Radiopharmaceutical MOF for medical imaging

Abstract

The present invention relates to MOFs for use in imaging and as radiolabelling tracers. More specifically, the present invention provides: a particle comprising an MOF, optionally at least one targeting moiety, and at least one short-lived radionuclide; a composition comprising the particles; the particle or the composition is used as an imaging agent; a method for diagnosing a proliferative disease by using the particle or the composition; a method for diagnosing a chronic inflammatory disease by using said particle or composition; and a kit comprising particles comprising a MOF, an optional targeting moiety, and a short-lived radionuclide cation.

Description

Technical Field

[0001] The present invention relates to MOFs for use in imaging and as radiolabeled tracers. More specifically, the present invention provides particles comprising a MOF and at least one short-lived radionuclide; particles comprising a MOF, at least one targeting moiety, and at least one short-lived radionuclide; a composition comprising the particles; the particles or composition for use as an imaging agent; the particles or composition for use in a method of diagnosing a proliferative disease; and a kit comprising particles containing a MOF and optionally a targeting moiety and a short-lived radionuclide cation. Background Art

[0002] Cancer is a widespread class of diseases that directly or indirectly affects millions of people. The WHO estimates that there were 19.3 million new cancer cases in 2020 and 50.6 million individuals with a 5-year life expectancy. Despite improvements in treatment over the decades, the American Cancer Society projects that by 2040, the number of new cancer cases will increase to 27.5 million per year and the number of people dying from cancer will rise to 16.2 million per year. Common cancer treatments include surgery, chemotherapy, and external beam irradiation. However, there remains a large unmet medical need for new and more effective cancer treatment options.

[0003] One treatment option with high potential for specificity and efficiency is so-called theranostic treatment, which combines the use of diagnostic and cancer-killing radioisotopes (such as γ-emitters and α-emitters). Theranostic treatment uses the same delivery compound, except that the radioisotope is changed. This allows for the assessment of the biodistribution of the diagnostic compound prior to the administration of a cancer-killing radiopharmaceutical such as radioimmunotherapy (RIT) or targeted alpha therapy (TAT). RIT drugs are based on tissue-targeting moieties linked to carriers that can bind and retain the radioisotope. The tissue-targeting moiety (usually an antibody) is used to bring the radioisotope near unwanted cell types (such as cancer cells), resulting in the local delivery of high-energy and highly cytotoxic radiation, killing the unwanted cells without killing healthy surrounding tissue. This type of specific cell killing can be necessary not only for the treatment of cancerous diseases such as sarcomas and epithelial carcinomas, but also for the treatment of proliferative and neoplastic diseases as well as chronic inflammatory diseases. In addition, systemic treatment using RIT can be extremely effective for patients with metastatic tumors, which would otherwise be difficult to achieve without harmful side effects.

[0004] The successful delivery of radiation to unwanted cells relies on stable radioisotope-carrier interactions to prevent unexpected side effects due to radioisotope leakage, especially for α-emitting radium isotopes, including radium-223 and radium-224, and new radiopharmaceuticals are being developed for therapy. A new radioisotope-carrier being explored is crystalline porous coordination polymer (PCP), also known as metal-organic framework (MOF), which consists of alternating inorganic and organic monomers in a porous three-dimensional network. The internal pores of MOF particles can have strong binding sites where cationic radioisotopes can be strongly bound, for example, by chelation. These MOF-based porous coordination polymer particles are different from, for example, coordination polymer nanoparticles (CPN), and different from the ultrasmall polyethylene glycolylated polyvinylpyrrolidone (PVP) particles containing encapsulated iron-gallate coordination complexes as disclosed by Jin, Q. et al, Nanoscale, 2017, Volume 9, Issue 34, pages 12609 to 12617, which involve non-porous organic salts in the form of dense particles.

[0005] RIT drugs are antibody-drug conjugates that use a targeting unit (antibody) to transport radioisotopes to tumors through the blood, where the emitted radiation then eradicates cancer cells. The controlled administration of radionuclides is an emerging form of targeted therapy for metastatic cancer: radionuclides that emit high-energy particles upon decay enable precise microirradiation of small cell clusters without harming neighboring healthy cells. However, unfortunately, not all patients or cancer forms can respond to such therapy due to the lack of co-localization of the drug and cancer cells.

[0006] For the identification and monitoring of diseases, medical imaging is usually performed. Functional assessment of metabolism can also be achieved by using imaging modalities, such as scintigraphy or positron emission tomography (PET), and imaging agents containing radionuclides. 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 can include SPECT, PET, PET / MRI, or PET / CT imaging. Radiopharmaceuticals for diagnostic purposes are short-lived radioactive tracers that emit gamma rays or positrons to produce 2-D images, or alternatively, 3-D images by applying tomography.

[0007] However, it remains difficult to predict how patients and patient indications will respond to a planned treatment with a radiopharmaceutical.

[0008] Accordingly, there is a need for improved radiotracers, imaging agents, and methods for selecting patients who are likely to respond to treatment with a radiopharmaceutical, particularly to treatment with a radiopharmaceutical in which a radioisotope is incorporated into MOF particles. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 A schematic diagram showing one embodiment of the present invention is presented.

[0010] Figure 2 A schematic diagram showing a network structure having an fcu topology is presented.

[0011] Figure 3 A pore in an fcu MOF is presented.

[0012] Figure 4 An example of a coordination site in a tetrahedral cage corner is presented.

[0013] Figure 5 An example of a coordination site in an octahedral pore corner is presented.

[0014] Figure 6 An example of a coordination site in an octahedral pore corner is presented.

[0015] Figure 7 An example of a coordination site in an octahedral cage corner is presented.

[0016] Figure 8 An example of a pore is presented in which several free functional groups extend into the pore.

[0017] Figure 9 MOF UiO-66 is presented.

[0018] Figure 10 MOF MIL-53 is presented.

[0019] Figure 11 A MOF having a zeolitic imidazolate framework and a so-called sod topology is presented.

[0020] Figure 12 Antibody (IgG)-conjugated UIO-66(COOH) is presented 2 For the BCA assay, see Example 1.

[0021] Figure 13Shows anti-CD37 conjugated MOF (NP1) binding to CD37 positive cells (Duadi cells), see Example 4.

[0022] Figure 14 Shows anti-EpCAM or anti-HER conjugated UiO-66-(COOH) 2 Binding to colorectal cancer cells (HTC116 and HT29) expressing both antigens, see Example 5.

[0023] Figure 15 Shows anti-HER2 conjugated UiO-66-(COOH) 2 Binding to HER2 positive cancer cells (JIMT1 cells), see Example 6.

[0024] Figure 16A And B respectively show their in vitro cell viability after exposing HT29 or HCT116 to UiO-66-(COOH) 2 For 24 and 48 hours, see Example 10.

[0025] Figure 17 Shows slices of mouse PET / CT scans overlaid after a 0.6 MBq dose of 68Ga-labeled NPs, and the images were acquired 10 to 30 minutes after injection, see Example 8. Summary of the Invention

[0026] The inventors have found that certain metal-organic-framework (MOF) structures containing certain free functional groups can adsorb selected radionuclides in a clinically relevant environment and act as their stable carriers. In addition, these particulate forms of MOF can be linked to targeting moieties, enabling targeted delivery of the particles in vivo and thus targeted delivery of radionuclides. Accordingly, these particles containing short-lived radionuclides or both a targeting moiety and a short-lived radionuclide represent promising candidates for radiotracers. The radiotracers of the present invention containing MOF as a carrier for short-lived radionuclides can be used, for example, in medical imaging, such as for pre-screening patients diagnosed with a proliferative disease to predict the response to treatment with an α-emitting radionuclide.

[0027] In one aspect, the present invention relates to particles comprising:

[0028] - MOF, wherein the MOF comprises:

[0029] - A repeating three-dimensional network of inorganic monomers and organic monomers forming pores, and

[0030] - At least one free functional group extending into the pores, where the functional group is selected from the group consisting of: carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof;

[0031] - At least one short-lived radionuclide;

[0032] And wherein the at least one radionuclide is located in at least one pore.

[0033] The present invention also relates to a targeting particle, the particle comprising:

[0034] - A MOF, wherein the MOF comprises:

[0035] - A repeating three-dimensional network of inorganic and organic monomers forming pores, and

[0036] - At least one free functional group extending into the pores, where the functional group is selected from the group consisting of: carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof;

[0037] - At least one targeting moiety that is attached to the particle on the outer surface of the particle; and

[0038] - At least one short-lived radionuclide:

[0039] And wherein the at least one radionuclide is located in at least one pore.

[0040] In a second aspect, the present invention relates to a kit, wherein the kit comprises in a first container:

[0041] Particles, the particles comprising:

[0042] - A MOF, wherein the MOF comprises:

[0043] - A repeating three-dimensional network of inorganic and organic monomers forming pores, and

[0044] - At least one free functional group extending into the pores, where the functional group is selected from the group consisting of: carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof;

[0045] - Optionally, at least one targeting moiety that is attached to the particle on the outer surface of the particle;

[0046] And in a second container comprises:

[0047] Short-lived radionuclide.

[0048] In a third aspect, the invention relates to a contrast agent composition as further disclosed, the composition comprising at least one particle as defined above and at least one pharmaceutically acceptable carrier, diluent, and / or excipient.

[0049] In a fourth aspect, the invention relates to the particle or the composition for use as an imaging agent, as further disclosed herein.

[0050] In a fifth aspect, the invention relates to the particle or the composition for use in a method of diagnosing a proliferative disease, as further disclosed herein. Detailed Description

[0051] Unless otherwise defined, all technical terms, symbols, and other scientific terms or terminology used herein are intended to have the meaning commonly understood by those of ordinary skill in the art to which this invention pertains. In some instances, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and such definitions included herein should not necessarily be construed as representing a significant difference from that commonly understood in the art.

[0052] Metal-organic frameworks (MOFs), also known as porous coordination polymers (PCPs), are solid compounds, typically in powder form, belonging to the class of coordination polymers. Chemically, an MOF contains a repeating network of polyhedral (polytopic) inorganic monomers in the form of metal ions or clusters and organic monomers (also known as bridging ligands or linkers). The inorganic and organic monomers are bound by coordination covalent or ionic bonds between Lewis acidic metal cations and Lewis basic organic functional groups (such as carboxylates / esters, amines, imines). The structure of an MOF can be well regulated by the selection of organic and inorganic monomers. The organic monomers of an MOF can all be the same, or an MOF can contain two or more different organic monomers with geometric structures having nearly identical framework coordination functional groups. The latter are referred to as "mixed linker MOFs". Similarly, the inorganic monomers of an MOF can be the same, or they can be different, resulting in "mixed metal MOFs".

[0053] An MOF can be crystalline, amorphous, or have a deformable structure. MOFs made from structurally rigid monomers tend to form repeating three-dimensional networks characterized by permanent porosity, i.e., they are crystalline. Such crystalline MOFs are characterized by having many pores. The term "pore" as used herein refers to any type of pore, cavity, channel, or hole in the MOF network. Based on the crystal structure of an MOF, an MOF can contain different proportions of pores of different shapes. However, the pores of a particular MOF are generally very similar to each other in terms of size and chemical environment.

[0054] The organic monomers of the MOF can include functional groups that do not directly interact 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 the crystalline MOF, they can be directed into the pores of the MOF, creating sites for the adsorption, coordination, and / or chelation of guest ions or molecules. The exact nature of such sites depends on the network topology (geometry) of the MOF and the type and number of functional groups directed into the pores. By selecting a suitable MOF based on, for example, the free functional groups, specific chelation sites (e.g., in the pores) can be constructed for the strong selective adsorption, coordination, and / or chelation of specific compounds. The term "chelation" and its variations as used herein refer to the coordination, complexation, and / or binding of a metal, such as a radionuclide cation, by at least two ligands. The term "ligand" refers to a moiety capable of coordinating, complexing, and / or binding to a metal, such as a molecule, a part of a molecule, a functional group.

[0055] Different functional groups can be used to alter the geometry and charge balance of the chelation sites. Since MOFs are constructed from coordination bonds between organic and inorganic monomers, additional functional groups that can act as coordination groups during the preparation of the MOF can produce undesired and / or unexpected products. Therefore, the introduction of free functional groups into MOFs requires careful design.

[0056] In the present invention, particles of a specific type of MOF are used as carriers for specific radionuclides suitable for imaging, thereby providing new radiolabeled tracers. As further disclosed below, suitable radionuclides are short-lived radionuclides that emit gamma rays or radionuclides that emit positrons. The MOFs used in the present invention are crystalline MOFs that contain potential metal-coordinating free functional groups that extend into the pores of the MOF in such a way that the free functional groups can coordinate and / or bind to short-lived radionuclides (e.g., radionuclide cations). Thus, each pore of these MOFs has the ability to function as a chelating macro-ligand for the radionuclide. MOF particles represent a new class of carriers and can have the ability to contain radioisotopes with little or no leakage. Therefore, it has now been found that MOFs suitable for carrying potent radioisotopes for therapy (commonly alpha-emitters) can be used as carriers for short-lived radionuclides for imaging. Using the same MOF carrier for different radioisotopes for imaging and therapy ensures that the biodistribution of the MOF carriers containing the imaging agent (e.g., gamma emitter) and the therapeutic agent (e.g., radium-223) is nearly identical, and the method allows for pre-treatment screening of patients to predict the response to therapy and prevent unnecessary treatment of non-responders.

[0057] Thus, in one aspect, the present invention relates to particles comprising a MOF, wherein the MOF comprises a repeating three-dimensional network of inorganic and organic monomers that form pores, wherein the pores are designed to chelate short-lived radionuclides, and wherein the particles comprise a short-lived radionuclide that is located in at least one of the pores. Optionally, the particles comprise at least one targeting moiety. Thus, in one embodiment, the particles comprise at least one targeting moiety attached to the particle on the outer surface of the particle.

[0058] In some embodiments, the present invention relates to particles comprising:

[0059] - a MOF, wherein the MOF comprises:

[0060] - a repeating three-dimensional network of inorganic and organic monomers that form pores, and

[0061] - at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof; and

[0062] - optionally, at least one targeting moiety attached to the particle on the outer surface of the particle; and

[0063] - at least one short-lived radionuclide;

[0064] and wherein the at least one radionuclide is located in at least one of the pores.

[0065] In one embodiment, the at least one targeting moiety is attached to the particle on the outer surface of the particle.

[0066] Figure 1 A non-limiting embodiment of the particle 1 of the present invention is schematically shown, which comprises a MOF 2 that forms pores 3 and has functional groups 4 extending into the pores 3, wherein the particle 1 comprises a targeting moiety 5, shown here as an antibody, and wherein the radionuclide 6 is located in the pores 3.

[0067] The MOF particles of the present invention comprise at least one short-lived radionuclide. The term "radionuclide" as used herein, which may also be referred to as radioactive nuclide, radioisotope or radioactive isotope, is an atom that has an excess of nuclear energy, making it unstable. Generally, this excess energy can be used in one of three ways: emitted from the nucleus as a gamma ray; transferred to one of its electrons and released as a conversion electron; or used to create and emit a new particle (alpha or beta particle) from the nucleus. During these processes, the radionuclide is considered to undergo radioactive decay. The resulting nuclide is called the daughter or progeny. The radionuclides in the particles of the present invention are short-lived radionuclides, which are suitable for use as radioactive tracers, i.e., as imaging agents. In some embodiments, at least one radionuclide is a gamma-ray emitting radionuclide, or it is a positron-emitting radionuclide. A positron emitter interacts 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 present invention is a gamma emitter, where a gamma emitter as used herein may also include a positron emitter. Diagnostic radioisotopes must be able to emit gamma rays and contain sufficient energy to escape from the body. Ideally, the decay rate of the radioisotope must be completed quickly after imaging, i.e., it is short-lived. In one embodiment, the half-life of the radionuclide is from 0.5 hours to 60 days, such as from 5 hours to 60 days, such as from 1 to 20 days, such as from 1 to 5 days, such as from 3 to 5 days.

[0068] The at least one radionuclide is located in the pores, e.g., present in the pores, e.g., surrounded by the pores, and preferably coordinated and / or chelated with at least one free functional group extending into the pores.

[0069] Preferably, the radionuclide is a radionuclide cation. More preferably, the radionuclide is a radionuclide selected from the group consisting of: Ga-68, Ti-45, Tc-99m, Ba-133m, F-18, In-111, Ga-67, Zr-89, Ba-131, Yb-169 and Sc-43. In some embodiments, the radionuclide is selected from the group consisting of: Zr-89, F-18 and Ga-67. If F-18 is used, the isotope itself is not a cation, but can form part of a cationic complex, e.g., such as aluminum- 18 F] fluoride ( 18 F]AlF 2 + ) complex. Thus, radiolabeled AlF 2 +will bind to the MOF as a cation. If Tc-99m is used, the isotope itself is not readily available as a cation in aqueous solution but can form part of a cationic complex, such as [Tc(H 2 O) 3 (CO) 3 + .

[0070] Suitable radionuclides have relatively short half-lives, are compatible with imaging procedures and clinical administration, and thus have great diagnostic potential, which is described for each isotope below (see Table 1). The radionuclide cations listed above can bind strongly to the negatively charged chelating groups of the MOF, such that leakage of the radioisotope that would otherwise occur due to competition with salts and other components in the body can be restricted. Daughter isotopes of these radioisotopes can also be trapped and retained in these MOFs. The half-life of the radionuclide must be long enough to allow purification, transportation, drug synthesis, and administration before too much activity is lost. However, too long a half-life can result in a significant dose increase to achieve an effect. In such cases, the chemical toxicity and the risk of radioactive accumulation in tissues increase.

[0071] Table 1: List of examples of isotopes (radionuclides) that can be used in the particles of the present invention Symbol explanations: β+: β plus decay (emission of a positron), β-: β minus decay (emission of an electron), ε: electron capture (accompanied by emission of a related γ-ray), IT: isomeric transition (nuclear rearrangement accompanied by related γ emission), γ: γ emission.

[0072]

[0073] In 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, which are independently selected from the group consisting of the short-lived radionuclides listed above. If the particle comprises more than one radionuclide, the radionuclides will generally be located in separate pores, although two radionuclides may also be present in the same pore. It should be noted that in all embodiments, it is not possible to expect complete control over the number of radionuclides in each particle; during the chelation process in which the particle is contacted with a solution containing the radionuclide, a statistical distribution of the radionuclides in each particle will result.

[0074] ​The MOF of the present invention comprises a repeating three-dimensional network of inorganic and organic monomers, i.e., they are crystalline. The organization of the inorganic and organic monomers in the repeating three-dimensional network results in the formation of pores; i.e., the rigidity and fixed geometry of the inorganic and organic monomers result in a fixed spatial separation between certain monomers, thereby forming pores. Due to the free orientation of the free functional groups, the MOF having free functional groups can be regarded as having a certain degree of dynamic pore size. The pore size can be measured, for example, by an "inclusion sphere", i.e., the largest sphere that can be placed in the pore without the sphere touching the van der Waals surface of the MOF. The size of the pore opening, also known as the "window size", can be measured by a "diffusion sphere", i.e., the smallest sphere that can move through the structure. The MOF for use in the present invention advantageously has a pore size of 0.3 to 3 nm for the inclusion sphere, preferably 0.5 to 1.5 nm for the inclusion sphere. In addition, the MOF of the present invention has a pore window of a certain size to allow the adsorption of radionuclides, preferably a diffusion sphere with a diameter of at least . The pore size can be controlled by the size, structure, and bonding of the inorganic and organic monomers. The pores can be of any shape, including but not limited to tetrahedral, octahedral, and hexagonal.

[0075] Among the approximately 100,000+ reported MOF structures, only a limited selection is available for the present invention. Useful MOFs are naturally limited by the pore topology and the ability of the MOF to accommodate (or incorporate after synthesis on the linker or inorganic cluster) functional groups that point into the pores rather than bind to the inorganic monomers. The MOF pore topology must allow the diffusion of radioactive ions from the outside into the pores, and the pore size must allow the presence of functional groups and adsorbed radioactive cations. Examples of MOF structures that meet this description include the list of MOFs provided herein. The appropriate pore size and pore window size are as described above.

[0076] Since the radioactive cations will be adsorbed into the negatively charged pockets in the MOF, the above-mentioned functional groups should have a negative or partially negative charge in an aqueous environment at physiological pH. A list of such functional groups is described herein. In some cases, such functional groups are directly available after MOF synthesis, such as UiO-66-(COOH)2 and UiO-66-NH2, where the carboxylate / ester and amine groups point into the pores, respectively. In some cases, the functional groups are available through post-synthesis modification, such as in the case of ZIF-90, which contains aldehyde groups pointing to the appropriate pores and can be converted to ZIF-8-COOH by reaction with hydrogen peroxide. In other examples, the functional groups are incorporated onto the inorganic monomers, such as the introduction of free imidazolium / ester groups into MOF-808 by reaction with histidine.

[0077] In one embodiment, the particles contain a MOF based on Zr(IV), Hf(IV), Ce(IV), Fe(III), Al(III), Ti(IV), Cr(III) with carboxylate / ester organic monomers or a MOF based on Zn(II) imidazolate / ester, as these are known to be stable in aqueous media and can thus be particularly used in the present invention.

[0078] Some examples of preferred MOFs are: zirconium-based UiO-66, which contains terephthalate / ester (C 6 H 4 (COO) 2 2- ) organic monomers and the cationic hexanuclear zirconium oxide cluster Zr 6 O 4 (OH) 4 12+ as the inorganic monomer, with each carboxylate / ester group of the terephthalate / ester coordinating 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 Hf 6 O 4 (OH) 4 12+ and Ce 6 O 4 (OH) 4 12+ oxide cluster inorganic monomers and the terephthalate / ester organic monomers. Another example of a zirconium-based MOF is MOF-808, C24H16O32Zr6, which contains a benzene-1,3,5-tricarboxylic acid linker. UiO-66, Hf-UiO-66 and MOFs with the same topology (network geometry) (referred to as the fcu network topology) contain tetrahedral pores and octahedral pores, with a dynamic ratio of 2:1 between the former and the latter. Each tetrahedral pore contains four corners where three organic linkers "meet", i.e., extend into the same spatial volume, and each octahedral pore contains six corners where four organic linkers "meet". In the most stable conformation, the free functional groups point to the corners of the octahedral pores, but due to the dynamic rotation of the linker around its connecting axis and the steric repulsion between adjacent carboxylate / ester groups, the free functional groups can also often be directed into the tetrahedral pores.

[0079] Figure 2 shows a schematic diagram of a network structure with the fcu topology, where the inorganic monomers are shown as spheres with a cuboctahedral coordination geometry and the organic monomers are shown as bridging rods. The pores are shown in Figure 3 and Figure 3Shows the octahedral (O) and tetrahedral (T) pores in fcuMOF. The large transparent spheres show the size of each pore.

[0080] M(IV)-based MOFs with carboxylate / ester-based organic monomers where M = Zr and / or Hf, i.e., MOFs where the inorganic monomer is based on the metals Zr and / or Hf in their +4 (M(IV)) oxidation state, such as UiO-66, Hf-UiO-66, and their derivatives, may be particularly suitable for in vivo applications for several reasons: (1) the monomers may have a favorable low toxicity in vivo; (2) as shown in Experiments 2 and 3, due to the stability of the M(IV)-carboxylate / ester bond to hydrolysis, the MOF may exhibit excellent stability in aqueous solutions such as human serum; and (3) the M(IV) oxidation cluster inorganic monomers may have high connectivity, i.e., a large number of organic monomers are connected to it such that the free functional groups of several organic monomers can be spatially close to each other, which may allow for the formation of highly coordinated chelation sites near the cluster. Thus, the MOF particles of the present invention represent particularly stable and effective carriers for radionuclides, which may have an unusually high adsorption capacity, enabling specific imaging with negligible leakage to other organs.

[0081] It is expected that the mixed-metal and / or mixed-linker derivatives of UiO-66 may also exhibit favorable properties similar to those of UiO-66. Related mixed-metal derivatives include derivatives that contain two or more metals in the inorganic monomer, the metals being from the group consisting of or comprising Zr(IV), Ce(IV), and Hf(IV). Related mixed-linker derivatives include derivatives having monomers known to those skilled in the art to have a coordination geometry similar to that of terephthalate / ester, the monomers being, for example, selected from the group consisting of or comprising aminoterephthalate / ester, hydroxyterephthalate / ester, benzenehexacarboxylate / ester, mellitate / ester, sulfoterephthalate / ester, muconate / ester, and combinations thereof. Suitable mixed-linker MOFs can be obtained by synthesis (in the presence of multiple linkers) or by linker exchange, both of which are well known to those skilled in the art.

[0082] In addition, MOFs with inorganic monomers based on Fe(III), Al(III), Ti(IV) and / or Cr(III) can also be particularly used in the present invention. The organic monomers can be selected, for example, from the group consisting of or comprising: terephthalates, aminoterephthalates, hydroxyterephthalates, mellitates, hemimellitates, sulfoterephthalates, muciconates, and combinations thereof. Although the MOFs cannot form the same topology as UiO-66, they can form other interesting topologies that function in the same way.

[0083] The MOF of the present invention comprises at least one free functional group extending into the pores. Preferably, the MOF comprises a repeating three-dimensional network of inorganic and organic monomers forming the pores, and at least one free functional group extending into each pore, i.e., each pore has at least one free functional group extending therein. In some embodiments, only a certain amount of the pores have at least one free functional group extending therein, such as 50% of the pores, such as 80% of the pores, such as 95%, such as 100% of the pores.

[0084] As used herein, the term "extending into the pores" means that the functional group is directed, pointed to, and / or present in one of the pores formed by the repeating three-dimensional network of inorganic and organic monomers. Thus, the free functional group can be used to coordinate, bind, and / or react with compounds, ions, etc. within the pores. In particular, the functional group can be used to coordinate, complex, and / or bind to radionuclides, such as radionuclide cations.

[0085] The at least one free functional group is connected to the inorganic monomer and / or the organic monomer. When the at least one free functional group is connected to the organic 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 thereto. In other embodiments, a predetermined amount of the organic monomers each have at least one free functional group connected thereto. In some embodiments, each inorganic monomer of the MOF has at least one free functional group connected thereto. In other embodiments, a predetermined amount of the inorganic monomers each have at least one free functional group connected thereto.

[0086] The free functional group is preferably Lewis basic and is preferably selected from the group consisting of or comprising: carboxylic acids, carboxylates, hydroxyls, sulfonic acids, sulfonates, mercaptans, primary amines, secondary amines, and combinations thereof. The secondary amines are selected from the group consisting of or comprising amines having the general structure -NHR, where R is selected from the group consisting of or comprising: C with at least one Lewis basic functional group (such as carboxylic acids, carboxylates, hydroxyls, mercaptans, sulfonic acids, sulfonates, primary amines, secondary amines, and combinations thereof) 1-C 8 alkyl, alkenyl, and alkynyl, such as C having at least one Lewis basic functional group (such as carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof). 1 -C 4 linear and branched alkyl, alkenyl, and alkynyl. Such functionality can be obtained, for example, by performing peptide condensation of an N-protected natural amino acid with the free primary amino group of the organic monomer of the MOF.

[0087] One or more free functional groups can be advantageously selected based on the choice of radionuclide. For example, if the radionuclide is known to the person skilled in the art to be oxophilic or "hard" in the HSAB theory (hard and soft (Lewis) acids and bases), the pores can advantageously contain at least one oxygen-containing functional group, namely carboxylic acid, carboxylate / ester, hydroxyl, mercapto, sulfonic acid, and / or sulfonate / ester. Correspondingly, if the radionuclide is "soft" in the HSAB theory, the pores can advantageously contain at least one amino group.

[0088] Thus, in some embodiments, the MOF contains at least one free functional group selected from the group consisting of or comprising carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof. In other embodiments, the MOF contains at least one free functional group selected from the group consisting of or comprising carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, mercapto, sulfonate / ester, and combinations thereof. In still other embodiments, the MOF contains at least one free functional group selected from the group consisting of or comprising primary amine and secondary amine, and combinations thereof.

[0089] Preferably, the MOF contains from 1 to 4 free functional groups, such as 1 to 2 functional groups, such as at least three, such as at least four free functional groups. In some embodiments, the MOF contains at least two free functional groups, and the free functional groups are the same, 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 contains at least three free functional groups, and the free functional groups are the same, 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 contains at least four free functional groups, and the free functional groups are the same, or at least two, such as at least three, such as all of the free functional groups are different from each other.

[0090] The MOF can be selected such that when the MOF contains at 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 point to a common spatial volume, such as a common point or volume within the pore. The MOF can be selected such that when the MOF contains at 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 be oriented in such a way that in the presence of a radionuclide cation, favorable interaction with the radionuclide cation can occur, for example by alignment with the outer orbitals of the radionuclide cation. In some embodiments, the distance between each free functional group and at least one (e.g., all) of the other free functional groups extending into the same pore is from 4 to e.g., from 4 to e.g., from 5 to

[0091] In addition, the selection and placement of the at least one free functional group can be used to alter the geometry of the coordination (e.g., binding, e.g., chelating) sites in the pore. Such sites can be formed by the presence of one or more free functional groups, but can also be generated by the size and / or geometry of the pore. In some embodiments, such sites are defined as containing all free functional groups extending into the same pore. In some embodiments, such sites are defined as containing free functional groups extending into the same pore and having a maximum distance from at least one other free functional group in the same pore not exceeding e.g., In some embodiments, such sites are present at the corners of the pore. This arrangement can allow the site to be accessed only from one direction, thereby limiting competitive adsorption. In addition, when such sites are present at the corners of the pore, or are otherwise present inside the pore rather than at the opening of the pore, other compounds, such as other cations, such as competing cations, can be present in the pore and spatially prevent the radionuclide from leaving the pore. In principle, such sites present at the corners can be constructed in all MOFs that can contain free functional groups. Some examples include

[0092] MOF Cr-MIL-100, Fe-MIL-100, and 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.

[0093] Figures 4 to 7 Some examples of coordination, binding, and / or chelating sites are shown. Figure 4Shows an example of a coordination, binding, and / or chelating site provided by three free carboxylate / ester groups led into the pores at the tetrahedral cage corners. Figure 5 Shows an example of such a site provided by four free carboxylate / ester groups led into the pores at the octahedral pore corners. Figure 6 Shows such a site provided by two free carboxylate / ester groups and two free amido groups led into the pores at the octahedral pore corners. The latter can be obtained, for example, by post-synthetic peptide condensation on the free primary amino group. Post-synthetic modification is discussed below. Figure 7 Shows such a site provided by two free carboxylate / ester groups and two free amido groups led into the octahedral cage corners, where one of the amido groups bears a DOTA chelator. Figure 8 Shows a pore into which several free functional groups extend.

[0094] Furthermore, at least one functional group led into the pores can be used to change the charge balance of the pores and / or the charge balance of the coordination (e.g., binding, e.g., chelating) sites in the pores. Advantageously, the MOFs of the present invention contain free functional groups or combinations of functional groups, which result in a net negative charge in the pores. This net negative charge can contribute to the strong selective adsorption of cations.

[0095] Introducing substituents on the benzene rings of the terephthalate / ester monomers of UiO-66 and UiO-66-type MOFs makes it easy to obtain crystalline MOFs containing at least one free functional group extending into the pores, where the at least one free functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof. For example, UiO-66-COOH, UiO-66-(COOH) 2 and UiO-66-NH 2 All are commercially available. UiO-66-COOH, UiO-66-(COOH) 2 , Hf-UiO-66-COOH and Hf-UiO-66-(COOH) 2 Represent preferred MOFs that have 6 to 12 free carboxylic acid functional groups extending into their pores, where three or four free functional groups form coordination sites in the pores and can thus chelate radionuclide cations in an effective and / or stable manner.

[0096] There are two main methods for so-called pore engineering (i.e., introducing free functional groups that extend into the pores). The synthesis of MOFs uses: "pre-integrated organic monomers" in which two different coordination sites coexist for framework construction and other purposes; and "post-synthesis modification", such as sequentially linking additional functional groups onto a pre-constructed MOF. The free functional groups in MOFs can be modified by chemical reactions, popularly known as "post-synthesis modification". In principle, all chemical reactions that can be carried out by standard wet chemical methods can also be carried out on the same functional groups in MOFs. For example, amino acids can react with the free primary amine groups in MOFs through peptide condensation reactions. Using this method, molecules with specific properties can be grafted onto MOFs, for example, into the pores of MOFs. Thus, MOFs with specific structures and specific free functional groups can be obtained by designing and synthesizing new MOFs and by modifying existing MOFs. Thus, derivatives of various MOFs with the UiO-66 structure, as well as derivatives of MOFs with other structures and containing multiple free functional groups, can be readily obtained. In some embodiments, at least one radionuclide chelator known to those skilled in the art, such as EDTA, such as DOTA, is grafted onto a group that extends into the pores such that at least one free functional group is a known chelator.

[0097] In addition, most MOFs can tolerate a certain proportion of linker vacancy defects, i.e., sites where the organic linker is missing in the structure, leaving coordination unsaturated sites on adjacent inorganic monomers. These unsaturated sites can be modified with coordinating molecules, such as molecules that can coordinate the inorganic monomers with at least one functional group and have a free functional group for extending into the pores, such as amino acids, which can contribute to the functional properties of the MOF.

[0098] Preferably, the MOF of the present invention comprises a repeating three-dimensional network of inorganic and organic monomers that form pores, and at least one free carboxylic acid or carboxylate / ester functional group that extends into each pore.

[0099] Figure 9 、 10 And 11 shows a schematic diagram of a preferred MOF. Figure 9 And 10 Shows a partial crystal structure of terephthalate / ester MOFs based on M(IV) and M(III). Figure 9 Shows UiO-66 (organic monomers are shown as rods, with each C / O atom at a corner, and inorganic monomers are shown as polyhedra). Figure 10 Shows MIL-53, where in addition to lines and polyhedra, the available pore space is shown by large spheres.

[0100] Figure 9 And 10The preferred MOFs shown may have M(IV) inorganic monomers. Suitable organic monomers are shown below (Structures I, II, III, IV, V, and VI):

[0101]

[0102] Structure I represents a terephthalic acid / terephthalate / ester organic monomer, which can form MOFs with inorganic monomers based on M(III) and M(IV) through metal-carboxylate / ester bonds. R 11 、R 12 、R 13 and R 14 may each independently be selected from the group consisting of or comprising: hydrogen, carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, and secondary amine, i.e., each R group can be hydrogen or a free functional group.

[0103] Structure II represents a biphenyl-4,4'-dicarboxylic acid organic monomer, which can form MOFs with inorganic monomers based on M(III) and M(IV) through metal-carboxylate / ester bonds. R 21 、R 22 、R 23 、R 24 、R 25 、R 26 、R 27 and R 28 may each independently be selected from the group consisting of or comprising: hydrogen, carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, and secondary amine, i.e., each R group can be hydrogen or a free functional group.

[0104] Structure III represents a trimesic acid (1,3,5-benzenetricarboxylic acid) organic monomer, which can form MOFs with inorganic monomers based on M(III) and M(IV) through metal-carboxylate / ester bonds. R 31 、R 32 and R 33 may each independently be selected from the group consisting of or comprising: hydrogen, carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, and secondary amine, i.e., each R group can be hydrogen or a free functional group.

[0105] Structure IV represents an adipic acid organic monomer, which can form MOFs with inorganic monomers based on M(III) and M(IV) through metal-carboxylate / ester bonds. R 41 、R 42 、R 43 and R 44may each independently be selected from the group consisting of or comprising: hydrogen, carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, and secondary amine, i.e., each R group may be hydrogen or a free functional group.

[0106] Structure V represents a 1,4-cyclohexanedicarboxylic acid organic monomer, which can form a MOF with M(III)- and M(IV)-based inorganic monomers through metal-carboxylate / ester bonds. R 61 , R 62 , R 63 , R 64 , R 65 , R 66 , R 67 , R 68 , R 69 and R 70 may each independently be selected from the group consisting of or comprising: hydrogen, carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, and secondary amine, i.e., each R group may be hydrogen or a free functional group.

[0107] Structure VI represents a naphthyl organic monomer, which can form a MOF with M(III)- and M(IV)-based inorganic monomers through metal-carboxylate / ester bonds. R 71 , R 72 , R 73 , R 74 , R 75 and R 76 may each independently be selected from the group consisting of or comprising: hydrogen, carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, and secondary amine, i.e., each R group may be hydrogen or a free functional group.

[0108] In each of Structures I to VI, the secondary amine may be selected from the group consisting of or comprising amines having the general structure -NHR, where R is selected from the group consisting of or comprising: C 1 -C 8 alkyl, alkenyl, and alkynyl having at least one Lewis basic functional group (such as carboxylic acid, carboxylate / ester, hydroxyl, mercapto, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof), e.g., C 1 -C 4 linear and branched alkyl, alkenyl, and alkynyl.

[0109] Figure 11 Shows a MOF having a zeolitic imidazolate / ester framework and the so-called sod topology. The organic monomers are shown as balls and sticks for representing atoms and bonds, and the Zn atoms are shown as tetrahedra.

[0110] Figure 11 The preferred MOFs shown may have M(II) inorganic monomers. Suitable organic monomers are shown below (Structure VII):

[0111]

[0112] Structure VII represents an imidazole organic monomer, which can form a MOF (also known as ZIF) with the M(II)-based inorganic monomer through a metal-imide bond. R 51 、R 52 and R 53 may each independently be selected from the group consisting of or comprising hydrogen, carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, and secondary amine, i.e., each R group can be hydrogen or a free functional group. The secondary amine can be selected from the group consisting of or comprising amines having the general structure -NHR, where R is selected from the group consisting of or comprising C 1 -C 8 alkyl, alkenyl, and alkynyl groups having at least one Lewis basic functional group (such as carboxylic acid, carboxylate / ester, hydroxyl, mercapto, sulfonic acid, sulfonate / ester, primary amine, secondary amine, and combinations thereof), e.g., C 1 -C 4 linear and branched alkyl, alkenyl, and alkynyl groups.

[0113] In the present invention disclosed herein, the MOF exists in the form of particles (such as microparticles or nanoparticles). Preferably, the particles are nanoparticles. The term "nanoparticle" as used herein refers to any particle having a diameter less than 1000 nm, e.g., a particle having a diameter of 1 to 1000 nm. Similarly, the term "nanoparticle" refers to a variety of particles having an average diameter of about 1 to 1000 nm. Referring to the "size" of a nanoparticle refers to the length of the maximum linear dimension of the nanoparticle. For example, the size of a perfectly spherical nanoparticle is its diameter. This size can refer, for example, to the hydrodynamic radius of the particle characterized by dynamic light scattering. In some embodiments, the particle size of the nanoparticles of the present invention is 1 to 200 nm. Accordingly, the term "microparticle" refers to any particle having a diameter less than 1000 μm, e.g., a particle having a diameter of 1 to 1000 μm.

[0114] It has been found that microparticles and nanoparticles have some uses in radiopharmaceuticals. In both the sense that the particles themselves should be completely stable or slowly degrade in order to reduce the risk of systemic toxicity and in the sense that the radionuclide should be strongly bound to the particles to avoid radionuclide leakage, an important factor when such particles are to be used is their stability. As the inventors have found and illustrated in Examples 2 and 3, the MOFs of the present invention are very stable. In addition, the presence of free functional groups, as well as the confinement effect of the pores themselves, ensures strong chelation of the radionuclide to the particles, as illustrated in Example 7. The choice of free functional groups can also lead to a high level of selectivity, for example because cations are preferably chelated rather than anions, and / or hard ions rather than soft ions. Thus, the present invention provides a particularly stable carrier for radionuclides to be used as imaging agents.

[0115] The MOF particles throughout the present invention have 10^3 to 10^5 pores and are capable of trapping radionuclide cations in a portion of them (i.e., the portion accessible from the outside of the particle). If a radionuclide cation is released from one pore, it can be trapped by an adjacent pore, preventing leakage from the particle. This ability to "re-adsorb" the desorbed radionuclide cations indicates that the MOF particles of the present invention can retain radionuclide cations more effectively compared to conventional chelating agents. In addition, the number of cations per particle can be adjusted, thereby adjusting the radioactivity level of the particle.

[0116] Due to the presence of pores with suitable diffusion spheres and free functional groups extending into the pores, if the particles according to the present invention are exposed to a solution containing radionuclide cations, these cations will readily adsorb and chelate in the pores. Another advantage of using the MOF particles according to the present invention is that any competing substances, such as any other cations present in the solution, can occupy the empty pores rather than displacing the radionuclide cations.

[0117] When used for imaging, the signal-to-noise ratio of the particles of the present invention greatly exceeds that of conventional molecular contrast agents limited to one or a few γ emitters. The particle has a high density of strong binding sites compatible with a wide range of α, β, and γ emitters and can be highly loaded with radioactive tracers. For use in therapy, the MOF (e.g., the MOF for imaging disclosed herein) can be loaded with α- or β-emitters (as "MOF-drugs"), and for use in imaging, the MOF can be loaded with γ-emitters or positron emitters (as "MOF-radiotracers"). The general loading concept and process enable the use of a single particle platform for both imaging and therapy, eliminating the need to develop separate particles for each purpose. Thus, it has been found that the MOFs disclosed herein can be used as carriers for radionuclides for either therapy or imaging.

[0118] In contrast to traditional molecular chelator approaches, the nanoparticle approach offers several key advantages. (1) Each particle can be loaded with a desired number of radioisotopes, which allows for flexible radiation density / dose. (2) Its outer surface can be functionalized with a variety of targeting antibodies, which provides flexibility in terms of affinity and opens up the possibility of using different antibodies on the same particle to ensure multispecificity. (3) The radioisotopes occupy a negligibly small number of uniformly binding pores in the particle. Thus, it accepts cations from its environment without competitive desorption of the radioisotopes, and if a radioisotope detaches from its binding site, it is likely to be recaptured by neighboring pores. (4) The lattice structure of the particle provides a barrier that inhibits the release of daughter isotopes into the environment ( Figure 1 ).

[0119] Accordingly, the applicant plans to use the same MOF carrier for different types of radioisotopes, for imaging and therapy respectively, which will ensure the same biodistribution of the imaging agent (e.g., containing a γ emitter) and the therapeutic agent (e.g., containing radium-223). This method allows for pre-treatment screening of patients with the MOF-radiotracer according to the present invention to predict the response to subsequent treatment with the MOF-drug, and / or to prevent unnecessary treatment of non-responders. The main challenge of targeted radiotherapy, such as RIT, is to achieve an ideal biodistribution with co-localization of the drug and the tumor, ensuring specific radiation of cancer cells. Each patient and cancer is unique, and although there are common disease characteristics, the same approach may not necessarily be applicable for treatment. Using the particles and methods of the present invention, including using the MOF-radiotracer as an imaging agent in pre-screening of subjects, is expected to improve the selection of subjects who will respond to treatment with the MOF-drug. Patients who do not meet the set selection criteria during diagnostic screening will not undergo treatment, which otherwise may lead to unnecessary side effects and loss of access to alternative treatment options. Patients who pass the selection criteria may receive treatment including treatment with an α emitter, i.e., treatment with the MOF-drug, and may respond well to the treatment. The selection criteria may be based, for example, on sufficient co-localization of the MOF-radiotracer and the tumor, predicting irradiation of cancer cells or cancer-supporting cells with the therapeutic MOF.

[0120] The MOF and its particles of the present invention can be obtained by any means known to those skilled in the art, such as commercially available, for example, synthesized using any synthetic protocol available to those skilled in the art.

[0121] In some embodiments, the particles of the present invention comprise at least one targeting moiety attached to the particle on the outer surface of the particle. As used herein, the term "outer surface" with respect to a particle refers to the surface on its exterior, as opposed to the surface of the pores within the particle. In the case where pores penetrate the particle and are visible therein, the outer surface is defined to include all surfaces at the outermost part of the particle, but not including the surfaces defining the pores.

[0122] As used herein, the term "targeting moiety" refers to a "tissue-targeting" moiety, such as a molecule, such as a part of a molecule, which is used to preferentially localize itself and any part connected thereto, such as a particle, to at least one tissue site where its presence is desired, for example, to deliver radioactive decay. The term "targeting moiety" can also refer to a functional group used to target or direct a particle to a specific location, cell type, diseased tissue, or conjugate. For example, a targeting moiety can be a moiety known to those skilled in the art to bind or complex with a biomarker, such as a cell surface marker, such as a receptor, transporter, cell adhesion molecule, present on a cell affected by a disease or on a cell near such a cell. Such cell surface markers include, but are not limited to, proteins that are expressed more on the surface of diseased cells than on the surface of healthy cells, or proteins that are expressed more on the surface of cells during cell growth or replication than on the surface of cells in a dormant phase. According to any aspect of the present invention, a component present near or associated with a target cell or tissue can also be used at the target for treatment. For example, if the presence, form, or concentration of a component present in or released into the matrix surrounding a target cell or tissue allows the region to be distinguished from healthy tissue, the component can be used for targeting.

[0123] Some non-limiting examples of targeting moieties include:

[0124] - Small molecule targeting moieties, such as folic acid; folates; carbohydrates; monosaccharides, such as glucose, mannose, galactose; urea derivatives; lipids; streptavidin; albumin; biotin; steroid and non-steroid hormones;

[0125] - Aptamers, which are single-stranded oligonucleotides that recognize the specific binding domain of a receptor;

[0126] - Macromolecules, such as biopolymers, such as antibodies; peptides, such as peptidomimetics, such as phage display peptides; proteins; nucleic acids; and

[0127] - Cells, such as natural cells, such as genetically engineered cells.

[0128] Preferred targeting moieties include antibodies, antibody fragments, antibody constructs, constructs of antibody fragments, microantibodies, nanobodies, intrabodies, unibodies, affibodies, and diabodies. As used herein, the term "antibody" refers to immunoglobulins, derivatives thereof that retain the ability to specifically bind, and proteins having binding domains that are homologous or substantially homologous to immunoglobulin binding domains. These proteins can be derived from natural sources or produced in part or in whole synthetically. The term "antibody" encompasses, for example, monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and / or chimeric antibodies. Antibodies can be members of any immunoglobulin class, including any one of the human classes: IgG, IgM, IgA, IgD, and IgE. Some examples of useful antibodies are conventional full-length antibodies (e.g., IgG) and camelid heavy-chain antibodies (VHH).

[0129] As used herein, the term "antibody fragment" refers to any derivative of an antibody that is less than full-length. In some exemplary embodiments, the antibody fragment retains at least most of the specific binding ability of the full-length antibody. Some examples of antibody fragments include, but are not limited to, Fab, Fab’, F(ab’) 2 , scFv, Fv, dsFv diabodies, and Fd fragments.

[0130] In some embodiments, the targeting moiety is one of two or more components that together serve to target the particles of the present invention to the desired tissue. This can be, for example, where one component binds to a specific tissue, tumor, or cell type (tissue binder), and the second or another component (targeting moiety) binds to the tissue binder. Suitable specific binding pairs for providing tissue binders and targeting moieties with mutual affinity are known in the art (e.g., biotin and avidin or streptavidin).

[0131] The targeting moiety can be obtained in any manner known to the person skilled in the art, for example commercially, or synthesized using any synthetic protocol available to the person skilled in the art (e.g., enzymatically produced, synthetically produced, and / or chemically produced).

[0132] In some embodiments, the particle contains only one targeting moiety. In other embodiments, the particle contains two or more targeting moieties, for example five, for example ten targeting moieties. The number of targeting moieties can be selected based on the size of the particle. The targeting moieties can be the same or different from each other. The mass ratio of the targeting moiety to the particle can depend on the molecular weight of the targeting moiety and the diameter of the particle.

[0133] Since it is possible to target more than one antigen, using two or more different targeting moieties can have the advantage of improving binding to tissues or cells expressing an antigen profile associated with the target (e.g., M2 tumor-associated macrophages expressing CD163 and CD206). Additional advantages can be the ability to target blood vessels (e.g., VCAM1) and tumor-specific antigens that accumulate at the tumor site.

[0134] At least one targeting moiety can be directly attached to the particle, for example, via a covalent bond, or at least one targeting moiety can be attached to the particle via a linker group. The targeting moiety can also be attached to a particle covalently conjugated to streptavidin, which strongly binds biotin / biotin derivatives. Then, streptavidin can function as both a linker and a binding moiety for biotinylated moieties. Thus, streptavidin-conjugated particles can bind to one or more biotinylated targeting moieties. Methods for attaching targeting moieties to surfaces are well known in the art; standard organic and / or inorganic chemistries can be used, such as carbodiimide coupling. Suitable linker groups can be readily determined by those skilled in the art; for example, a series of linker groups are known from the field of antibody-drug conjugates. Some non-limiting examples of linker groups include poly(ethylene glycol) (PEG), 2-(maleimidomethyl)-1,3-di ane (MD), and maleimidocaproyl succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC). The outer surface of the MOF particle can contain the same organic functional groups as the interior of the pores, which can undergo the same reactions. However, to perform reactions on the outer surface rather than in the pores, size discrimination can be used, which involves using reagents that are sterically prohibited from entering the MOF pores, thereby enabling the targeting moiety to selectively attach to the outer surface of the particle.

[0135] At least one targeting moiety can be a targeting moiety for targeting cells affected by a proliferative disease, such as tumor cells, cancer cells, cells affected by a hyperplastic disease, cells affected by a neoplastic disease. In some preferred embodiments, the targeting moiety is a targeting moiety for targeting cancer cells. As used herein, the terms "cancer cells" and "tumor cells" refer to cells that divide at an abnormal, elevated rate. Cancer cells include, but are not limited to, epithelial carcinomas such as squamous cell carcinoma, non-small cell carcinoma (e.g., non-small cell lung cancer), small cell carcinoma (e.g., small cell lung cancer), basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchogenic carcinoma, melanoma, renal cell carcinoma, liver cancer - hepatocellular carcinoma, cholangiocarcinoma, cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, breast cancer, gastrointestinal cancer, colon cancer, bladder cancer, prostate cancer, and squamous cell carcinoma of the neck and head region; sarcomas such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synovial sarcoma, and mesothelioma; hematological cancers such as myeloma, leukemia (e.g., acute myelocytic leukemia, chronic lymphocytic leukemia, granulocytic leukemia, monocytic leukemia, lymphocytic leukemia), lymphoma (e.g., follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, malignant lymphoma, plasmacytoma, reticulosarcoma, or Hodgkin's disease), and tumors of the nervous system, including glioma, glioblastoma multiforme, meningioma, medulloblastoma, schwannoma, and ependymoma. Those skilled in the art are aware of targeting moieties that can be used to target specific types of cells (especially cancer cells) affected by a proliferative disease.

[0136] In another embodiment, the particles of the present invention do not contain a targeting moiety. Whether the drug is administered to a human body via the oral, intravenous, or parenteral route, they will be metabolized by the hepatic portal system (liver), which is the site of most metabolism, and the delivered substance will be degraded by metabolic enzymes for easy removal from the body. Thus, the particles of the present invention that do not contain a targeting moiety will be transported to the liver after being administered to a subject and can be very suitable for imaging of the liver. In addition, the natural biodistribution of the particles can also be used to obtain a radioisotope at a given site and radiate the tissue in situ.

[0137] The particles disclosed herein are such particles that comprise a MOF, wherein the MOF comprises a repeating three-dimensional network of inorganic and organic monomers that form pores, and at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof; wherein the particles optionally further comprise at least one targeting moiety that is attached to the particles on the outer surface thereof; and at least one radionuclide, wherein the at least one radionuclide is selected from the disclosed short-lived radionuclides, and wherein the at least one radionuclide is located in at least one of the pores; and may have at least the following advantages compared to the prior art:

[0138] -(a) Compared with existing small molecule chelating agents, the MOF particles contain many chelation sites, which can enable dose control by loading the particles with a predetermined number of radionuclides.

[0139] -(b) The network structure of the MOF can actively affect the ability of the particles to contain radioactive substances, for example, through the following mechanisms:

[0140] -(1) Compared with the molecular chelating agents of the prior art, the MOF is capable of accommodating daughter isotopes that appear through the decay chain of radionuclides by physical adsorption, so as to keep the daughters also close to tumor cells.

[0141] -(2) Compared with the molecular chelating agents of the prior art, the radionuclides adsorbed in the MOF may be less likely to be competitively adsorbed by other ions, because these can be adsorbed by the empty pores, and

[0142] -(3) The desorbed radionuclides can be re-adsorbed by adjacent empty pores.

[0143] Generally speaking, the present invention can thus provide an improved imaging method.

[0144] Regarding (b)(2), competitive adsorption can be relevant not only during the preparation and storage of the particles and during the adsorption of radionuclide cations, but also when the particles are used as imaging agents.

[0145] The particles of the present invention may also comprise one or more molecules for modifying the outer surface of the particles. Such one or more molecules may be attached to the particles on the outer surface thereof, for example covalently bound thereto, for example coordinated thereto. Similarly, size discrimination may be used in order to react on the outer surface rather than in the pores. For example, the outer surface of a MOF containing free carboxyl or amino groups may be functionalized with one or more compounds selected from the group consisting of or comprising: PEG derivatives, N-hydroxysuccinimide (NHS), N-hydroxysulfosuccinimide (sulfo-NHS), MD linker, Mal-PAB, albumin. Albumin can be used to prevent aggregation and increase the blood half-life of the particles.

[0146] The particles of the present invention may also comprise one or more additional compounds, such as molecules, such as ions, which are located in at least one pore. Some non-limiting examples include buffers and / or specific ions, such as ions for restricting radionuclide leakage by steric blockade.

[0147] MOF particles are generally produced by hydrothermal synthesis at 20 °C to 100 °C, wherein a solution of a suitable inorganic precursor of an inorganic monomer is mixed with a solution of an organic monomer. In some cases, the organic monomer is directly dissolved in the solution of the inorganic precursor, or vice versa. In some cases, a growth control factor (also referred to as a growth regulator) is added to affect the particle growth rate. As the structure forms, the MOF particles precipitate out of the solution. Published procedures for producing MOF may be followed.

[0148] The targeting moiety may be attached, linked, bound (generally referred to as conjugated) to the MOF particles directly or via a linker. For example: carboxyl MOF can be conjugated to an amino group (present on the target unit) via carbodiimide (EDC, NHS / sulfo-NHS)-based crosslinking.

[0149] Radioactive labeling may be carried out by uniformly mixing a solution or suspension of a radionuclide cation with a suspension of the particles for > 1 minute, and subsequently separating the labeled particles from the remaining unbound radionuclide cation, for example by centrifugation or column purification. If the targeting moiety is present on the particles prior to performing the radioactive labeling, the radioactive labeling process may be more convenient, for example in terms of the time taken, product purification, etc.

[0150] Thus, the particles of the present invention may be prepared by: providing particles comprising a MOF, such as nanoparticles,

[0151] wherein the MOF comprises:

[0152] - A repeating three-dimensional network of inorganic and organic monomers that form pores, and

[0153] - At least one free functional group that extends into the pores, where the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof,

[0154] wherein the particles optionally comprise:

[0155] - Optionally, at least one targeting moiety that is attached to the particle on the outer surface of the particle;

[0156] and contacting the particles with a short-lived radionuclide.

[0157] The radionuclide cation can be present, for example, in a composition containing a liquid.

[0158] In another aspect, the present invention relates to a kit that contains in a first container:

[0159] Particles that comprise:

[0160] - A MOF, where the MOF comprises:

[0161] - A repeating three-dimensional network of inorganic and organic monomers that form pores, and

[0162] - At least one free functional group that extends into the pores, where the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof;

[0163] - Optionally, at least one targeting moiety that is attached to the particle on the outer surface of the particle; and

[0164] and contains a short-lived radionuclide in a second container.

[0165] Suitable radionuclides for this aspect are as disclosed in the first aspect.

[0166] Those skilled in the art will understand that the first and second containers can also contain a liquid, such as a solvent for dissolving or suspending any component, and additional components, such as at least one carrier, diluent, and / or excipient.

[0167] Particles of the invention comprising at least one short-lived radionuclide are used in suitable imaging modalities, such as scintigraphy or positron emission tomography (PET). Scintigraphy and PET imaging with a suitable radiotracer enable functional or molecule-based imaging of diseases. Such imaging can provide information on tumor metabolism, indicating which tumors are metabolically active and malignant, or indicating which tumors have recurred. 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 particles comprising MOFs loaded with short-lived radionuclides provides an assessment of metabolic function, and this can be combined with other imaging modalities (such as x-ray, MR, or ultrasound), for example, to image the pathology.

[0168] The particles disclosed herein can be present as an active ingredient in a desired dosage unit formulation, such as a pharmaceutical composition containing a conventional pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" as used herein means that the compound must be physiologically acceptable to the recipient and, if part of a composition, compatible with the other components of the composition. The term "composition" refers to a mixture of one or more compounds according to the invention with one or more additional chemical components in any formulation.

[0169] Thus, in another aspect, the invention relates to a composition comprising at least one particle and at least one pharmaceutically acceptable carrier, diluent, and / or excipient, wherein at least one particle comprises an MOF,

[0170] wherein the MOF comprises:

[0171] - a repeating three-dimensional network of inorganic and organic monomers forming pores, and

[0172] - at least one free functional group extending into the pores, wherein the functional group is selected from the group comprising: carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof,

[0173] wherein the particle comprises:

[0174] - optionally at least one targeting moiety attached to the particle on the outer surface of the particle, and

[0175] - at least one short-lived radionuclide,

[0176] and wherein at least one radionuclide is located in at least one pore.

[0177] The particles are defined as disclosed above. They can be microparticles or nanoparticles. Preferably, the particles are nanoparticles.

[0178] The composition can be considered a pharmaceutical contrast agent composition since it contains an active agent, i.e., particles, in combination with at least one pharmaceutically acceptable carrier, diluent, and / or excipient, and thus renders the composition particularly suitable for diagnostic use, e.g., during imaging procedures.

[0179] The composition preferably contains a large number of the particles of the present invention. The particles can be the same or different, i.e., with respect to the type and number of radionuclides and / or targeting moieties. In some embodiments, the composition is a particulate suspension comprising monodisperse or polydisperse particles labeled with a radionuclide cation.

[0180] The composition may further contain one or more of any conventional pharmaceutically acceptable excipients and / or carriers such as: solvents, fillers, diluents, binders, lubricants, glidants, viscosity modifiers, surfactants, dispersants, disintegrants, emulsifiers, wetting agents, suspending agents, thickening agents, buffers, pH regulators, absorption retardants, stabilizers, antioxidants, preservatives, antimicrobial agents, antibacterial agents, antifungal agents, chelating agents, adjuvants, sweeteners, flavoring agents, and coloring agents. Conventional formulation techniques known in the art, such as conventional mixing, dissolving, suspending, granulating, drageemaking, milling, emulsifying, encapsulating, entrapping, or tabletting processes can be used to prepare the composition.

[0181] In some embodiments, the composition is formulated for a particular method of administration to a subject.

[0182] The amount of the particles according to the present invention present in the composition can vary. In some embodiments, the amount of the particles according to the present invention present in the composition is from 0.1% to 50% by weight, such as 1% to 30% by weight, such as 50% to 20% by weight. In other embodiments, the amount of the particles according to the present invention present in the composition is from 30% to 70% by weight, such as 40% to 60% by weight. In yet other embodiments, the amount of the particles according to the present invention present in the composition is from 50% to 100% by weight, such as 50% to 70% by weight, such as 50% to 80% by weight, such as 60% to 98% by weight, such as 70% to 95% by weight.

[0183] The composition may also comprise MOF particles that do not contain a radionuclide cation, such as particles comprising a MOF, wherein the MOF comprises a repeating three-dimensional network of inorganic monomers and organic monomers that form pores, and at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof, wherein the particles comprise at least one targeting moiety that is attached to the particle on the outer surface of the particle. Such particles may be the same as the particles of the present invention except for the absence of a radionuclide cation, or they may be different. The ratio of particles containing a radionuclide cation to particles not containing a radionuclide cation may vary. In some preferred embodiments, at least 90% of the particles contain a radionuclide cation. The activity per mg of particles is typically from 10 kBq to about 900,000 MBq, such as 100 kBq to 900,000 MBq, or 100 kBq to 1000 MBq. Using zirconium-89 as an example (specifically 831,450 MBq), this corresponds to a mass ratio of up to 5% (percentage of the radioisotope of each MOF).

[0184] In addition, the composition is substantially free of contaminants or impurities. In some embodiments, the level of contaminants or impurities in the composition other than residual solvents is less than about 5% relative to the total weight of the particles according to the present invention and the other expected components. In certain embodiments, the level of contaminants or impurities in the composition other than residual solvents does not exceed about 2% or 1% relative to the total weight of the particles according to the present invention and the other expected components.

[0185] In certain embodiments, the particles or composition according to the present invention are sterile. Sterilization can be achieved by any suitable method (including but not limited to by applying heat, chemicals, irradiation, high pressure, filtration, or combinations thereof).

[0186] The particles of the present invention can be included in a composition and used as a contrast agent. Thus, in another aspect, the present invention relates to particles comprising:

[0187] - a MOF, wherein the MOF comprises:

[0188] - a repeating three-dimensional network of inorganic monomers and organic monomers that form pores, and

[0189] - at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof; and

[0190] - optionally at least one targeting moiety that is attached to the particle on the outer surface of the particle; and

[0191] - at least one short-lived radioactive nuclide;

[0192] and wherein at least one of the radioactive nuclides is located in at least one pore;

[0193] or relates to a composition comprising the particles and at least one pharmaceutically acceptable carrier, diluent, and / or excipient;

[0194] The particle or the composition is used as a contrast agent.

[0195] The particles of the present invention and the composition comprising the particles can be used for diagnosis, for example, for targeted delivery of radioactive decay to one or more specific sites in the body, such as specific cells, tissues, organs, etc. The targeting moiety targets the particles to a specific site where radioactive decay (e.g., emission of gamma rays) is desired to occur, and the MOF acts as a chelating agent with the advantageous properties discussed above. When the particles do not contain a targeting moiety, according to the biodistribution characteristics of the nanoparticles, the particles will be transported to other organs, such as the liver, where the radioactivity will decay. Thus, in one embodiment, the particles can be used diagnostically for indications of natural nanoparticle transport, particularly liver cancer.

[0196] For the various aspects of the present invention related to use as an imaging agent and / or imaging or diagnosis of diseases, particularly for selective targeting of diseased tissue, in all embodiments, the diseased tissue can be located at a single site in the body (e.g., in the case of a local solid tumor), or can be located at multiple sites (e.g., in the case of a disseminated or metastatic cancerous disease).

[0197] The particles and compositions of the present invention can be particularly used for imaging procedures, for diagnostic procedures, and particularly for imaging of proliferative diseases. Thus, in another aspect, the present invention relates to particles comprising:

[0198] - a MOF, wherein the MOF comprises:

[0199] - a repeating three-dimensional network of inorganic and organic monomers forming pores, and

[0200] - at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof;

[0201] - optionally at least one targeting moiety, which is attached to the particle on the outer surface of the particle; and

[0202] - at least one short-lived radioactive nuclide;

[0203] and wherein at least one of the radioactive nuclides is located in at least one pore;

[0204] or relates to a composition comprising the particles and at least one pharmaceutically acceptable carrier, diluent, and / or excipient;

[0205] The particles or the composition are for use in a diagnostic method.

[0206] In particular, in one embodiment, the particles or a composition comprising the particles are for use in a method of diagnosing a proliferative disease in a subject. Such a diagnostic method may include imaging screening and biodistribution control. In particular, the diagnostic method includes the step of assessing information regarding the biodistribution and uptake of the MOF in relevant tissues (especially proliferative tissues) of the subject. The method can provide powerful insights into the distribution, binding, and other biological effects of the particles comprising the MOF. The method allows the use of the particles according to the invention as imaging agents for pre-treatment screening of a subject to predict response to subsequent treatment (such as the use of MOF-drugs), and / or to prevent unnecessary treatment of non-responders.

[0207] In one embodiment, the diagnostic method is followed by a subsequent treatment step with particles comprising the same MOF as used in the diagnosis but carrying a therapeutic radionuclide. Thus, after the diagnostic method, a subsequent treatment can be carried out with particles comprising

[0208] - an MOF, wherein the MOF comprises:

[0209] - a repeating three-dimensional network of inorganic and organic monomers forming pores, and

[0210] - at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof;

[0211] - optionally at least one targeting moiety attached to the particle on the outer surface of the particle; and

[0212] - at least one radionuclide, wherein the at least one radionuclide is selected from the group consisting of radium-223, radium-224, radium-225, bismuth-212, bismuth-213, lead-212, actinium-225, thorium-227, terbium-149, and terbium-161;

[0213] and wherein the at least one radionuclide is located in at least one of the pores.

[0214] Thus, the diagnostic method using the MOF-radiotracer is followed by treatment with the MOF-drug. In the two steps, the carrier MOF is preferably the same, while the carried nucleotides are different and are a gamma-emitter or a positron emitter and an alpha-emitter, respectively.

[0215] Particles are defined as disclosed herein and can be nanoparticles or microparticles, preferably nanoparticles.

[0216] As used herein, the term "administer" and variations thereof refer to (1) providing, giving, dosing, and / or prescribing a formulation, composition, or combination according to the present disclosure by a health practitioner or their authorized agent or under their direction, or by self-administration, and (2) the intake, consumption, or ingestion of a formulation, composition, or combination according to the present disclosure by the subject itself.

[0217] As used herein, "subject" means any human or non-human animal selected for treatment or therapy, and encompasses and may be limited to "patient". Neither of these terms should be construed as requiring the supervision (ongoing or otherwise) of a medical professional (e.g., doctor, nurse, nurse practitioner, physician assistant, caregiver, clinical research associate, etc.) or a scientific researcher. The subject is preferably a human subject. The subject can be male or female. In some embodiments, the subject is an adult (i.e., 18 years of age or older). In certain embodiments, the subject is an elderly person. In certain embodiments, the subject is not an elderly person. The subject is preferably a subject diagnosed with a proliferative disease such as cancer.

[0218] The diseased tissue to be targeted can be located at a soft tissue site, a calcified tissue site, or multiple sites, which can all be in soft tissue, all in calcified tissue, or can 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 targeted site and the site of origin of the disease can be the same, but alternatively can be different. In cases involving more than one site, this can include the site of origin or can be multiple secondary sites. The term "soft tissue" is used herein to denote tissue without a "hard" mineralized matrix. In particular, soft tissue as used herein can be any tissue that is not bone tissue. Accordingly, "soft tissue disease" as used herein denotes a disease that occurs in "soft tissue" as defined herein. The present invention is particularly suitable for treating cancer and "soft tissue diseases", and thus encompasses epithelial cancer, sarcoma, myeloma, leukemia, lymphoma, and mixed cancers that occur in any "soft" (i.e., non-mineralized) tissue, as well as other non-cancerous diseases of such tissue. Cancerous "soft tissue diseases" include solid tumors that occur in soft tissue as well as metastatic and micrometastatic tumors. In fact, soft tissue diseases can include at least one metastatic tumor of soft tissue and a primary solid tumor of soft tissue in the same patient. Alternatively, "soft tissue disease" can consist of only a solid tumor or only a metastatic tumor (the primary tumor being a bone disease).

[0219] When the particles or compositions of the present invention are used as imaging agents and / or in diagnostic methods according to the present invention, the targeting moiety can be selected based on a specific biomarker (e.g., an antigen) that is expressed by or in the vicinity of a tissue, cell, or organ affected by a proliferative disease.

[0220] In some embodiments, the proliferative disease is cancer, a non-cancerous tumor, a neoplastic disease, or a hyperplastic disease.

[0221] In some preferred embodiments, the proliferative disease is cancer. As used herein, the terms “cancer” and “tumor” refer to any neoplastic growth in a subject, including the primary tumor and any metastases. Cancer can be of the liquid tumor type or the solid tumor type. Liquid tumors include tumors of hematological origin, including, for example, myelomas (e.g., multiple myeloma), leukemias (e.g., Waldenstrom’s syndrome, chronic lymphocytic leukemia, other leukemias), and lymphomas (e.g., B-cell lymphoma, non-Hodgkin’s lymphoma). Solid tumors can originate from organs and include, but are not limited to, lung cancer, brain cancer, breast cancer, prostate cancer, ovarian cancer, colon cancer, kidney cancer, and liver cancer.

[0222] In some embodiments, the cancer is selected from the list consisting of or comprising: lung cancer, pancreatic cancer, colorectal cancer; liver cancer, glioma, kidney cancer, non-Hodgkin’s lymphoma, neuroblastoma, CNS metastases, peritoneal cancer, follicular lymphoma, colorectal cancer, small cell lung cancer, epithelial cancer, sarcoma, myeloma, leukemia, lymphoma, prostate cancer, or mixed cancer.

[0223] In some specific embodiments, the cancer is metastatic cancer. It is well known that metastatic cancer is difficult to treat using conventional anti-cancer therapies, but the targeted MOF carriers of the present invention represent a promising approach for diagnosing and / or screening such cancers and for subsequent treatment.

[0224] The targeting moiety of the particles will be selected based on the specific disease to be treated. For example: CD37 is highly expressed in most B cells and B-cell lymphomas, is absent in normal stem cells, and is lost again after differentiation into plasma cells. Due to the high incidence of CD37 on the surface of B lymphoma, CD37 is the target of several different agents in clinical development. Thus, for such cancers, anti-CD37 can be a useful targeting moiety.

[0225] Since non-Hodgkin’s lymphoma spreads around the lymphatic system, it is difficult to treat with conventional therapies (surgery, radiation). Additionally, non-Hodgkin’s lymphoma can metastasize to other tissue types, which is another reason why the present invention is particularly effective against non-Hodgkin’s lymphoma.

[0226] In addition, the present invention can also be used for the following imaging: chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis; inflammatory bowel diseases such as ulcerative colitis and / or Crohn's disease; and / or chronic obstructive pulmonary disease. Thus, in another aspect, the present invention relates to particles comprising:

[0227] - a MOF, wherein the MOF comprises

[0228] - a repeating three-dimensional network of pore-forming inorganic and organic monomers, and

[0229] - at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof;

[0230] - optionally at least one targeting moiety, which is attached to the particle on the outer surface of the particle; and

[0231] - at least one short-lived radionuclide;

[0232] and wherein at least one radionuclide is located in at least one pore;

[0233] or relates to a composition comprising the particles and at least one pharmaceutically acceptable carrier, diluent, and / or excipient;

[0234] The particle or the composition for use in a method of diagnosing a chronic inflammatory disease.

[0235] In these embodiments, the subject is preferably a subject diagnosed with a chronic inflammatory disease such as rheumatoid arthritis, psoriatic arthritis; inflammatory bowel diseases such as ulcerative colitis and / or Crohn's disease; and / or chronic obstructive pulmonary disease. The inflammatory process in the body plays an important function in the control and repair of injury. Commonly referred to as the inflammatory cascade, or simply inflammation, it can have two basic forms: acute and chronic. Acute inflammation, which is part of the immune response, is the body's immediate response to injury or attack caused by physical trauma, infection, stress, or a combination of all three. Acute inflammation helps prevent further damage and promotes the healing and recovery process.

[0236] When inflammation becomes self - perpetuating, it can lead to chronic or long - term inflammation. This is called chronic inflammation and persists beyond the actual injury; sometimes lasting for months or even years. It becomes a problem in itself and requires medical intervention to control or prevent further inflammation - mediated damage. An imbalance between the inflammatory and anti - inflammatory components of the immune system can lead to chronic inflammatory diseases. Re - balancing the immune system by killing inflammatory cells with MOFs loaded with radioisotopes can prevent chronic inflammation and treat patients.

[0237] Particles or compositions used as imaging agents and / or for diagnostic methods according to the present invention include administering the particles or compositions to a subject in a diagnostically effective dose. In one embodiment, the method or application includes imaging a subject to whom an imaging agent has been previously administered. The term "effective dose" as used herein means an amount of the particles according to the present invention that is effective to produce a desired imaging effect in a subject at a reasonable benefit / risk ratio. The effective dose amount can vary depending on the route of administration and dosage form. Additionally, the dose can depend on the type of particle, radionuclide cation, and / or radioactive decay of its progeny to be used, the stage of the disease, the age and weight of the subject, etc., and can be routinely determined by a skilled practitioner according to principles well - known in the art.

[0238] In some embodiments, the amount of radionuclide cation used per patient dose can be from 1 kBq to 10 GBq, such as from 1 MBq to 1 GBq, preferably from 2 MBq to 400 MBq, more preferably from 100 MBq to 400 MBq, even more preferably from 3 MBq to 400 MBq. The dose and maximum dose can be determined by those skilled in the art based on common general knowledge regarding suitable doses and maximum doses. It is well - recognized in the art that a realistic and conservative estimate of the toxic side effects of the progeny isotopes must be employed.

[0239] In some embodiments, the particles are administered at a dose of from 10 Bq to 100 MBq / kg body weight, such as at a dose of from 10 kBq to 10 MBq / kg body weight, such as at a dose of from 10 kBq to 4 MBq / kg body weight, preferably from 50 kBq to 4 MBq / kg, such as from 100 kBq to 2 MBq / kg, more preferably from 75 to kBq / kg, especially from 4 to 6 MBq / kg. Correspondingly, a single dose unit can contain approximately any of these ranges multiplied by a suitable body weight, such as 30 to 150 Kg, preferably 40 to 100 Kg (such as in the range of 100 kBq to 10 GBq / dose, etc.). The dose, particles, and route of administration can be such that the dose of the progeny produced in the body 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.

[0240] The diagnostic effective dose of the particles or compositions according to the invention can be administered as a single dose or in separate doses. The particles or compositions 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 particles or compositions according to the invention are administered once a day, preferably shortly before the imaging procedure. In other embodiments, the dose and frequency of administration of the treatment with the particles or compositions according to the invention are determined by a medical professional based on factors including but not limited to the stage of the disease, the severity of the symptoms, the route of administration, the age, weight, general health, sex and / or diet of the subject, and / or the response of the subject to the treatment.

[0241] The particles or compositions according to the invention should be administered by a medical professional. In some embodiments, the particles or compositions according to the invention are administered at a specific time of day.

[0242] The particles or compositions according to the invention used as imaging agents and / or for diagnostic methods can be administered locally or systemically. The particles or compositions according to the invention can be administered by any route of administration, including but not limited to via the lung, orally, intraperitoneally, intravenously, intramuscularly, intratumorally, sublingually, subcutaneously, intrathecally, buccally, rectally, vaginally, ophthalmically, nasally, transdermally and transcutaneously. In some embodiments, the particles or compositions are administered intravenously. In these embodiments, water is a particularly useful excipient. Aqueous salt solutions and aqueous dextrose and glycerol solutions can also be used as liquid excipients, especially for injectable solutions.

[0243] The compositions of the invention can be in unit dose form as a single dose, wherein all active and inactive ingredients are combined in a suitable system and there is no need to mix the components before administration. Alternatively, the composition can be presented as a kit as disclosed above, for example, and can include instructions for storing, preparing, administering and / or using the composition.

[0244] In certain embodiments, the particles or compositions according to the invention are administered alone. In other embodiments, the particles or compositions according to the invention are administered in combination with one or more other imaging agents, for example for use with other imaging modalities other than radiopharmaceuticals. When using separate formulations, the particles or compositions according to the invention can be administered simultaneously with, intermittently with, staggered with, before, after, or in combination with the administration of another imaging agent.

[0245] The embodiments and features described in the context of one aspect (e.g., with respect to the particles or compositions) of the invention also apply to other aspects of the invention, such as using it as an imaging agent or for diagnostic methods.

[0246] In another aspect, the present invention provides a diagnostic method, which comprises the step of administering to a subject in need thereof an effective amount of the particles or compositions of the present invention.

[0247] In another aspect, the present invention provides a method for diagnosing a proliferative disease, which comprises the step of administering to a subject in need thereof an effective amount of the particles or compositions of the present invention.

[0248] In another aspect, the present invention provides a method for diagnosing a chronic inflammatory disease, which comprises the step of administering to a subject in need thereof an effective amount of the particles or compositions of the present invention.

[0249] In another aspect, the present invention provides the use of the particles or compositions of the present invention as a contrast agent.

[0250] In another aspect, the present invention provides the use of the particles or compositions of the present invention for diagnosing a proliferative disease.

[0251] In yet another aspect, the present invention provides the use of the particles or compositions of the present invention for diagnosing a chronic inflammatory disease.

[0252] The present invention should not be limited to the illustrated embodiments and examples. Although multiple embodiments of the present disclosure are described herein, it will be apparent to those skilled in the art that such embodiments are provided only by way of example. Without departing from the present disclosure, various modifications, changes, variations, and substitutions to the embodiments described herein will be apparent to those skilled in the art. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the present disclosure.

[0253] It should be understood that each embodiment of the present disclosure may optionally be combined with any one or more of the other embodiments described herein.

[0254] It should be understood that each component, compound, particle, or parameter disclosed herein should be construed as being disclosed for use alone or in combination with one or more of each of the various and each other component, compound, or parameter disclosed herein. It should also be understood that each amount / value of each component, compound, or parameter disclosed herein, or the range of its amount / value, should be construed as also being disclosed in combination with each amount / value of any other component, compound, or parameter disclosed herein, or the range of its amount / value. And thus, for the purposes of this specification, any combination of the amounts / values or the ranges of the amounts / values of two or more components, compounds, or parameters disclosed herein are also disclosed in combination with each other. Any and all features described herein, and combinations of such features, are included within the scope of the present invention, provided that such features are not mutually inconsistent.

[0255] It should be understood that for the same components, compounds or parameters, each lower limit of each range disclosed herein should be construed as being disclosed in combination with each upper limit of each range disclosed herein. Accordingly, the disclosure of two ranges should be construed as the disclosure of four ranges derived by combining each lower limit of each range with each upper limit of each range. The disclosure of three ranges should be construed as the disclosure of nine ranges derived by combining each lower limit of each range with each upper limit of each range, and so on. In addition, the specific amounts / values of components, compounds or parameters disclosed in the specification or examples should be construed as the disclosure of the lower or upper limits of a range, and can thus be combined with any other lower or upper limits, or ranges or specific amounts / values of the same components, compounds or parameters disclosed elsewhere in this application to form ranges of such components, compounds or parameters.

[0256] Examples

[0257] Example 1: Conjugation of anti-CD37 IgG with UIO-66-(COOH) 2 Conjugation

[0258] UIO-66-(COOH) 2 The MOF was prepared by a method based on the method of Zhiijie Chen et al, CrystEngComm 2019, 14, 2409-2415, but using oxychloride salts instead of oxynitrates as the precursors for the MOF. UIO-66-(COOH) 2 Antibody conjugation was evaluated by analyzing the UIO-66-(COOH) 2 antibody-conjugated particles via the bicinchoninic acid assay (BCA). The BCA protein assay combines the well-known reduction of Cu 2+ to Cu 1+ by proteins in an alkaline medium with the highly sensitive and selective colorimetric detection of cuprous cations (Cu 1+ ) by bicinchoninic acid (BCA). The first step is the chelation of copper with proteins 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 colored chelate complex with copper ions in an alkaline environment containing potassium sodium tartrate.

[0259] In the colorimetric reaction of the second step, BCA reacts with the reduced (cuprous) cations formed in step one. The chelation of two BCA molecules with one cuprous ion produces a deep purple reaction product.

[0260] Procedure:

[0261] Dissolve 5 mg of UiO-66-(COOH) 2 in 0.05 M 2-(N-morpholino)ethanesulfonic acid (MES) buffer (pH 6.3), treat with 1.2 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and 1.2 mg of N-hydroxysulfosuccinimide (sulfo-NHS) for 15 minutes, and then wash the particles twice with 0.05 M MES buffer (pH 6.3). Then resuspend the particles in 0.05 M MES buffer (pH 6.3) containing 100 μg of anti-CD37 IgG. Incubate the reaction mixture with continuous shaking for 3 hours. Wash the MOF-antibody particles with 0.05 M MES buffer (pH 6.3) and resuspend in 100 mM Tris buffer, and then wash the particles with 0.05 M MES buffer (pH 6.3) and store them.

[0262] Antibody (IgG)-conjugated UIO-66(COOH) 2 and albumin standards were evaluated by BCA assay as Figure 12 shown. The trend line equation of albumin was used to calculate the protein concentration of UIO-66(COOH) 2 -IgG particles / mL: absorbance - blank: 0.096, corresponding to 77 μg / mL (77% of the antibody input)

[0263] Example 2: Structural stability and barium retention ability of MOF in human serum

[0264] In this experiment, barium (II) was used as a cold isotope to simulate 133 / 131Ba.

[0265] Procedure:

[0266] Dissolve 200 mg of UiO-66-(COOH) 2Wash once with 0.05 M MES buffer (pH 6.3) and suspend it in 40 mL of an aqueous solution of barium(II) acetate (14.7 μg Ba / mL). Stir the suspension for 60 minutes at room temperature. Recover the MOF, wash once with 5 mL of 0.05 mol / L MES buffer (pH 6.3), and then suspend it in human serum. Keep the MOF / serum suspension stirring at room temperature for 11 days. Collect samples after 15 minutes and after 1, 2, 4, and 7 days. After digesting the serum samples for 1 hour at 70 °C using a 1:1 volume mixture of aqueous HNO3 (65%) and aqueous H2O2 (33%), perform elemental analysis using the MP-AES method.

[0267] Elemental analysis showed that the MOF adsorbed 97.2% of the Ba2+ in the solution, resulting in a Ba2+ concentration in the MOF of 2.87 μg / mg (0.287% wt). Analysis of the serum samples collected after 15 minutes and after 1, 2, 4, and 7 days showed that the total Ba2+ leakage from the serum was 6.6%, 8.4%, 9.4%, 8.3%, and 5.5%, respectively. This indicates that after the initial leakage, the MOF contained all of the Ba2+.

[0268] Separate the MOF from the serum after 11 days and analyze it by powder X-ray diffraction and energy-dispersive X-ray spectroscopy. The powder X-ray diffraction pattern of UiO-66-(COOH) 2 as received and after the 11-day stability test clearly showed that the MOF crystalline structure remained intact. EDS showed that the mass ratio of Ba / Zr in the MOF was 1.10%, which was in very good agreement with the value of 1.14% 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) within the experimental error range.

[0269] ID ppm [Ba2+] in the MOF-serum suspension 19.10889 [Ba2+] in the serum after 15 minutes 1.259 [Ba2+] in the serum after 24 hours 1.608 [Ba2+] in the serum after 48 hours 1.802 [Ba2+] in the serum after 96 hours 1.5955 [Ba2+] in the serum after 168 hours 1.0475

[0270] Table 2 shows the barium concentrations present in Example 2.

[0271] Therefore, this experiment demonstrated that the MOF particles themselves were stable in human serum for at least 11 days, and the chelation of barium cations in the MOF particles was stable for at least 11 days. Incidentally, this experiment also demonstrated the ability of the MOF to adsorb large amounts of Ca2+, K+, and Na+ without leaking Ba2+.

[0272] Example 3: Structural Stability and Barium Retention Capacity of MOF in Human Serum

[0273] This experiment confirmed the results from Example 2 using different Ba2+ sources and two different concentrations.

[0274] Procedure:

[0275] 120 mg of UiO-66-(COOH) in two separate portions 2 was washed three times with 5 mL of 0.05 mol / L MES buffer (pH 6.3) and subsequently suspended in two separate 5 mL aqueous solutions of barium nitrate(II) (1.165 mg / mL Ba and 0.109 mg / mL Ba, respectively). The suspensions were stirred at room temperature for 90 minutes. The MOF was recovered, washed once with 5 mL of 0.05 mol / L MES buffer (pH 6.3), and then suspended in human serum. Samples were collected after 24 hours and 48 hours. The MOF / serum suspension was kept stirred at room temperature for 2 days. Samples were collected after 24 hours and 48 hours. After digesting the serum samples with a 1:1 volume mixture of aqueous HNO3 (65%) and aqueous H2O2 (33%) at 70 °C for 1 hour, elemental analysis was performed using the MP-AES method.

[0276] From the 1.165 mg / mL Ba solution: Elemental analysis showed that the MOF adsorbed 98.8% of the Ba2+ in the solution, resulting in a Ba2+ concentration in the MOF of 48.0 μg / mg (4.8% wt). Analysis of the serum samples collected after 24 hours and 48 hours showed that the total Ba2+ leakage in the serum was 8.8% and 9.2%, respectively. This indicates that Ba2+ leakage is negligible between 24 and 48 hours. EDS showed that the mass ratio of Ba / Zr in the MOF was 19.4%, which is in very good agreement with the value of 19.1% 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) within the experimental error range.

[0277] From 0.109 mg / mL Ba solution: Elemental analysis showed that the MOF adsorbed 92.0% of Ba2+ in the solution, resulting in a Ba2+ concentration of 4.19 μg / mg (0.42% wt) in the MOF. Analysis of serum samples collected after 24 hours and 48 hours showed that the total Ba2+ leakage in the serum was 6.4% and 6.0%, respectively. This indicates that there was no Ba2+ leakage from 24 to 48 hours. EDS showed that the mass ratio of Ba / Zr in the MOF was 1.43%, which was in good agreement with the value of 1.67% 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) within the experimental error range.

[0278] ID Solution 1 (ppm) Solution 2 (ppm) [Ba2+] in the MOF-serum suspension 575.505 50.23833 [Ba2+] in the serum after 24 hours 50.4425 3.213 [Ba2+] in the serum after 48 hours 52.7845 3.027

[0279] Table 3 shows the barium concentration present in Example 3.

[0280] Example 4: MOF-IgG Cell Interaction

[0281] This experiment demonstrated that anti-CD37 conjugated MOF (NP1) binds to CD37 positive cells (Daudi cells). The Daudi cell line is composed of B lymphoblasts isolated from the peripheral blood of a Burkitt lymphoma patient, indicating that anti-CD37 conjugated MOF can recognize blood-derived cancer cells.

[0282] Procedure:

[0283] Transfer 66,000 Daudi cells to a flow tube containing the following: phosphate buffered saline (PBS), isotype control, UiO-66-(COOH) 2 Anti-CD37 stability study sample (incubated at 20 °C for 6 months) or freshly conjugated UiO-66-(COOH) 2 Anti-CD37. Incubate the samples and continuously mix for 30 minutes, then add 400 μL of 10% fetal bovine serum (FBS) in PBS and centrifuge at 350 g for 8 minutes. Discard the supernatant, then add 100 μL of anti-CD37-PE (10 μL of anti-CD37-PE mixed with 90 μL of PBS) to the PBS sample or to the isotype control and UiO-66-(COOH) 2100 μL of anti-mouse-PE (10 μL of anti-mouse-PE mixed with 90 μL of PBS) was added to the aCD37 sample. The sample was incubated with continuous mixing for 30 minutes, then 400 μL of 10% FBS in PBS was added and centrifuged at 350 g for 8 minutes. The supernatant was discarded, then 400 μL of 10% FBS in PBS was added and flow cytometry analysis was performed.

[0284] The stability control sample used in this experiment was prepared by storing UiO-66-(COOH) 2 anti-CD37 at 20 °C for 6 months.

[0285] Figure 13 Results are provided showing that anti-CD37 conjugated MOF (NP1) binds to CD37 positive cells and is stable for at least 6 months at room temperature.

[0286] Example 5: MOF-anti-EpCAM and MOF-anti-HER2 cells binding to colorectal cell lines

[0287] This experiment demonstrated that anti-EpCAM or anti-HER conjugated UiO-66-(COOH) 2 binds to colorectal cancer cells (HTC116 and HT29) expressing both antigens. HTC116 cells were derived from the colon of an adult male colon cancer patient. And the HT29 cell line was derived from the primary tumor of a female patient with colorectal adenocarcinoma. Thus, it was shown that anti-EpCAM and anti-HER-antibody (IgG) conjugated UiO-66-(COOH) 2 both can recognize cancer cells of colorectal origin.

[0288] Procedure:

[0289] Cells were seeded at 50,000 cells / well in a 96-well plate and cultured overnight in complete 10% fetal bovine serum (FBS) Roswell Park Memorial Institute (RPMI) cell medium. The next day, the medium was discarded from each well, then 2 μg of anti-EpCAM, 2 μg of isotype control, or 15 μL of UiO-66-(COOH) diluted in pre-warmed cell medium was added 2(NP1)Up to a total volume of 200 μL per well. Incubate the samples at 37 °C for 30 minutes, then discard the medium and gently add 200 μL of PBS (phosphate buffered saline) twice. Add 100 μL of PBS and 100 μL of anti-human IgG-HRP solution (2.5 μL of anti-human IgG-HRP solution / mL) to each sample and incubate at room temperature for 30 minutes. After secondary staining, gently wash the cells twice with PBS, then add 100 μL of TMB (3,3’,5,5’-tetramethylbenzidine) HRP (horseradish peroxidase) substrate solution to each well and incubate for 15 minutes. Add 100 μL of stop solution to each well to terminate the reaction, then measure the absorbance of each well at 450 nm. The absorbance is recorded as “HRP signal” in the figure. Figure 14 Results showing the binding of anti-EpCAM and anti-HER2 UiO-66-(COOH) 2 to colorectal cancer cells (HTC116 and HT29) are provided.

[0290] Example 6: MOF-anti-HER2 breast cancer cell interaction

[0291] This experiment demonstrated that anti-HER2 conjugated UiO-66-(COOH) 2 binds to HER2-positive cancer cells (JIMT1 cells). JIMT1 cells are epithelial cells derived from a female patient with ductal adenocarcinoma of the breast. Thus, the JIMT1 cell interaction illustrates how anti-HER2 conjugated UiO-66-(COOH) 2 can recognize cancer cells of breast origin.

[0292] Procedure: For the JIMT1 cell interaction, use the same procedure as for the colorectal cancer cell interaction, see Example 5 ( Figure 14 ).

[0293] Figure 15 Results showing the binding of anti-HER2 conjugated UiO-66-(COOH) 2 to breast cancer cells JIMT1 cells are provided.

[0294] Example 7: Adsorption and retention of MOF in fetal bovine serum 68 Ga 3+ Adsorption and retention

[0295] Procedure:

[0296] UiO-66-(COOH) conjugated with anti-EpCAM antibody and polyethylene glycol (PEG) was prepared in 20 mM histidine chloride buffer (pH 7) 2Two suspensions, where the MOF concentration is 175 mg / L (A) and 250 mg / L (B). 68 GaCl 3 solution was added to the desired radioactivity concentration (RAC): 50 MBq / mL in A and 30 MBq / mL in B. After 10 minutes, the dose was added to fetal bovine serum (FBS) in a diagnostic injection volume ratio, i.e., 25 μL per dose in 400 μL FBS. After 15 minutes, the serum samples were filtered through a 100 kDa molecular cut-off filter in a centrifuge (14 000 g, 10 minutes) to separate the MOF binding activity in the filter from the dissolved activity in the filtrate, which was performed using a Hidex γ-counter instrument. Sample A showed 87% retention, and sample B showed 89% retention. Baseline correction was applied (using a MOF-free control in parallel).

[0297] Example 8: Biodistribution of 68 Ga-loaded UiO-66-(COOH) 2 in healthy mice.

[0298] Procedure:

[0299] A 0.6 MBq dose of sample B from Example 7 was suspended in a 5% w / v dextran solution for injection into healthy mice (administration). The mice were analyzed by PET / CT to evaluate the biodistribution at consecutive time points.

[0300] Figure 17 Slices of mouse PET / CT scans overlaid after a 0.6 MBq dose of 68Ga-labeled NPs are provided. The images were acquired 10 to 30 minutes after injection, and the results showed that the activity from 68 Ga-loaded UiO-66-(COOH) 2 was mainly present in the liver and bladder, with some accumulation in the spleen. This is a significantly different biodistribution compared to, for example, 68 Ga]GaCl3 solution or 68 Ga-labeled molecules, because 68 GaCl 3It is systemically present in the blood and in the bladder (Steinberg, J.D., Raju, A., Chandrasekharan, P. et al. Negative contrast Cerenkov luminescence imaging of blood vessels in a tumor mouse model using [68Ga] gallium chloride. EJNMMI Res 4, 15 (2014). https: / / doi.org / 10.1186 / 2191-219X-4-15).

[0301] Example 9. Planned experiment: Bio-distribution of UiO-66-(COOH) 2 (NP) conjugated with anti-HER2, anti-EpCAM antibodies and polyethylene glycol (PEG) to study tumor targeting of NPs with and without antibodies.

[0302] Procedure:

[0303] The bio-distribution of γ-isotope-loaded UiO-66-(COOH) 2 targeting EpCAM or HER2 will be studied, as well as its ability to localize in tumors, using tumor models representing HER2+ breast cancer and EpCAM colorectal cancer. To study the specificity of nanoparticles (NPs), NPs with and without attached antibodies on the particles in addition to radioactivity will also be used. Mice will be sacrificed on days 0 to 30 after treatment to study the bio-distribution of the drug over time and how specific the bio-distribution is to tumors. Mice will be sacrificed with each drug at each time point. For the two EpCAM-targeting drugs, this will be studied in two or more models (e.g., HCT116 and HT29) where tumors grow, for example, in the liver and intraperitoneally. For intraperitoneally growing tumors, the substance will be injected intravenously (iv) or intraperitoneally (ip) to study which injection form has the best bio-distribution for tumors growing in the peritoneal cavity. The two HER2-targeting drugs will be studied in at least two models resulting in breast cancer, liver tumors, and peritoneal tumors, such as SKBR3 (cell line) and BBRC160 (PDX).

[0304] Example 10. Viability test of UiO-66-(COOH) 2 (NP) conjugated with PEG shows no toxicity in vitro.

[0305] HT29 and HCT116 were exposed to increasing doses of NPs over two days, and then cell viability was analyzed, showing that NPs did not induce cell death under these conditions.

[0306] Procedure:

[0307] HT29 or HCT116 was exposed to 0.001 to 500 μg / well of UiO-66-(COOH) 2 (NP), and cultured in a humidified incubator at 37 °C in 5% CO 2 for 24 and 48 h, then the supernatant was discarded and 100 μL of fresh cell medium (10% fetal bovine serum (FBS), Roswell Park Memorial Institute (RPMI)) and 20 μL of CellTiter AQueous OneSolution Reagent (Promega) containing the 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) were added. Each plate was incubated in a humidified incubator at 37 °C in 5% CO 2 for 1.5 h, and then the absorbance at 490 nm was measured in a plate reader.

[0308] Figure 16A A and B respectively show the in vitro cell viability of HT29 or HCT116 after exposure to UiO-66-(COOH) 2 for 24 and 48 h. The absorbance did not change under all conditions, thus meaning that the cell content per well did not change over the 48-h period.

Claims

1. A particle, comprising: - a MOF, wherein the MOF comprises: - a repeating three-dimensional network of inorganic and organic monomers forming pores, and - at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof; - optionally at least one targeting moiety, the targeting moiety being attached to the particle on the outer 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.

2. The particle according to claim 1, wherein the MOF is based on Zr(IV), Hf(IV), Ce(IV), Fe(III), Al(III), Ti(IV) or Cr(III) having carboxylate / ester organic monomers, or based on Zn(II) imidazole salt / ester.

3. The particle according to claim 1 or 2, wherein the MOF is UiO-66-COOH, MOF-808 or UiO-66-(COOH) 2 .

4. The particle according to any one of claims 1 to 3, wherein the radionuclide is a γ-emitter or a positron emitter.

5. The particle according to any one of the preceding claims, wherein the half-life of the radionuclide is from 0.5 hours to 60 days.

6. The particle according to any one of the preceding claims, wherein the at least one radionuclide is selected from the group consisting of Ga-68, Ti-45, Tc-99m, Ba-133m, F-18, In-111, Ga-67, Zr-89, Ba-131, Yb-169 and Sc-43.

7. The particle according to any one of the preceding claims, wherein the particle is a nanoparticle.

8. The particle according to any one of the preceding claims, wherein there is at least one targeting moiety.

9. The particle according to any one of the preceding claims, wherein there is at least one targeting moiety, and the targeting moiety is an antibody.

10. A kit, comprising in a first container: particles, the particles comprising: - a MOF, wherein the MOF comprises: - a repeating three-dimensional network of inorganic and organic monomers forming pores, and - at least one free functional group extending into the pores, wherein the functional group is selected from the group consisting of carboxylic acid, carboxylate / ester, hydroxyl, sulfonic acid, sulfonate / ester, mercapto, primary amine, secondary amine, and combinations thereof; - optionally at least one targeting moiety, the targeting moiety being attached to the particle on the outer surface of the particle; and in a second container: short-lived radionuclides.

11. An imaging agent composition, comprising at least one particle according to any one of claims 1 to 9 and at least one pharmaceutically acceptable carrier, diluent and / or excipient.

12. The particle according to any one of claims 1 to 9 or the composition according to claim 11, for use as an in vivo imaging agent.

13. The particle according to any one of claims 1 to 9 or the composition according to claim 11, for use in a method for diagnosing a proliferative disease.

14. The particle according to any one of claims 1 to 9 or the composition according to claim 11 for use according to claim 13, wherein the proliferative disease is cancer.

15. The particle according to any one of claims 1 to 9 or the composition according to claim 11 for use according to claim 14, wherein the cancer is epithelial cancer, sarcoma, myeloma, leukemia, lymphoma or mixed cancer.

16. The particle according to any one of claims 1 to 9 or the composition according to claim 11 for use according to claim 13, wherein the proliferative disease is a hyperplastic disease or a neoplastic disease.

17. The particle according to any one of claims 1 to 9 or the composition according to claim 11 for use in a method for diagnosing a chronic inflammatory disease.

18. The particle according to any one of claims 1 to 9 or the composition according to claim 11 for use in a method for diagnosing a subject, followed by a subsequent treatment step with a particle comprising the same MOF as used in the diagnosis and carrying a therapeutic radionuclide.

19. The particle according to any one of claims 1 to 9 or the composition according to claim 11 for use in a method for diagnosing liver cancer, wherein the particle does not comprise any targeting moiety.

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