorectal cancer; liver cancer, glioma, renal cancer, nonhodgkin lymphoma, neuroblastoma, CNS metastases, peritoneal cancer, follicular lymphoma, colorectal cancer, small cell lung cancer, carcinoma, sarcoma, myeloma, 25 leukemia, lymphoma, prostate cancer or mixed type cancer.In specific embodiments, the cancer is a metastatic cancer. Treatment of metastatic cancers is notoriously difficult using conventional anticancer therapies, but the targeted MOF vehicles of the invention represent a promising line of diagnosis and/or screening for 30 such cancer, and subsequent treatment.The targeting moiety of the particles will be selected based on the particular disease to be treated. E.g.: CD37 is highly expressed on the majority of B-cells and B-cell lymphomas, is absent on normal stem cells and is lost again following differentiation into plasma cells. 34901639141284/mwwBecause of its high prevalence on the surface of B-lymphomas, CD37 is a target for several different agents in clinical development. Thus, for such cancers, anti-CD37 may be a useful targeting moiety.5 Non-Hodgkins lymphoma is difficult to treat with conventional therapy (surgery, radiation) as it is spreads around the lymph system. In addition, non-Hodgkin’s lymphomas can metastase to other tissue types, which is another reason why the present invention can be especially effective against non-Hodgkin’s lymphoma.10 The following aspect is not according to the invention and is presented for illustration purposes only. Further, the invention may also be useful in imaging of chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease such as ulcerative colitis and/or Crohn’s disease, and/or chronic obstructive pulmonary disease. Thus,15 A particle comprising- a MOF, wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the 20 functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof;- optionally at least one targeting moiety connected to the particle on an external surface of the particle; and25 - at least one short-lived radionuclide;and wherein the at least one radionuclide is located in at least one of the pores, or a composition comprising said particle together with at least one pharmaceutically acceptable carrier, diluent, and/or excipient,may be suitable for use in a method for the diagnosis of a chronic inflammatory disease.30In these embodiments, the subject is preferably a subject that has been diagnosed with a chronic inflammatory disease, such as rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease such as ulcerative colitis and/or Crohn’s disease, and/or chronic obstructive pulmonary disease. The inflammatory process in the body serves an important 35 function in the control and repair of injury. Commonly referred to as the inflammatory cascade, or simply inflammation, it can take two basic forms, acute and chronic. Acute 34901640141284/mwwinflammation, part of the immune response, is the body’s immediate response to injury or assault due to physical trauma, infection, stress, or a combination of all three. Acute inflammation helps to prevent further injury and facilitates the healing and recovery process.5When inflammation becomes self-perpetuating, it can result in chronic or long-term inflammation. This is known as chronic inflammation, and lasts beyond the actual injury; sometimes for months or even years. It can become a problem itself, and require medical intervention to control or stop further inflammation-mediated damage. Unbalance of 10 inflammatory and anti-inflammatory components of the immune system can result in chronic inflammatory disease. Rebalancing the immune system by killing the inflammatory cells with radioisotope loaded MOFs can prevent the chronic inflammation and treat the patients.15 The particle or composition for use as an imaging agent and/or in a method of diagnosis according to the invention, comprises administering to a subject the particles or composition in a diagnostically effective dose. In one embodiment, the method or use comprises imaging a subject previously administered with the imaging agent. The term “effective dose” as used herein means the amount of particle according to the invention 20 which is effective for producing the desired imaging effect in a subject at a reasonable benefit/risk ratio. The effective dosage amount may vary depending upon the route of administration and dosage form. Further, dosages may depend on the particle to be used, the type of radioactive decay of the radionuclide cation and/or its daughters, the stage of the condition, age and weight of the subject, etc. and may be routinely determined by the 25 skilled practitioner according to principles well known in the art.In some embodiments, the amount of radionuclide cation used per patient dosage may be in the range of from 1 kBq to 10 GBq, e.g.1 MBq to 1 GBq, preferably 2 MBq to 400 MBq, more preferably 100 MBq to 400 MBq, even more preferably in the range of from 3 MBq to 30 400 MBq. The dosage and the maximum dosage may be determined by the person skilled in the art based on common general knowledge about suitable dosages and maximum dosages. It is accepted in the art that a realistic and conservative estimate of the toxic side effects of daughter isotopes must be adopted.35 In some embodiments, the particles are administered at a dosage of 10 Bq to 100 MBq/kg bodyweight, such as at a dosage of 10 kBq to 10 MBq/kg bodyweight, e.g. at a dosage of 34901641141284/mww10 kBq to 4 MBq/kg bodyweight, preferably 50 kBq to 4 MBq/kg, such as 100 kBq to 2 MBq/kg, more preferably 75 to KBq/kg, especially 4 to 6 MBq/kg. Correspondingly, a single dosage unit may comprise around any of these ranges multiplied by a suitable bodyweight, such as 30 to 150 Kg, preferably 40 to 100 Kg (e.g. a range of 100 kBq to 10 5 GBq per dose etc). The dosage, the particle and the administration route may be such that the dosage of progeny generated in vivo is less than 300 kBq/kg, such as less than 200 kBq/kg, preferably less than 150 kBq/kg, such as less than 100 kBq/kg.The diagnostically effective dose of the particle or composition according to the invention 10 can be administered in a single dose or in divided doses. The particle or composition according to the invention can be administered once, twice or more times a day, once every two days, once every three days, twice a week or once a week, or as deemed appropriate by a medical professional and coordinated with the imaging procedure. In certain embodiments, the particle or composition according to the invention is15 administered once daily, preferably shortly before an imaging procedure. In other embodiments, the dosage and the frequency of administration of treatment with the particle or composition according to the invention is determined by a medical professional, based on factors including, but not limited to, the stage of the disease, the severity of symptoms, the route of administration, the age, body weight, general health, gender 20 and/or diet of the subject, and/or the response of the subject to the treatment.The particle or composition according to the invention should be administered by a medical professional. In some embodiments, the particle or composition according to the invention is administered at specific times of day.25The particle or composition for use as an imaging agent and/or in a method of diagnosis according to the invention may be administered locally or systemically. The particle or composition according to the invention may be administered by any administration route, including but not limited to, pulmonary, orally, intraperitoneally, intravenously,30 intramuscularly, intratumour, sublingually, subcutaneously, intrathecally, buccally, rectally, vaginally, occularly, nasally, transdermally, and cutaneously. In some embodiments, the particle or composition is administered intravenously. In these embodiments, water is a particularly useful excipient. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions.35 34901642141284/mwwA composition of the invention may be presented in unit dosage form as a single dose wherein all active and inactive ingredients are combined in a suitable system and components do not need to be mixed before administration. Alternatively, a composition may be presented as a kit such as disclosed above, and may contain instructions for 5 storing, preparing, administering and/or using the composition.In certain embodiments, the particle or composition according to the invention is administered alone. In other embodiments, the particle or composition according to the invention is administered in combination with one or more other imaging agents, e.g. for 10 use with other imaging modalities than radiopharmacy. When using separate formulations, the particle or composition according to the invention may be administered simultaneously, intermittent, staggered, prior to, subsequent to, or combinations of these, with the administration of another imaging agent.15 The embodiments and features described in the context of one aspect, e.g. for the aspect directed to the particle or the composition, also apply to the other aspects of the invention, such as the use thereof as an imaging agent or in a method of diagnosis.In a further aspect, the invention provides a method of diagnosis, the method comprising 20 the step of administering an effective amount of a particle or composition of the invention, to a subject in need thereof.In a further aspect, the invention provides a method of diagnosis of a proliferative disease, the method comprising the step of administering an effective amount of a particle or 25 composition of the invention, to a subject in need thereof.As further disclosed herein is a method of diagnosis of chronic inflammatory disease, the method comprising the step of administering an effective amount of a particle or composition of the invention, to a subject in need thereof.30In a further aspect, the invention provides the use of a particle or composition of the invention as a contrast agent.In a further aspect, the invention provides the use of a particle or composition of the 35 invention for diagnosis of a proliferative disease. 34901643141284/mwwIn yet a further aspect, the invention provides the use of a particle or composition of the invention for diagnosis of a of chronic inflammatory disease.The invention shall not be limited to the shown embodiments and examples. While various 5 embodiments of the present disclosure are described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous modifications and changes to, and variations and substitutions of, the embodiments described herein will be apparent to those skilled in the art without departing from the disclosure. It is to be understood that various alternatives to the embodiments described 10 herein can be employed in practicing the disclosure.It is to be understood that every embodiment of the disclosure can optionally be combined with any one or more of the other embodiments described herein.15 It is to be understood that each component, compound, particle, or parameter disclosed herein is to be interpreted as being disclosed for use alone or in combination with one or more of each and every other component, compound, or parameter disclosed herein. It is further to be understood that each amount/value or range of amounts/values for each component, compound, or parameter disclosed herein is to be interpreted as also being 20 disclosed in combination with each amount/value or range of amounts/values disclosed for any other component(s), compound(s), or parameter(s) disclosed herein, and that any combination of amounts/values or ranges of amounts/values for two or more component(s), compound(s), or parameter(s) disclosed herein are thus also disclosed in combination with each other for the purposes of this description. Any and all features 25 described herein, and combinations of such features, are included within the scope of the present invention provided that the features are not mutually inconsistent.It is to be understood that each lower limit of each range disclosed herein is to be interpreted as disclosed in combination with each upper limit of each range disclosed 30 herein for the same component, compound, or parameter. Thus, a disclosure of two ranges is to be interpreted as a disclosure of four ranges derived by combining each lower limit of each range with each upper limit of each range. A disclosure of three ranges is to be interpreted as a disclosure of nine ranges derived by combining each lower limit of each range with each upper limit of each range, etc. Furthermore, specific amounts/values 35 of a component, compound, or parameter disclosed in the description or an example is to be interpreted as a disclosure of either a lower or an upper limit of a range and thus can 34901644141284/mwwbe combined with any other lower or upper limit or a range or specific amount/value for the same component, compound, or parameter disclosed elsewhere in the application to form a range for that component, compound, or parameter.5 34901645141284/mwwExamplesExample 1: Conjugation of anti-CD37 IgG to UIO-66-(COOH)2The UIO-66-(COOH)2 MOF was prepared by a method based on the method of Zhiijie 5 Chen et al, CrystEngComm 2019, 14, 2409-2415, however an oxychloride salt was used rather than an oxynitrate salt as a precursor for the MOF. UIO-66-(COOH)2 antibody conjugation was assessed by analysing UIO-66-(COOH)2 antibody conjugated particles by bicinchoninic acid assay (BCA). The BCA Protein Assay combines the well-known reduction of Cu2+ to Cu1+ by protein in an alkaline medium with the highly sensitive and 10 selective colorimetric detection of the cuprous cation (Cu1+) by bicinchoninic acid (BCA).The first step is the chelation of copper with protein in an alkaline environment to form a light blue complex. In this reaction, known as the biuret reaction, peptides containing three or more amino acid residues form a coloured chelate complex with cupric ions in an alkaline environment containing sodium potassium tartrate.15In the second step of the colour development reaction, BCA reacts with the reduced (cuprous) cation that was formed in step one. The intense purple-coloured reaction product results from the chelation of two molecules of BCA with one cuprous ion.20 Procedure:5 mg of UiO-66-(COOH)2 was dissolved in 0.05 M 2-(N-morpholino)ethanesulfonic acid (MES) buffer, pH 6.3, treated with 1.2 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1.2 mg N-hydroxysulfosuccinimide(sulfo-NHS) for 15 min, before the particles were washed twice times with 0.05 M MES buffer (pH 6.3). The particles were then re-25 suspended in 0.05 M MES buffer (pH 6.3), containing 100 µg of anti-CD37 IgG. The reaction mixture was incubated with continuous rocking for 3 hours. The MOF-antibody particles were washed with 0.05 M MES buffer (pH 6.3) and resuspended in 100 mM Tris buffer prior to washing and storing the particles with 0.05 M MES buffer (pH 6.3).30 Antibody (IgG) conjugated UIO-66(COOH)2 and an albumin standard was assessed by the BCA assay, shown in Figure 12. The trendline equation from the albumin was used to calculate the protein concentration of the UIO-66(COOH)2-IgG particles per mL:Absorbance – blank:0.096, corresponding to 77 µg/mL (77% of the antibody input).35 34901646141284/mwwExample 2: Structural stability and barium retention ability of a MOF in human serumIn this experiment, barium(II) was used as a cold isotope to mimic 133/131 Ba.5 Procedure:200 mg UiO-66-(COOH)2 was washed once with 0.05 M MES buffer (pH 6.3) and suspended in 40 mL aqueous solution of barium(II)acetate (14.7 ug Ba/mL). The suspension was agitated at room temperature for 60 minutes. The MOF was recovered, washed once with 5 mL 0.05 mol/L MES buffer (pH 6.3) before being suspended in 10 human serum. The MOF/serum suspension was kept stirring at room temperature for 11 days. Samples were taken after 15 minutes, plus after 1, 2, 4, and 7 days. Elemental analysis was carried out using the MP-AES method following digestion of serum samples using a 1:1 volumetric mixture of HNO3 (65 %) aq. And H2O2 (33%) aq at 70 C for 1 hour.15Elemental analysis showed that the MOF adsorbed 97.2 % of the Ba2+ in solution, giving a Ba2+ concentration in the MOF at 2.87 ug/mg. (0.287 % wt.). Analysis of serum samples taken after 15 minutes, plus after 1, 2, 4, and 7 days, showed a total leakage of Ba2+ into the serum of 6.6 %, 8.4 %, 9.4 %, 8.3 % and 5.5 %, respectively. This indicates 20 that, after initial leakage, the MOF contains all the Ba2+.The MOF was separated from the serum after 11 days and analysed by powder X-ray diffraction and energy dispersive X-ray spectroscopy. Powder X-ray diffraction patterns of UiO-66-(COOH)2 as received and after a 11-day stability test clearly show that the MOF 25 crystal structure is still intact. EDS shows that the mass ratio of Ba/Zr in the MOF is 1.10 %, closely matching the value measured by MP-AES (0.287 % wt.) compared to the theoretical mass percentage of Zr in the MOF (25.1 %, from the formula Zr6O4(OH)4(COO)12(C8H4O4)6), 1.14 %, within the margin of error of the experiments.ID ppm[Ba2+] in MOF-serum suspension 19.10889 [Ba2+] in serum after 15min 1.259 [Ba2+] in serum after 24h 1.608 [Ba2+] in serum after 48h 1.802 [Ba2+] in serum after 96h 1.5955 [Ba2+] in serum after 168h 1.047530 Table 2 shows the barium concentrations found in experiment 2. 34901647141284/mwwHence, the experiment shows that the MOF particle in itself is stable in human serum for at least 11 days, and that the chelation of barium cations in the MOF particle is stable for at least 11 days. Incidentally, the experiments also show the MOF’s ability to adsorb substantial quantities of Ca2+. K+ and Na+ without leaking Ba2+.5Example 3: Structural stability and barium retention ability of a MOF in human serumThis experiment corroborates the results from Experiment 2, using a different Ba2+ source and two different concentrations.10Procedure:2 separate portions of 120 mg UiO-66-(COOH)2 were washed three times with 5 mL 0.05 mol/L MES buffer (pH 6.3) and then suspended in two 5 mL separate aqueous solutions of barium(II)nitrate (1.165 mg/mL Ba, 0.109 mg/mL Ba, respectively). The suspensions 15 were agitated at room temperature for 90 minutes. The MOF was recovered, washed once with 5 mL 0.05 mol/L MES buffer (pH 6.3) before being suspended in human serum. Samples were taken after 24 and 48 hours. The MOF/serum suspension was kept stirring at room temperature for 2 days. Samples were taken after 24 and 48 hours. Elemental analysis was carried out using the MP-AES method following digestion of serum samples 20 using a 1:1 volumetric mixture of HNO3 (65 %) aq. And H2O2 (33%) aq at 70 C for 1 hour.From the 1.165 mg/mL Ba solution: Elemental analysis showed that the MOF adsorbed 98.8 % of the Ba2+ in solution, giving a Ba2+ concentration in the MOF at 48.0 ug/mg. (4.8 % wt.). Analysis of serum samples taken after 24 and 48 hours, showed a total 25 leakage of Ba2+ into the serum of 8.8 % and 9.2 %, respectively. This indicates that there was negligible leaking of Ba2+ between 24 and 48 hours. EDS shows that the mass ratio of Ba/Zr in the MOF is 19.4 %, closely matching the value measured by MP-AES (4.8 % wt.) compared to the theoretical mass percentage of Zr in the MOF (25.1 %, from the formula Zr6O4(OH)4(COO)12(C8H4O4)6), 19.1 %, within the margin of error of the 30 experiments.From the 0.109 mg/mL Ba solution: Elemental analysis showed that the MOF adsorbed 92.0 % of the Ba2+ in solution, giving a Ba2+ concentration in the MOF at 4.19 ug/mg. (0.42 % wt.). Analysis of serum samples taken after 24 and 48 hours, showed a total 35 leakage of Ba2+ into the serum of 6.4 % and 6.0 %, respectively. This indicates that there was no leaking of Ba2+ between 24 and 48 hours. EDS shows that the mass ratio of 34901648141284/mwwBa/Zr in the MOF is 1.43 %, closely matching the value measured by MP-AES (0.42 % wt.) compared to the theoretical mass percentage of Zr in the MOF (25.1 %, from the formula Zr6O4(OH)4(COO)12(C8H4O4)6), 1.67 %, within the margin of error of the experiments.5ID Solution 1 Solution 2(ppm) (ppm)[Ba2+] in MOF-serum suspension 575.505 50.23833[Ba2+] in serum after 24h 50.4425 3.213[Ba2+] in serum after 48h 52.7845 3.027Table 3 shows the barium concentrations found in experiment 3.Example 4: MOF-IgG cell interaction10 This experiment shows that anti-CD37-conjugated MOFs (NP1) bind CD37 positive cells (Duadi cells). The Daudi cell line is composed of B lymphoblasts isolated from the peripheral blood of a Burkitt's Lymphoma patient, illustrating that the anti-CD37-conjugated MOFs can identify blood derived cancer cells.15 Procedure:66 000 Daudi cells were transferred to flow tubes containing: phosphate buffered saline (PBS), isotype control, UiO-66-(COOH)2 anti-CD37 stability study sample (incubated at 20 degree C for 6 months) or UiO-66-(COOH)2 anti-CD37 freshly conjugated. Samples were incubated with continuous mixing for 30 minutes prior to adding 400 µL of 10% fetal bovin 20 serum (FBS) in PBS and centrifugating at 350 g for 8 min. The supernatant was discarded prior to adding 100 µL anti-CD37-PE (10 µL anti-CD37-PE mixed with 90 µL PBS) to the PBS sample, or 100 µL anti-mouse-PE (10 µL anti-mouse-PE mixed with 90 µL PBS) to the isotype control and UiO-66-(COOH) 2 aCD37 samples. Samples were incubated with continuous mixing for 30 minutes prior to adding 400 µL of 10% FBS in PBS and25 centrifugating at 350 g for 8 min. The supernatant was discarded prior to adding 400 µL 10% FBS in PBS and flow cytometry analysis.The stability control sample used in this experiment was prepared by storing UiO-66-(COOH)2 anti-CD37 at 20 degrees for 6 months.30Figure 13 provides the results showing that anti-CD37-conjugated MOFs (NP1) binds CD37 positive cells and is stable for at least 6 months at room temperature. 34901649141284/mwwExample 5: MOF-anti-EpCAM and MOF-anti-HER2 cell binding to colorectal cell linesThis experiment shows that anti-EpCAM or anti-HER-conjugated UiO-66-(COOH)2 bind colorectal cancer cells (HTC116 and HT29) expressing both antigens. HTC116 cells 5 originates from the colon of an adult male, colon cancer patient. And HT29 cell line is derived from the primary tumour of a female patient with colorectal adenocarcinoma. Thus, illustrating that both anti-EpCAM and anti-HER-antibodies (IgG) conjugated UiO-66-(COOH)2 can identify colorectal derived cancer cells.10 Procedure:Cells were seeded at 50000 cells per well in 96-well plates and cultured overnight in complete 10% Fetal bovine serum (FBS) Roswell Park Memorial Institute (RPMI) cell culture media. The next day, media was discarded from each well prior to adding 2 µg anti-EpCAM, 2 µg isotype control or 15 µL UiO-66-(COOH) 2 (NP1) diluted in prewarmed 15 cell culture media to the total volume of 200 µL per well. The samples were incubated for 30 min at 37 degree C prior by discarding the media and adding 200 µL PBS (phosphate buffered saline) twice gently.100 µL of PBS and 100 µL anti-human IgG-HRP solution (2.5 µL anti-human IgG-HRP solution/mL) was added per sample and incubated for 30 min at room temperature. After secondary staining, cells were washed with PBS twice 20 gently prior to adding 100 µL of TMB (3,3',5,5'-Tetramethylbenzidine) HRP (horseradish peroxidase) substrate solution to each well and incubating for 15 min.100 µL of stopping solution was added per well to stop the reaction prior to measuring the absorbance of each well at 450 nm. The absorbance is reported in the graph as “HRP signal”.Figure 14 shows that anti-EpCAM and anti-HER2 UiO-66-(COOH)2 bind colorectal cancer 25 cells (HTC116 and HT29).Example 6: MOF-anti-HER2 breast cancer cell interactionThis experiment shows that anti-HER2-conjugated UiO-66-(COOH)2 binds HER2 positive cancer cells (JIMT1 cells). JIMT1 cells are epithelial cells originating from a female 30 patient with breast ductal adenocarcinoma. Thus, JIMT1 cell interaction illustrates how anti-HER2-conjugated UiO-66-(COOH)2 can identify breast derived cancer cells.Procedure: The same procedure was used for JIMT1 cell interaction as for colorectal cancer cell interaction, see example 5 (figure 14).35 34901650141284/mwwFigure 15 shows the anti-HER2-conjugated UiO-66-(COOH) 2 binds to breast cancer cells, JIMT1 cells.Example 7: Planned experiment: Gamma emitter adsorption and retention of a MOF 5 in human serumProcedure:0.0085 mg (low), 0.085 mg (medium) and 0.85 mg (high) UiO-66-(COOH)2 conjugated to anti-HER2 antibody and polyethylene glycol (PEG) will be mixed with an amount of a 10 gamma emitter and agitated at room temperature for 60 minutes. The MOF will be recovered, washing twice with distilled water before measuring the total gamma emitting activity with an Hidex instrument (A). After discarding the supernatant, the remaining pellet of the 0.85 mg (high) UiO-66-(COOH)2 will be suspended in human serum (HS) and distributed into one tube per timepoint for the stability study. The MOF/serum suspension 15 will be incubated with mixing at 37 degree C for 7 days analysing the total supernatant after centrifugation after 30 min, 2 hours, 1 day, 3 days, 5 days and 7 days (B).Example 8: Planned experiment: Biodistribution of gamma emitter loaded UiO-66-(COOH)2 in healthy mice.20Procedure:A dose of the gamma emitter/0.085 mg MOF from Example 7 will be incubated for 1 hour prior to washing (centrifugation and discarding supernatant prior to adding distilled water) and resuspended in physiological salt water for injection into healthy mice (dose). The 25 mice will be analysed by PET/CT to assess biodistribution on sequential timepoints, or sacrificed prior to harvesting all major organs for analysis by the Hidex gamma counter.Example 9. Planned experiment: biodistribution of UiO-66-(COOH)2 (NPs)30 conjugated to anti-HER2, anti-EpCAM antibodies and polyethylene glycol (PEG) to investigate the tumour targeting of NPs with and without antibodies.Procedure:The biodistribution of gamma isotope loaded UiO-66-(COOH)2 targeting EpCAM or HER2 35 will be investigated, along with their ability to localize to the tumours using tumour models representing HER2+ breast cancer and EpCAM colorectal cancer. To investigate the 34901651141284/mwwspecificity of the nanoparticles (NPs), the NPs with and without antibodies attached to the particles will be used in addition to radioactivity. The mice will be sacrificed from day 0 to 30 post treatment to investigate the drug’s biodistribution over time, and how specific the biodistribution will be considering the tumour. Mice will be sacrificed at each timepoint with 5 each drug. For the two EpCAM targeting drugs this will be investigated in two or more models (for example HCT116 and HT29), with tumour growing in for example the liver and intraperitoneally. For tumour growing intraperitoneally, the substances will be injected either intra Intravenous (iv) or Intraperitoneal (ip) to investigate which injection form has the best biodistribution with regards to tumour growing in the peritoneal cavity. The two 10 HER2 targeting drugs will be investigated in at least two models, for example SKBR3 (cell line) and BBRC160 (PDX) resulting in breast cancer, liver tumours and peritoneal tumours.Example 10. viability test of UiO-66-(COOH)2 (NPs) conjugated with PEG15 demonstrate no toxicity in vitro.Exposing HT29 and HCT116 with an increasing dose of NPs over two days before analysing the cell viability demonstrate that NP does not induce cell death under these conditions.20 Procedure:HT29 or HCT116 was exposed to 0.001 to 500 µg per well of UiO-66-(COOH)2 (NPs) and cultured at 37 degree C at 5% CO2 in a humidified incubator for 24 and 48 hours prior to discarding the supernatant and adding 100 µL fresh cell culture media (10% Fetal bovine serum (FBS) Roswell Park Memorial Institute (RPMI)) and 20 µL the CellTiter 96® 25 AQueous One Solution Reagent (Promega) containing tetrazolium compound [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling reagent (phenazine ethosulfate; PES). Each plate was incubated at 37 degree C at 5% CO2 in a humidified incubator for 1.5 hours before measuring the absorbance at 490 nm in a plate reader.30Ref. Figure 16 A and B) the absorbance was unchanged under all conditions thus implying that the cell content per well was unchanged over the period of 48 hours.
Claims
34901652Claims1. A particle comprising- a MOF, wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof;- optionally at least one targeting moiety connected to the particle on an external surface of the particle; and- at least one short-lived radionuclide, wherein the radionuclide is a radionuclide cation with a half-life in the range of 0.5 hours to 60 days;and wherein the at least one radionuclide is adsorbed within at least one of the pores by the at least one free functional group that extends into the pore.2. The particle according to claim 1, wherein the MOF is UiO-66-COOH, MOF-808 or UiO-66-(COOH)2.3. The particle according to claim 1 or claim 2, wherein the radionuclide is a gamma-emitter or a positron-emitter.4. The particle according to any of the preceding claims, wherein the at least one radionuclide is selected from the group comprising Ga-68, Ti-45, Tc-99m, Ba-133m, In-111, Ga-67, Zr-89, Ba-131, Yb-169 and Sc-43.5. The particle according to any of the preceding claims, wherein the particle is a nanoparticle.6. The particle according to any of the preceding claims, wherein at least one targeting moiety is present.7. The particle according to any of the preceding claims, wherein at least one targeting moiety is present and is an antibody.8. A kit comprising,34901653141284/mwwin a first container,a particle comprising- a MOF, wherein the MOF comprises- a repeating three-dimensional network of inorganic monomers and organic monomers, forming pores, and- at least one free functional group that extends into a pore, wherein the functional group is selected from the group comprising carboxylic acid, carboxylate, hydroxyl, sulfonic acid, sulfonate, sulfhydryl, primary amines, secondary amines, and combinations thereof;- optionally at least one targeting moiety connected to the particle on an external surface of the particle; andand in a second container,a short-lived radionuclide, wherein the radionuclide is a radionuclide cation with a half-life in the range of 0.5 hours to 60 days;and wherein the at least one radionuclide is adsorbed within at least one of the pores by the at least one free functional group that extends into the pore.9. An imaging agent composition comprising at least one particle according to any of claims 1-7 together with at least one pharmaceutically acceptable carrier, diluent, and/or excipient.10. The particle according to any of claims 1-7 or the composition according to claim 9 for use as an in vivo imaging agent.11. The particle according to any of claims 1-7 or the composition according to claim 9 for use as an in vivo imaging agent according to claim 10, in a method for the diagnosis of a proliferative disease, wherein the proliferative disease is a cancer, a non-cancerous tumour, a neoplastic disease, or a hyperplastic disease.12. The particle according to any of claims 1-7 or the composition according to claim 9 for use according to claim 11, wherein said proliferative disease is cancer.13. The particle according to any of claims 1-7 or the composition according to claim 9 for use according to claim 12, wherein said cancer is a carcinoma, sarcoma, myeloma, leukaemia, lymphoma or mixed type cancer.3490165414. The particle according to any of the claims 1-7 or the composition according to claim 9 for use as an in vivo imaging agent according to claim 10, wherein the use comprises- a step of administering the imaging agent to a subject, followed by- a subsequent treatment step comprising administering to the subject a particle comprising the same MOF as used as an in vivo imaging agent, carrying a therapeutic radionuclide.15. The particle according to any of the claims 1-7 or the composition according to claim 9, for use as an in vivo imaging agent according to claim 10 in a method for the diagnosis of a liver cancer, wherein the particle does not comprise any targeting moiety.34901655Kravsett1. Partikkel omfattende- en MOF, hvori MOF-en omfatter- et repeterende tredimensjonalt nettverk av uorganiske monomerer og organiske monomerer, som danner porer, og- minst én fri funksjonell gruppe som strekker seg inn i en pore, hvori den funksjonelle gruppen er valgt fra gruppen omfattende karboksylsyre, karboksylat, hydroksyl, sulfonsyre, sulfonat, sulfhydryl, primære aminer, sekundære aminer, og kombinasjoner derav;- eventuelt minst én målrettingsdel koblet til partikkelen på en ytre overflate av partikkelen; og- minst ett kort-levd radionuklid, hvori radionuklidet er et narionuklid kation med en halveringstid i området fra 0,5 timer til 60 dager;og hvori det minst ene radionuklidet er adsorbert i minst en av porene av den minst ene frie funksjonelle gruppen som strekker seg inn i poren.2. Partikkelen ifølge krav 1, hvori MOF-en er UiO-66-COOH, MOF-808 eller UiO-66-(COOH)2.3. Partikkelen ifølge krav 1 eller krav 2, hvori radionuklidet er en gamma-emitter eller en positron-emitter.4. Partikkelen ifølge hvilket som helst av de foregående kravene, hvori det minst ene radionuklide er valgt fra gruppen omfattende Ga-68, Ti-45, Tc-99m, Ba-133m, In-111, Ga-67, Zr-89, Ba-131, Yb-169 og Sc-43.5. Partikkelen ifølge hvilket som helst av de foregående kravene, hvori partikkelen er en nanopartikkel.6. Partikkelen ifølge hvilket som helst av de foregående kravene, hvori minst en målrettingsdel er til stede.7. Partikkelen ifølge hvilket som helst av de foregående kravene, hvori minst én målrettingsdel er til stede og er et antistoff.8. Sett omfattende,34901656141284/mwwi en første beholder,en partikkel omfattende- en MOF, hvori MOF-en omfatter- et repeterende tredimensjonalt nettverk av uorganiske monomerer og organiske monomerer, som danner porer, og- minst én fri funksjonell gruppe som strekker seg inn i en pore, hvori den funksjonelle gruppen er valgt fra gruppen omfattende karboksylsyre, karboksylat, hydroksyl, sulfonsyre, sulfonat, sulfhydryl, primære aminer, sekundære aminer, og kombinasjoner derav;- eventuelt minst én målrettingsdel koblet til partikkelen på en ytre overflate av partikkelen; ogi en andre beholder,et kortlevd radionuklid, hvori radionuklidet er et radionuklid kation med en halveringstid i området fra 0,5 timer til 60 dager;og hvori det minst ene radionuklidet er adsorbert i minst en av porene av den minst ene frie funksjonelle gruppen som strekker seg inn i poren.9. Avbildningsmiddelsammensetning omfattende minst én partikkel ifølge hvilket som helst av kravene 1-7 sammen med minst én farmasøytisk akseptabel bærer, fortynningsmiddel og/eller hjelpestoff.10. Partikkelen ifølge hvilket som helst av kravene 1-7 eller sammensetningen ifølge krav 9 for anvendelse som et in vivo avbildingsmiddel.11. Partikkelen ifølge hvilket som helst av kravene 1-7 eller sammensetningen ifølge krav 9 for anvendelse som et in vivo avbildingsmiddel ifølge krav 10, i en fremgangsmåte for diagnostisering av en proliferativ sykdom, hvori den proliferative sykdommen er en kreft, en ikke-kreftsvulst, en neoplastisk sykdom, eller en hyperplastisk sykdom.12. Partikkelen ifølge hvilket som helst av kravene 1-7 eller sammensetningen ifølge krav 9 for anvendelsen ifølge krav 11, hvori nevnte proliferative sykdomm er kreft.13. Partikkelen ifølge hvilket som helst av kravene 1-7 eller sammensetningen ifølge krav 9 for anvendelsen ifølge krav 12, hvori nevnte kreft er et karsinom, sarkom, myelom, leukemi, lymfom eller kreft av blandet type.3490165714. Partikkelen ifølge hvilket som helst av kravene 1-7 eller sammensetningen ifølge krav 9 for anvendelse som et in vivo avbildingsmiddel ifølge krav 10, hvori anvendelsen omfatter - et trinn med administrering av avbildningsmiddelet til et individ, etterfulgt av - et påfølgende behandlingstrinn omfattende administrering av en partikkel omfattende den samme MOF som brukes som et in vivo avbildningsmiddel, som bærer et terapeutisk radionuklid, til individet.15. Partikkelen ifølge hvilket som helst av kravene 1-7 eller sammensetningen ifølge krav 9, for anvendelse som et in vivo avbildningsmiddel ifølge krav 10 i en fremgangsmpte for diagnostiseringen av en leverkreft, hvori partikkelen ikke omfatter noen målrettingsdel.
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Patent classes

IPC classesA61K 51/06A61K 51/12A61K 51/10A61P 35/00CPC classesA61K 51/06A61K 51/1244A61K 51/1045A61K 51/1051A61P 35/00

Citations

JIN, Q. ET AL. Ultra-small iron-gallic acid coordination polymer nanoparticles for chelator-free labeling of 64Cu and multimodal imaging-guided photothermal therapy. Nanoscale, 2017, vol 9., no. 34, p. 12609-12617. ()TAO, Y. ET AL. Versatile labeling of multiple radionuclides onto a nanoscale metal-organic framework for tumor imaging and radioisotope therapy. Biomater. Sci., 2021, vol. 9, p. 2947-2954. ()ZENG, Y. ET AL. PEGylated Nanoscale Metal-Organic Frameworks for Targeted Cancer Imaging and Drug Delivery. Bioconjugate Chem., 2021, vol. 32, p. 2195-2204. ()LIU, Y. ET AL. In situ polymerization on nanoscale metal-organic frameworks for enhanced physiological stability and stimulus-responsive intracellular drug delivery. Biomaterials, 2019, vol. 218, 119365. ()CN 114806546 A (A)US 10272157 B2 (B2)US 2010/226991 A1 (A1)

Applicants, owners and inventors

Owners
Node Pharma AS
Postboks 8600 Majorstuen 0349 OSLO NO (OSLO Municipality, Oslo county)Org. number: 927025965Inventors
Erik Mjåland
Observatorie Terrasse 5 A 0270 OSLO NO (OSLO Municipality, Oslo county)
Tor Espen Stav-Noraas
Ekrekroken 25 1356 BEKKESTUA NO (BÆRUM Municipality, Akershus county)
Sigurd Øien-Ødegaard
Dalbakkveien 43 0682 OSLO NO (OSLO Municipality, Oslo county)

Agent

BRYN AARFLOT AS
BRYN AARFLOT AS

Org. number: 979993269

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Open in The Brønnøysund Register Centre
Stortingsgata 8 0161 OSLO NO (OSLO Municipality, Oslo county)
Org. number: 979993269
Reference: 141284/IMO

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