WO2023069767A1 - METAL ORGANIC FRAMEWORK PARTICLES AS β EMISSION DETECTORS IN AQUEOUS SYSTEMS - Google Patents

Abstract

This present disclosure is directed to methods for detecting and quantifying radioisotopes ( e.g., radiopharmaceuticals) in a liquid and compositions involving the same. Metal-organic frameworks (MOFs) can be synthesized and used for measuring low-energy radioisotope decay from alpha-emitter, beta-emitters, and gamma emitters directly in water. Zirconium metal organic framework particles are disclosed herein.

Description

METAL ORGANIC FRAMEWORK PARTICLES AS p EMISSION DETECTORS IN AQUEOUS SYSTEMS

[0001] STATEMENT OF FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0002] This invention was made with government support under Grant No. #CHE 1807343 awarded by National Science Foundation. The government has certain rights in the invention.

FIELD OF THE INVENTION

[0003] The field of the invention relates generally to the detection of radioisotopes.

BACKGROUND

[0004] This background information is provided for the purpose of making information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the information disclosed herein constitutes prior art against the present invention.

[0005] Radioisotope (RI) labels remain a key tool for drug discovery applications, particularly for measuring analytes that are not inherently detected by traditional optical microscopy or electrochemical methods. Though new analytical approaches, including mass spectrometry, allow sensitive detection of label free mixtures, the high sensitivity and small sample requirements are unparalleled, making radioassays indispensable.

[0006] RI labels play a fundamental role in the investigation of biological, medical environmental, and nuclear systems, particularly for analytes that are not detectable by traditional optical microscopy or electrochemical approaches. RI labels have a key role in the high sensitivity detection of compounds as diverse as small molecule enzyme inhibitors, receptor agonists and antagonists, carbohydrates and carbohydrate derivatives, proteins and many others. RIs facilitate highly sensitive detection with minimal perturbation of the size and structure of the analyte, compared to fluorescent labels, a particularly important property in drug discovery applications. This property makes them particularly amendable for studies such as drug screening, identification and functional assays, environmental tracing, in vivo and in vitro imaging, and nuclear waste management and proliferation studies. For example, small molecule pesticides can be readily labeled with ³H, ¹⁴C, ³⁵S, ³³P or other radioisotopes and subsequently detected in water, agricultural and other samples to better understand the pesticide fate, metabolism and distribution. Additionally, heavy metal isotopes such as ⁶⁴Cu, ²³⁵U, ²²⁵ Ac, ²²⁷Th and others, are increasingly used for nuclear medicine and functional imaging, detection of nuclear proliferation and understanding of waste runoff and disposal applications. Further, radioactive ions such as ²²Na and ⁸⁶Rb enable highly sensitive ion flux assays. These applications are in addition to more traditional assays that rely on radioisotopes to better understand metabolic processes in biological and environmental samples that enable determination of fate, lifetime, distributions and other factors of environmental contaminants and biological pathways. RI labels provide unparalleled sensitivity and precision for ligand-receptor binding assays, including G-protein coupled receptor assays.

[0007] Though recent decades have witnessed significant advances in molecular analysis platforms, RI labels continue to provide a critical approach for detection of a wide range of biologically important applications. Beta-particle emitters have proven valuable to label small and large organic molecules. Of the beta emitters, ³H is among the most important radioisotopes for biological studies based on low mass differences between labeled and unlabeled compounds, a reasonable half-life (12.3 years) for storage, low maximum decay energy (Emax=18.6 keV), short penetration depth in water (<2.0 pm), and relative safety. ³⁵S and ³³P are also commonly used labels for the same reasons, although they have a slightly higher maximum decay energies (Emax=167 keV and 249 keV respectively), longer penetration depths in water (up to 31 pm and 60 pm), and shorter half-lives (87.4 and 25.3 days). ³²P is higher in energy (Emax=1.71 MeV) but is still commonly used in traditional protein and DNA/RNA assays. The ubiquity of these atoms in biological and pharmaceutical structures, makes it possible to synthesize labeled variants that exhibit minimal perturbations to the chemical and biochemical activity, and thus enable analyses that cannot be performed using larger fluorescent labels. [0008] A single [3-particle, emited from an RI label, can produce hundreds of photons or more, depending on its energy, as it passes through a scintillating medium. Due to the lack of an excitation source, this detection approach occurs with zero background leading to remarkable sensitivity. Scintillant materials that are sensitive to low-energy [3- emission are essential for enabling the study of manifold biological processes. A key challenge in sensing low-energy radioisotopes with scintillant materials is the relatively short penetration depth of their decay products (e.g., alpha-, beta-, gamma particles) and the typically low decay energies of common radioisotopes used for biological, environmental and nuclear applications. For example, tritium (³H) exhibits a mean penetration depth of only around 0.5 pm in aqueous systems with a maximum penetration of dept of 1.5 pm., which requires the scintillant material to be within 1.5 pm of a decaying radionuclide for detection.

[0009] In some instances, it is important to measure the specific molecule that contains the radioactive label, conditions for which LSC and SSC lack the inherent molecular specificity required. For example, when the products of an enzymatic reaction are the analytes, the Rl-labeled substrate and any labeled products will be detected indiscriminately. Finally, the organic solvent component of LSC, in particular, is incompatible with detection directly in biomolecular and biological systems since the organic liquid can disrupt key molecular species in the analysis, e.g. proteins. Additionally, measurements in LSC generate large volumes of radioactive mixed waste that must be collected and disposed according to state and federal regulations, and the toxicity and volatility of the primary solvent components of many LSC formulations complicate their transport, storage, and disposal.

[0010] Solid scintillant materials prepared from dye-doped polymers or scintillating inorganic glasses provide an alternative to detect [3-emission and have the advantage of functioning in aqueous environments. Doped glass matrices can be ground into microparticles with irregular shapes and high density compared to synthetic particles. Polymer matrices that incorporate scintillant fluorophores facilitate the transfer of energy from the [3-emission to visible photons, in a manner analogous to scintillation cocktails. In fact, scintillating polymer particles function simply as a solid version of scintillation cocktail. Polymer materials can be formed into microparticles or molded into various sample geometries, including 96-well plates, that enable high throughput detection. Due to the minimized organic solvent, solid materials generate much less organic waste. The primary drawback of solid scintillation counting is the reduced scintillation efficiency that arises from the increased separation distance between scintillating particles and individual [3-emission events compared to dyes dispersed in solvent, leading to poor photon conversion.

[0011] Low-energy beta ( ) radioemitters (³H, ¹⁴C, ³³P, ³⁵S) can be quite useful as labels in biological research, but the sensing and quantifying of P emission is challenging given its characteristic low decay energy and short penetration depth in aqueous solutions. Current proximity-based P emitter sensing options are often based on scintillating fluorophore-doped polymeric particles or yttrium silicate spheres, but intrinsic aqueous instabilities, chemical instability, and/or low efficiencies result in low sensitivity and limit their applicability in biological fields. Unfortunately, the low energy and short penetration depth of most common, biologically relevant RIs also complicate detection, limiting the capabilities for this approach.

[0012] Scintillation proximity assay (SPA) provides molecular selectivity, via integration of selective molecular binding events; however, there are fundamental limitations of conventional polymer or inorganic SPA materials that limit the applicability of these materials for a wide range of environmental, medical, and biological problems that might be better addressed using RI labels if sufficient detection capabilities can be obtained.

[0013] Metal-organic frameworks (MOFs) are crystalline materials consisting of metal nodes/clusters coordinated with organic linkers to yield continuous and repetitive motifs in an ordered three-dimensional network. MOFs elegantly maintain advantageous characteristics of both the organic small molecule linker component (e.g., tunable fluorescence) and the coordinated inorganic structure component (e.g., stability, porosity, surface properties). MOFs have been prepared with significant structural and functional variations through substitution of the inorganic or organic components. Since their discovery in 1995, MOFs have found wide-ranging applications in fluorescent sensing, adsorption/storage/separation, organic catalysis, and biomedical studies.

[0014] The optical properties of fluorescent MOFs are particularly intriguing. A defining characteristic of fluorescent MOFs is spatial confinement of coordinated fluorophores, which is imparted by their rigid structure and mitigates aggregation-induced optical quenching that is commonly observed in fluorophore-encapsulated materials. This unique and highly advantageous characteristic has played a key role in the rapid integration of MOFs into fluorescence bioimaging, OLED displays, advanced photonics, and scintillant materials.

[0015] Additionally, MOFs exhibit exceptional stability to various solvents and environments, surfaces that are conducive to chemical modification, and dispersibility in water. While other studies have demonstrated the use of fluorophores to endow MOFs with observable scintillation and the use of MOFs for detecting continuous X-rays, the inventor surprisingly discovered their application for measuring low-energy radioisotope decay from e.g., alpha-emitter, [3-emitters, and gamma emitters directly in water.

BRIEF DESCRIPTION OF THE FIGURES

[0016] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0017] Particular non-limiting embodiments of the present invention will now be described with reference to accompanying drawings.

[0018] FIG. Iprovides a functional scheme for zirconium metal organic framework (Zr-MOF) particles based scintillation proximity assay to quantify radioligands in aqueous solution. Upon radioactive decay, beta particles released by proximal radioligands are absorbed by Zr-MOF particles which transduce this energy into visible scintillation events. The magnitude of the scintillating signal is a function of the amount of radioligands proximal to Zr-MOF particles.

[0019] FIG. 2A-B. Characterization of Zr-MOF particles. (A) Scanning electron microscope image demonstrates successful preparation of Zr-MOF particles. (B) Energy dispersive spectrum obtained with Zr-MOF particles supporting the analysis that UiO-68 composition and structure was attained. The x-axis shows energy in kilo electron volts (KeV) and the y- axis shows counts.

[0020] FIG. 3 Zr-MOF characterization. The normalized fluorescence spectra for the free organic linker 9,10-diphenylanthracene (indicated as dash or broken line) and linker when prepared in Zr-MOFs (indicated as a solid line) with excitation at 390 nm. The shift in fluorescence emission of the solid line is characteristic of successful incorporation of organic linker in UiO-68 Zr-MOF particle. Inset shows optical images of Zr-MOF particles under white light (left) and 365 nm UV radiation (right).

[0021] FIG. 4 provides a functional demonstration of scintillating Zr-MOF particles. The scintillation response of (a) aqueous solution (negative control), shown as squares and (b) Zr-MOF particles, prepared with 9,10-diphenylanthracene linker (shown as red circles), in aqueous solution after incubating with 200, 400, 600, 800 nanocuries (nCi) mb'¹ tritiated acetate for 30 mins. The amount of Zr-MOF particles was 0.25 mg ml/¹ for a single measurement. The error bars represent the standard deviation of three independent measurements. Limit of detection (LOD) for tritiated acetate: 10 nCi mL’¹.

[0022] FIG. 5A shows core chemical structures of prolinkers: terphenyl, trans-stilbene, 1,4- phenylene-2,2’-bisoxazole, PPD and PPO. Prolinkers are subsequently functionalized to provide compounds that are capable of forming MOFs.

[0023] FIG. 5B provides exemplary synthetic pathways to synthesize MOF-forming linkers with the requisite luminescent core that are subsequently used to prepare scintillatable MOFs.

[0024] FIG. 5C shows chemical structures of organic luminescent linkers (L) that may be incorporated into scintillating MOF particles (as exemplary embodiments of the invention) and characterized as low-energy [3 emission sensing particles.

[0025] FIG. 6 provides characterization data for MOF particles fabricated with linkers 1-5 from FIG. 5C demonstrating their functionality for detection of low energy [3 emission. The ‘Linker in solution’ column refers to the maximal emission wavelength for the linkers in solution, when not incorporated in MOFs. The ‘Incorporated in MOFs’ column refers to the wavelength of maximal emission for the linkers once incorporated in MOFs; serving as evidence for successful preparation of MOFs. ‘Scintillation response’ column specifies the concentration of MOF particles, intensity of radioactivity by addition of tritium acetate, and the scintillation counts-per-minute (CPM).

[0026] FIG. 7 provides chemical structures of proposed additional organic linkers (L), primary fluorescent additives, secondary fluorescent additives-wavelength shifters; and fluorescent substances with high Stokes shift, that have potential in MOF scintillating particles.

[0027] FIG. 8 shows chemical structures and synthesis of DPA carboxylic derivative linker 4,4'-(9,10-Anthracenediyl)bis[benzoic acid, cas# 42824-53-3. [0028] FIG. 9A-D. (A) scintillation responses of Zr-UiO68-MOFs having DPA linker in the presence of ³H-acetate and shows effect of Zr-UiO68-MOFs concentration. The concentration of Zr-UiO68-MOFs was increased from 25 to 100 pg«mL^-1 in the presence ( circles) and absence (squares ) of 1000 nCbrnL'¹ of ³H-acetate.

[0029] (B) shows effect of ³H radioactivity. Radioactivity of ³H-acetate was increased in range from 0 to 2500 nCbrnL'¹ while in the presence (circles) and absence (squares) of 250 pg’mL'¹ of Zr-UiO68-MOFs.

[0030] (C) shows time-dependent scintillation measurement of 200 pg«mL^-1 of Zr-UiO68- MOFs in the presence of 1000 nCi’mL'¹ of ³H-acetate.

[0031] (D) shows effect of BSA. Radioactivity of ³H-acetate was increased in range from 0 to 2500 nCbrnL'¹ while in the presence (circles) and absence (squares) of 250 pg«mL^-1 ofZr- UiO68-MOFs in 1 mg*mL^_| BSA (bovine serum albumin) solutions. The error bars represent the standard deviation of three independent measurements.

[0032] FIG. 10 lists some common low energy [3 emitters with nonradioactive counterparts found ubiquitously in natural molecules, have the advantage to replicate the molecular interaction in more native way and are commonly used to label organic molecules for biological, biochemical and environmental applications.

[0033] FIG. 11 illustrates the differences in penetration depth of low energy [3 emitters and mean path length of radionuclides in water.

[0034] FIG. 12A-B. Schematic illustration of (A) synthesis of scintillating metal-organic frameworks (MOFs) via a hydrothermal reaction, and (B) subsequent scintillation detection of low-energy radionuclides. ³H-labelled analyte first emits a low-energy [3 particle during radioactive decay, which subsequently excites the Zr node, releasing absorbed energy to stimulate the fluorescent linker into an excited electronic state. Relaxation of the linker to the ground state results in the emission of visible photons that can be detected.

DESCRIPTION

[0035] Definitions

[0036] For the purposes of promoting an understanding of the principles of the invention, reference will now be made to certain embodiments and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, and alterations and modifications in the illustrated invention, and further applications of the principles of the invention as illustrated therein are herein contemplated as would normally occur to one skilled in the art to which the invention relates.

[0037] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0038] For the purpose of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any definition set forth below conflicts with the usage of that word in any other document, including any document incorporated herein by reference, the definition set forth below shall always control for purposes of interpreting this specification and its associated claims unless a contrary meaning is clearly intended (for example in the document where the term is originally used).

[0039] The use of “or” means “and/or” unless stated otherwise.

[0040] The use of “a” or “an” herein means “one or more” unless stated otherwise or where the use of “one or more” is clearly inappropriate.

[0041] The use of “comprise,” “comprises,” “comprising,” “include,” “includes,” and “including” are interchangeable and not intended to be limiting. Furthermore, where the description of one or more embodiments uses the term “comprising,” those skilled in the art would understand that, in some specific instances, the embodiment or embodiments can be alternatively described using the language “consisting essentially of’ and/or “consisting of.”

[0042] As used herein, the term “about” refers to a ±10% variation from the nominal value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.

[0043] “Scintillatable”, as used herein, refers to a material that is capable of emitting photons of light of a defined wavelength in response to the absorption of an alpha particle, a beta particle, or gamma irradiation emitted by a radioisotope as the radioisotope decays .

[0044] “Metal-organic framework” or “MOF”, as used herein, refers to metal-organic frameworks that are organic -inorganic hybrid crystalline porous materials that consist of a regular array of positively charged metal ions surrounded by organic 'linker' molecules. The metal ions form nodes that bind the arms of the linkers together to form a repeating, cage-like structure. Due to this hollow structure, MOFs have an extraordinarily large internal surface area. Compounds such as ZrC14 (cas#I0026-l 1-6), ZrOC12(cas#7699-43- 6), and ZrOC12 with 8H2O(cas#13520-92-8) may be used to prepare MOF disclosed herein.

[0045] The term “polyaromatic organic linker compound” as used herein refers to a moiety with 2 or more aryl and/or heteroaryl rings with one or more metal binding functionalities. Metal binding functionalities include carboxylic acid, amine, thiol, sulfate, nitrite, nitro, azide and other ligands that include a lone pair of electrons. The polyaromatic organic linker compound may be substituted or unsubstituted. In embodiments, the polyaromatic organic linker compound is preferably includes one or more carboxylic acid functionalities.

[0046] As used herein, the term “heteroaromatic”, “heteroaryl”, or like terms, refers to groups having 5 to 14 ring atoms; 6, 10 or 14 pi-electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms. The term “heteroaromatic”, “heteroaryl encompasses a monocyclic or a polycyclic, unsaturated radical containing at least one heteroatom, in which at least one ring is aromatic. Polycyclic heteroaryl rings must contain at least one heteroatom, but not all rings of a polycyclic heteroaryl moiety must contain heteroatoms. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quatemized, oxygen and sulfur, including sulfoxide and sulfone.

[0047] The point of attachment of a heteroaromatic or heteroaryl ring may be at either a carbon atom or a heteroatom. Heteroaryl groups may be optionally substituted with one or more substituents.

[0048] The term “aryl” as used herein by itself or as part of another group refers to monocyclic, bicyclic, polycyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as the carbocyclic groups phenyl, naphthyl or tetrahydronaphthyl.

[0049] “Weak gamma photon energy”, as used herein refers to gamma rays having an energy less than about 8 MeV.

[0050] The term “radioisotope” as used herein refers to a radioactive isotope that is “free” (in other words not bound to another molecule or molecular entity), or that is bound to a molecule. In some embodiments, the radioisotope may be bound to an organic or inorganic molecule to obtain as “radioligand”. For example, the radioligand may be configured such that the organic or inorganic molecule is chemically modified such that it contains a radioactive (radioisotope) atom in one or more positions. The radioisotope may be associated with the organic or inorganic molecule via ionic bonds, Van der Waals interactions, etc.

[0051] Examples of radioligands include molecules (e.g. drug candidates) that have been labeled with ³H, pesticides that have been labeled with ¹⁴C, proteins labeled with ³⁵S, nucleic acids labeled with ³³P and any other combination of molecule and radioisotope. Radioligands may be bound to a secondary biochemical moiety, such as an antibody, membrane receptor, enzyme, nucleic acid or other chemically selective moiety.

[0052] List of Abbreviations:

[0053] a-NPO: 2-(l-naphthyl)-5-phenyloxazole, CAS#846-63-9.

[0054] BBO: 2,5-Di(4-biphenylyl)oxazole, CAS#2083-09-2.

[0055] DPS: trans-4,4’-diphenylstilbene, CAS#2039-68-l.

[0056] POPOP: l,4-Bis(5-phenyl-2-oxazolyl)benzene, CAS#1806-34-4.

[0057] bis-MSB: l,4-bis(2- methylstyryl)benzene, CAS#13280-61-0.

[0058] DM-POPOP: l,4-bis(4-methyl-5-phenyl2-oxazolyl)benzene, CAS#3073-87-8.

[0059] BBOT: 2,5-bis(5-tert-butylbenzoxazol-2-yl)thiophene, CAS#7128-64-5.

[0060] TPB: 1, 1, 4, 4-tetraphenyl-l, 3- butadiene, CAS#1450-63-l.

[0061] DPA: 9,10-diphenylanthracene, CAS#1499-10-l.

[0062] Coumarin 510: 2,3,6,7-tetrahydro-10-(3-pyridinyl)-lH,5H,l 1H- [l]benzopyrano[6,7,8-ij]quinolizin-l 1-one, CAS#: 87349-92-6.

[0063] Coumarin 540A: 2,3,6,7-tetrahydro-9-(trifhioromethyl)-lH,5H,l 1H- [l]benzopyrano(6,7,8-ij)quinolizin-l l-one; CAS#: 53518-18-6.

[0064] Coumarin 515: 3-(2-Nmethylbenzimidazolyl)-7-N,N-diethylaminocoumarin, CAS#41044-12-6.

[0065] Coumarin 7: 3-(2-benzimidazolyl)-7-(diethylamino)coumarin, CAS#27425-55-4.

[0066] DPH: l,6-diphenyl-l,3,5-hexatriene, CAS#1720-32-7.

[0067] BBQ:7H-benzimidazo(2,l-a)benz(de)isoquinoline-7-one, CAS#23749-58-8.

[0068] The inventors surprisingly discovered a method for quantifying a radioisotope in a liquid, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0069] The radioisotope used within the invention disclosed herein is selected from the group consisting of a free radioisotope, a radioisotope bound to a radioligand, and a combination thereof.

[0070] Another aspect of the invention is a composition, comprising: a radioisotope; a plurality of scintillatable metal-organic framework particles; and a liquid in which the radioisotope and the particles are disposed; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound; wherein the radioisotope, as it decays, emits an alpha particle, a beta particle, or gamma photon energy.

[0071] A further aspect of the invention pertains to a method for quantitative analysis of radioisotopes emitting low-energy alpha particles, beta particles or gamma photon energy in water, said method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0072] One advantage of the invention is that suspensible microparticles prepared from metal organic framework (MOF) can directly, and with high sensitivity, detect radioisotopes and radioisotope labeled species directly in aqueous solution. The MOF detection platform, as encompassed by the invention can be used in a traditional SSC/LSC format or it can be chemically modified to enable molecularly selective and specific detection using scintillation proximity assay. [0073] There are numerous applications where it is desirable to detect radioisotopes directly in aqueous solutions compared to scintillation cocktails. For example, the addition of proteins, nucleic acids and other biological samples and/or biopolymers to scintillation cocktail leads to loss of structure, thereby “inactivating” the molecule leading to an “endpoint” analysis and a subsequent lack of temporal resolution and continuous monitoring. The ability to measure directly in aqueous solution alleviates these problems and enables direct, time resolved measurements. Furthermore, many radioisotopes are particularly expensive and cannot be recovered and reused for additional experiments once added to scintillation cocktail. Conversely, purification from aqueous solutions is generally straight forward enabling researchers to maximize the value of the isotopes.

[0074] Radiopharmaceuticals represent a large and growing market for radioisotope detection. Though radiopharmaceutical describe a broad range of research related activities, broadly speaking we see several key areas of radiopharmaceutical growth, as well as a more traditional areas of pharmaceutical chemistry and drug discovery that will benefit from the unique capabilities presented by metal-organic framework (MOF) scintillators.

[0075] The increased need for novel and selective cancer therapeutics has led to the investigation of novel radioisotopes for tumor targeting. Whereas traditional beta (with some gamma) emitters have been used for decades in therapeutic and imaging applications, the longer decay lengths of these isotopes can lead to tissue damage in the bordering tissue. Furthermore, many are not selective to specific cells. The advent of radiolabeled drugs, that bind specifically to receptors that are highly expressed in tumor cells has further expanded the radiopharmaceutical paradigm but identification of new drugs and new radioisotopes is needed to advance this further.

[0076] MOF scintillators enable new research in this arena by providing unprecedented capabilities to measure radioisotopes in native aqueous solutions. Another aspect of the invention pertains to MOF scintillator particles to detect alpha and beta emitters directly in aqueous solutions, said particles comprise a metal and a polyaromatic organic linker compound, wherein the linker compound comprises a functional group selected from the group consisting of terphenyl, trans-stilbene, l,4-phenylene-2, 2 ’-bisoxazole, PPD, PPO, DPA, and derivatives thereof.

[0077] . These particles may be used for quantitative analysis of low-energy fl-emitting radioisotopes in water. For example:

[0078] In some embodiments, the metal is present in the particles from about 15 wt% to about 35 wt%.

[0079] In some embodiments, the invention pertains to particles prepared with 9,10- diphenylanthracene (DPA) as the organic linker compound. Due to the crystalline structure and ability to covalently incorporate organic fluorophores, the issues of fluorescence quenching and dye leakage are largely mitigated with MOFs. The metal ions/nodes in MOFs enable efficient radiation absorption and energy transfer to nearby organic fluorophores.

[0080] Additionally, MOFs exhibit exceptional stability to various solvents and environments, surfaces that are conducive to chemical modification, and dispersibility in water.

[0081] A further aspect of the invention pertains to a method for performing liquid scintillation measurements of radioisotopes, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0082] A further aspect of the invention pertains to a method for biocompatible scintillation for biochemical, biomedical research, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0083] A further aspect of the invention pertains to a method for detecting of radiopharmaceuticals by quantifying a radioisotope in a liquid, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0084] A further aspect of the invention pertains to a method for radioisotope tracing, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0085] Advantages of the disclosed MOFs include, higher scintillation response, stability in aqueous, organic, or mixed solvents, methods to enable continuous monitoring for direct, time-resolved measurements, and maximizing value of isotopes through purification from aqueous solutions.

[0086] To improve the detection efficiency, solid scintillators can be fabricated into three- dimensional materials with nanometer and micron dimension enabling homogeneous dispersion of scintillating particles (SPs) throughout the system. Key requirements for scintillating particles are: i) efficient absorption of [3-emission, ii) efficient energy transfer scintillant fluorophores, iii) stable and suspensible physical structure and size, and iv) a surface that enables chemical modification.

[0087] In one embodiment, we provide a robust alternative based on the zirconium metalorganic frameworks, namely scintillating UiO 68, to measure low-energy [3 emitters in aqueous media. UiO-68 compositions are composed of Zr oxo clusters containing Zr (zirconium) and O (oxygen) 2. UiO-68 is one of the UiO series MOFs, UiO refers to Universitetet i Oslo (University of Oslo).

[0088] As under an elevated concentration of 3H-acetate, the distance between UiO68 and 3H-acetate decreases so the detectability of 3H-acetate increases, and the scintillating signal (CPM) is a linear function of added 3H-acetate.The scintillating UiO 68 is homogeneously constructed from Zr metal clusters connected with a luminescent linker, 9,10-diphenylanthracene, to build the crystalline mesoporous nanostructure. The scintillating properties of UiO68 originate from Zr clusters functioning as energy absorbers of emission from proximal [3 particles, and subsequently emitting photoelectrons that excite nearby linkers that emit visible light upon relaxation. The limit of detection using UiO68 was 10 nCi/mU for ³H. In addition to being stable in aqueous solutions, the scintillating UiO68 are also stable and functional in a wide range of organic and aqueous-organic systems, such as DMF, ethanol, methanol, chloroform. This approach offers an underexplored strategy to design a versatile format and open opportunities for the scintillating proximity assay in various biological fields.

[0089] In addition to being stable in aqueous solutions, the scintillating Zr-MOFs are also stable and functional in a wide range of organic and aqueous-organic systems and uniquely allow control of excitonic transport within the particle in order to avoid energy dissipation during exciton transfer, making it possible to achieve an ultrasensitive platform to sense [3 emitters in biological systems. The scintillating Zr-MOFs mesoporous nanostructures are composed of Zr metal clusters and organic luminescent linkers such as 9,10-diphenylanthracene. An exemplary scheme for the invention is provided in FIGS. 1, FIG. 12A and FIG. 12B. Successful fabrication of UiO-68 Zr-MOF scintillation particles is supported in FIGS. 2A, 2B and 3. Demonstration of the proposed invention, Zr-MOF scintillation particles, functioning as low-energy beta ([3) emitter sensors can be found in FIG. 4.

[0090] Zr metal in conjunction with a broad spectrum of exemplary organic luminescent linkers (U) shown in FIGS. 5A, 5B, 5C and 7 have been used to prepare an array of MOF scintillating particles ranging in size from on the order of 100 nm diameter up to on the order of 10 um diameter.

[0091] In some embodiments, Zr-UiO68-MOFs may be prepared with the dicarboxylated derivative of DPA as the organic component, as shown in, example FIG. 8. Figure 12A in panel A, illustrates the preparation of luminescent MOFs, denoted as Zr-UiO68- MOFs, by self-assembly of Zr ions/nodes/oxoclusters, acid modulators, and organic linkers. DPA was selected primarily because of its efficient fluorescence, featuring a near-unity photoluminescence quantum yield and emission wavelength that is well- suited for detection with commercially available scintillation counters. Without wishing to be limited by any particular theory, along with the exceptional stability attained by Zr- MOFs in aqueous systems, the Zr-oxoclusters are efficient at absorbing ionizing radiation and for energy transfer to nearby organic fluorophores. Zr-oxoclusters also provide exposed active sites that enable surface functionalization to tailor the surface chemistry for future applications, e.g. scintillation proximity assays, if desired.

[0092] LIST OF NON-LIMITING EMBODIMENTS

[0093] Embodiment 1. A composition, comprising: a radioisotope; a plurality of scintillatable metal-organic framework particles; and a liquid in which the radioisotope and the particles are disposed; wherein the metal-organic framework particles comprise a metal (specifically, a metal ion) and a polyaromatic organic linker compound; wherein the radioisotope, as it decays, emits an alpha particle, a beta particle, or gamma photon energy.

Embodiment 2. The composition of embodiment 1, wherein the radioisotope is selected from the group consisting of a free radioisotope, a radioligand, and a combination thereof.

Embodiment 3. The composition of embodiment 1, wherein the liquid comprises an organic solvent.

Embodiment 4. The composition of embodiment 3, wherein the organic solvent is selected from the group consisting of dimethylformamide (DMF), ethanol, methanol, chloroform, and a combination of any two or more of the foregoing organic solvents. Embodiment 5. The composition of any one of the proceeding embodiments, wherein the liquid comprises water.

Embodiment 6. The composition of embodiment 5, wherein the water is present in the liquid at a concentration from about 0.01 wt% to 100 wt%; wherein, when the water is present in the liquid at 100 wt%, the liquid does not comprise an organic solvent.

Embodiment 7. The composition of any one of the preceding embodiments, further comprising a primary fluorescent additive.

Embodiment 8. The composition of embodiment 7, wherein the primary fluorescent additive is selected from the group consisting of PPD, PTP, PBD, PPO, a-NPD, pyrene, BBD, BPO, PBO, PBBO, 0415, 0408, DAT, BIBUQ, BPBD a derivative of any one of the foregoing primary fluorescent additives, and a combination of any two or more of the foregoing primary fluorescent additives. In some embodiments, the additive is preferably PTP.

Embodiment 9. The composition of any one of embodiment 7 or embodiment 8, wherein the mixture further comprises a secondary fluorescent additive.

Embodiment 10. The composition of embodiment 9, wherein the secondary fluorescent additive is selected from the group consisting of a-NPO, BBO, DPS, POPOP, bis-MSB, DM- POPOP, BBOT, TPB, 9,10-diphenylanthracene (DPA), Coumarin 510, Coumarin 540A, Coumarin 515, Coumarin 7, DPH, BBQ, a derivative of any one of the foregoing secondary fluorescent additives, and a mixture of any two or more of the foregoing secondary fluorescent additives.

Embodiment 11. The composition of any one of the preceding embodiments, wherein the metal is selected from the group consisting of Zr, Fe, Cr, Al, Eu, Cu, Zn, Ni, Mn, Ag, Ca, Pb, Tb, Sr, Yb, Gd, Sm, Ce, and Hf.

Embodiment 12. The composition of any one of the preceding embodiments, wherein the linker compound comprises a functional group selected from the group consisting of terphenyl, trans-stilbene, l,4-phenylene-2,2’-bisoxazole, PPD, PPO, DPA, and derivatives thereof.

Embodiment 13. The composition of any one of the preceding embodiments, wherein the beta particle emitting radioisotope is selected from the group consisting of ³H, ¹⁴C, ²²Na, ³³P, ³⁵S, ⁴⁵Ca, ¹²⁵1, ³²P, ²³⁵U, ²²⁵ Ac and ⁸⁶Rb.

Embodiment 14. The composition of any one of the preceding embodiments, wherein the scintillatable metal-organic framework particles are present in the composition from about 0.1 mg/mL to about 30 mg/mL.

Embodiment 15. The composition of any one of the preceding embodiments, wherein the metal is present in the particles from about 15 wt% to about 35 wt%.

Embodiment 16. The composition of any one of the preceding embodiments, wherein the gamma photon energy emitted by the isotope is weak gamma photon energy.

Embodiment 17. The composition of Embodiment 16, wherein the gamma photon energy emitting radioisotope is ¹²⁵I.

Embodiment 18. The composition of any one of the preceeding embodiments, wherein the alpha particle emitting radioisotope is selected from the group consisting of ²⁰⁹Bi, ²¹¹Bi, ²¹²Bi, ²¹³Bi, ²¹⁰Po, ²¹¹Po, ²¹²Po, ²¹⁴Po, ²¹⁵Po, ²¹⁶Po, ²¹⁸Po, ²¹⁵At, ²¹⁷At, ²¹⁸At, ²¹⁸Rn, ²¹⁹Rn, ²²⁰Rn, ²²²Rn, ²²⁶Rn, ²²¹Fr, ²²³Ra, ²²⁴Ra, ²²⁶Ra, ²²⁵ Ac, ²²⁷ Ac, ²²⁷Th, ²²⁸Th, ²²⁹Th, ²³⁰Th, ²³²Th, ²³¹Pa, ²³³U, ²³⁴U, ²³⁵U, ²³⁶U, ²³⁸U, ²³⁷Np, ²³⁸Pu, ²³⁹Pu, ²⁴⁰Pu, ²⁴⁴Pu, ²⁴¹Am, ²⁴⁴Cm, ²⁴⁵Cm, ²⁴⁸Cm, ²⁴⁹Cf, and ²⁵²Cf.

Embodiment 19. A method of quantifying a radioisotope in a liquid, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metalorganic framework particles, and a liquid; and quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound; wherein the radioisotope is selected from the group consisting of a free radioisotope, a radioisotope bound to a radioligand, and a combination thereof.

Embodiment 20. The method of embodiment 19, wherein the liquid comprises an organic solvent.

Embodiment 21. The method of embodiment 20, wherein the organic solvent is selected from the group consisting of DMF, ethanol, methanol, chloroform, and a combination of any two or more of the foregoing organic solvents.

Embodiment 22. The method of any one of embodiments 19 through 21, wherein the liquid comprises water.

Embodiment 23. The method of embodiment 22, wherein the water is present in the liquid at 0.01 wt% to 100 wt%. When the water is present in the liquid at 100 wt%, the liquid does not comprise an organic solvent.

Embodiment 24. The method of any one of embodiments 19 through 23, wherein the mixture further comprises a primary fluorescent additive.

Embodiment 25. The method of embodiment 24, wherein the primary fluorescent additive is selected from the group consisting of PPD, PTP, PBD, PPO, a-NPD, pyrene, BBD, BPO, PBO, PBBO, 0415, 0408, DAT, BIBUQ, BPBD a derivative of any one of the foregoing primary fluorescent additives, and a combination of any two or more of the foregoing primary fluorescent additives.

Embodiment 26. The method of any one of embodiment 24 or embodiment 25, wherein the mixture further comprises a secondary fluorescent additive.

Embodiment 27. The method of embodiment 26, wherein the secondary fluorescent additive is selected from the group consisting of a-NPO, BBO, DPS, POPOP, bis-MSB, DM-POPOP, BBOT, TPB, DPA, Coumarin 510, Coumarin 540A, Coumarin 515, Coumarin 7, DPH, BBQ, a derivative of any one of the foregoing secondary fluorescent additives, and a mixture of any two or more of the foregoing secondary fluorescent additives.

Embodiment 28. The method of any one of embodiments 19 through 27, wherein the metal is selected from the group consisting of Zr and Hf.

Embodiment 29. The method of any one of embodiments 19 through 28, wherein the linker compound comprises a functional group selected from the group consisting of terphenyl, stilbene (e.g. trans-stilbene), l,4-phenylene-2, 2 ’-bisoxazole, PPD, PPO, DPA, and derivatives thereof.

Embodiment 30. The method of any one of embodiments 19 through 29, wherein the radioisotope selected from the group consisting of ³H, ¹⁴C, ¹⁸F, ²²Na, ³³P, ³⁵S, ⁴⁵Ca, ⁶⁸Ga, ⁸⁶Rb, "Tc, ¹¹ Tn, ¹²⁵I, ¹³ , ¹⁷⁷Lu, ²¹¹ At, ²¹³Bi, ²²³Ra, ²²⁵ Ac, ²²⁷Th, ²³²Th, and ²³⁵U.

Embodiment 31. The method of any one of embodiments 19 through 30, further comprising forming the radioligand.

Embodiment 32. The method of any one of embodiments 19 through 31, wherein the gamma photon energy is weak gamma photon energy.

Embodiment 33. The method of any one of embodiments 19 through 32, further comprising using the quantified luminescence at the predetermined wavelength, or the predetermined plurality of wavelengths, to calculate a quantity of radioligand present in the mixture.

Embodiment 34. A method of preparing a scintillatable metal-organic framework particle, the method comprising: dispersing a metal salt, a polyaromatic organic linker and acid in a first solvent to form a mixture; heating the mixture; cooling the mixture to room temperature to obtain a solid; isolating the solid (e.g. by centrifugation); washing the solid with a second solvent (e.g., solvents such as dimethylformamide, an alcohol (such as methanol), etc.); and, drying the solid (e.g., under vacuum) to obtain the scintillatable metal-organic framework particle.

Embodiment 35. The method of embodiment 34, wherein a metal in the metal salt is selected from the group consisting of Zr, Fe, Cr, Al, Eu, Cu, Zn, Ni, Mn, Ag, Ca, Pb, Tb, Sr, Yb, Gd, Sm, Ce, and Hf.

Embodiment 36. The method of embodiment 35, wherein the linker comprises a functional group selected from the group consisting of terphenyl, trans-stilbene, l,4-phenylene-2,2’- bisoxazole, PPD, PPO, DPA, and derivatives thereof.

[0094] Embodiment 37. The scintillatable metal-organic framework particle of Embodiment 34 prepared by any one of the preceding embodiments.

[0095] Embodiment 38. The method of embodiment 34, wherein the acid is selected from the group consisting of an organic acid, inorganic acid, and combinations thereof.

[0096] Embodiment 39. The method of embodiment 38, wherein the inorganic acid is a mineral acid such as hydrochloric acid.

[0097] Embodiment 40. The method of embodiment 38, wherein the organic acid is selected from the group consisting of benzoic acid, benzoic acid derivative (Pentafluorobenzoic acid, cas#602-94-8), acetic acid, acetic acid derivative (e.g., trifluoroacetic acid), and combinations thereof.

[0098] Embodiment 40. The method of embodiment 38, wherein the first solvent is a polar solvent or a nonpolar solvent, or a combination thereof.

[0099] Embodiment 41. The method of embodiment 40, wherein the polar solvent is selected from the group consisting of water, dimethyl formamide (DMF), and dimethyl sulfoxide (DMSO, cas#67-68-5).

[0100] Embodiment 42. The method of embodiment 40 , wherein the nonpolar solvent is N,N-diethylformamide (DEF, cas#617-84-5) or 1,4-dioxane (cas#123-91-l).

[0101] Embodiment 43. The method of embodiment 34, wherein the heating the mixture is performed by heating the mixture to about 90-130 °C. For example, the mixture may be heated at about 100 °C or 120 °C. In some embodiments, the mixture may be heated at a temperature of about 100 °C for about 45 to about 50 hours, or the mixture may be heated at a temperature of about 120 °C for about 24 hours.

[0102] Embodiment 43. The method of embodiment 34, wherein the second solvent is dimethylformamide, or an alcohol (e.g., methanol).

[0103] Embodiment 43. The method of embodiment 34, wherein the mixture is sealed in a reaction vessel prior to heating.

[0104] Embodiment 44. A scintillatable metal-organic framework particle, wherein said particle prepared according to a method comprising: dispersing a metal salt, a polyaromatic organic linker and acid in a first solvent to form a mixture; heating the mixture; cooling the mixture to room temperature to obtain a solid; isolating the solid (e.g. by centrifugation); washing the solid with a second solvent (e.g., solvents such as dimethylformamide, an alcohol (such as methanol), etc.); and, drying the solid (e.g., under vacuum) to obtain the scintillatable metal-organic framework particle.

[0105] Embodiment 45. A MOF scintillator particle to detect alpha, beta, and gamma emitters directly in aqueous solutions, said particle comprising a metal and a polyaromatic organic linker compound, wherein said linker compound comprises a functional group selected from the group consisting of terphenyl, trans-stilbene, l,4-phenylene-2, 2 ’-bisoxazole, PPD, PPO, DPA, and derivatives thereof.

[0106] These particles may be used for quantitative analysis of low-energy -emitting radioisotopes in water. For example:

[0107] In some embodiments, the metal is present in the particles from about 15 wt% to about 35 wt%.

[0108] In some embodiments, the invention pertains to particles prepared with 9,10- diphenylanthracene (DPA) as the organic linker compound. Due to the crystalline structure and ability to covalently incorporate organic fluorophores, the issues of fluorescence quenching and dye leakage are largely mitigated with MOFs. The metal ions/nodes in MOFs enable efficient radiation absorption and energy transfer to nearby organic fluorophores.

[0109] Embodiment 46. A method for performing liquid scintillation measurements of radioisotopes, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0110] Embodiment 47. A method for biocompatible scintillation for biochemical, biomedical research, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0111] Embodiment 48. A method for detecting of radiopharmaceuticals by quantifying a radioisotope in a liquid, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0112] Embodiment 49. A method for radioisotope tracing, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metal-organic framework particles, and a liquid; quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound.

[0113] EXAMPLES

[0114] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, described herein.

[0115] Example 1. Method of preparing zirconium metal organic framework (MOF) particles with 9, 10 diphenylanthracene linker.

[0116] Zirconium MOF particles having polyaromatic organic linkers 1, 2, 3 or 4 (chemical structure shown in FIG. 5C) were prepared as per the protocol described by Wang et al. in https://doi.org/10.1021/ja500671h. ZrCE (11.5 mg, 0.05 mmol), H2L (H2L is an abbreviation to show 2COOH (carboxylic) terminal groups of the linker (L) as H2) chosen core linker in the lists as L (linker 1-4, 0.05 mmol), and trifluoroacetic acid (50 pL, 0.8 mmol) were dispersed in dimethylformamide (DMF) (10 mb), sealed in a vial, and placed in an oil bath. The temperature was kept at 100 °C for 48 hours. After cooling to room temperature, the resulting solid was isolated by centrifugation, and washed with DMF and methanol repeatedly before being dried under vacuum. Linkers 1-5 are provided in FIG. 5C.

[0117] Zirconium metal organic framework particles having linker 5 (chemical structure provided in FIG. 5C) were prepared by a method adapted from Decker et al. (https://doi.org/10.1021/acs.chemmater.9b01383). ZrCh (89 mg, 0.386 mmol), H2L (linker 5, 1.315 mmol), and water (400 pL, 22 mmol) were dispersed in DMF (15 mL), sealed in a vial, and placed in an oil bath. The temperature was kept at 110 °C for 24 hours. After cooling to room temperature, the resulting solid was isolated by centrifugation, and washed with DMF and methanol repeatedly before being dried under vacuum.

[0118] Five organic luminescent linkers (L) that were both incorporated into scintillating MOF particles and characterized as low-energy [3 emission sensing particles are provided in FIG. 5C and characterization data are presented in FIG. 6. ‘Source’ column in FIG. 5C refers to how the various linkers were obtained for use in MOF particles. Linkers LI and L2 were synthesized by inventors and linkers L3, L4 and L5 were purchased from commercial vendors (TCI America, Inc. and AbAChemScene, Inc.). The linkers are the following carboxylic acid derivatives:

[0119] Linker 1: 4,4'-(9,10-Anthracenediyl)bis[benzoic acid, cas# 42824-53-3;

[0120] Linker 2: 4,4'-(2,l,3-Benzothiadiazole-4,7-diyl)bis[benzoic acid], cas# 1581774-76- 6;

[0121] Linker 3: 4,4'-(l,2-Ethenediyl)bis[benzoic acid], cas# 100-31-2;

[0122] Linker 4: 2,6-Naphthalenedicarboxylic acid, cas# 1141-38-4;

[0123] Linker 5: [l,l'-Biphenyl]-4,4'-dicarboxylic acid, cas# 787-70-2.

[0124] In FIG. 6, the ‘Linker in solution’ column refers to the maximal emission wavelength for the linkers in solution, not incorporated in MOFs. The ‘Incorporated in MOFs’ column refers to the wavelength of maximal emission for the linkers once incorporated in MOFs; serving as evidence for successful preparation of MOFs. ‘Scintillation response’ column specifies the concentration of MOF particles, intensity of radioactivity by addition of tritium acetate, and the scintillation counts-per-minute (CPM). In the initial characterization, MOFs formed using linker 1 (LI) provided the highest scintillation response upon incubation with 2000 nCi/mL 3H-acetate. Linker 5 provided the second highest level, though it was approximately 3.5 fold less than MOFs formed with LI . MOFs prepared within linkers 2-5 yielded no or negligible scintillation response.

[0125] Example 2. Method of preparing hafnium MOF particles.

[0126] Hafnium MOF particles were prepared by the protocol as described by Wang et al. (https://doi.org/10.1021/ja500671h). HfCL (16 mg, 0.05 mmol), H2L (21 mg, 0.05 mmol), and trifluoroacetic acid (50 pL, 0.8 mmol) were dispersed in DMF (10 m ), sealed in a vial, and placed in an oven. The temperature was kept at 100 °C for 48 hours. After cooling to room temperature, the resulting solid was isolated by centrifugation, and washed with DMF and methanol repeatedly before being dried under vacuum.

[0127] Example 3. Synthesis of Zr MOFs with DPA linker.

[0128] Zirconium chloride (ZrC14, 0.05 mmol), fluorescent organic DPA linker (0.05 mmol) from Example 2, and trifluoroacetic acid (TFA, 62 pL, 0.8 mmol) were dispersed in N, N-dimethylformamide (DMF, 10 mL), sealed in a vial, and then sonicated until all reactants dissolved before placed in a preheated oil bath. The temperature was kept at 100 °C for 48 hr. After cooling to room temperature, the obtained MOFs were isolated by centrifugation, and washed with methanol and water repeatedly, then dispersed in water. The synthesized MOFs were stable in water and stored at room temperature.

[0129] Example 4. Characterization of Zr MOFs prepared with DPA linker

[0130] The Zr MOFs prepared in Example 3 with DPA linker were characterized. The fluorescent spectra of Zr-MOFs were measured under 365 nm excitation by using a PTI fluorometer using Felix software. The scintillating signals were obtained by Beckman LS 6000 IC liquid scintillation counter (LSC) by using a HDPE 7mL scintillation vial with a screw cap. The Scanning Electron Microscope (SEM) imaging was performed by FEI Inspect S SEM operating at 30 kV equipped with a Thermo Noran System Six X- ray microanalysis system as an energy-dispersive X-ray spectrometer (EDS).

[0131] 4-Carboxyphenylboronic acid (97%), 9,10-dibromoanthracene (98%), bovine serum albumin (BSA, > 96%), potassium carbonate anhydrous (K2CO3, > 99.9%),bis(triphenylphosphine) palladium (II) dichloride (PdCl^_,2(PPh3)2, 98%), concentrated hydrochloric acid (HC1), zirconium chloride (ZrC14, metals basis, > 99.5%), sodium hydroxide, acetonitrile, ethanol, methanol, N, N-dimethylformamide (DMF), tetrahydrofuran (THF), hexane, trifluoroacetic acid (TFA, 98%) were purchased from Fisher Scientific and used as received. All the solvents used were HPLC grade. Tritium-labeled sodium acetate (3H-acetate, specific activity: 1.59 Chmmol-l) was obtained from Perkin Elmer (Waltham, MA). Ultrapure water (18.2 M «cm) was used throughout the experiments.

[0132] The fluorescence spectrum of Zr-UiO68-MOFs was obtained in water and compared to the free DPA confirmed that the fluorescence was maintained in the MOF. The peak emission was red-shifted from 420 nm (for free dicarboxylated-DPA) to 475 nm, possibly due to a stabilized molecular configuration in the microenvironment of Zr- UiO68-MOFs without molecular aggregation - corresponding to lower energetic state(s) with preserved fluorescence emission.

[0133] Thermal gravimetric analysis , scanning electron microscopy , and energy dispersive x-ray spectroscopy were employed to validate the composition of Zr-UiO68-MOFs. It is known in the art that characteristic thermal decomposition occurs at approximately 560 °C. Energy dispersive X-ray spectra contained the characteristic peaks for Zr metal oxo clusters. Additionally, SEM images revealed the expected octahedral topology with a mean particle diameter of ~1.5 pm; a microscale size targeted based on prior research that showed micron-sized MOFs provided a good compromise between stability and functionality for absorption high-energy ionizing radiation, yet remained sufficiently small to facilely disperse in aqueous solutions.

[0134] FIG. 12B, illustrates the processes by which Zr-UiO68-MOFs detect low-energy radioisotopes. A linear scintillation response as a function of mass concentration of Zr- UiO68-MOF SPs was observed for MOF mass concentrations up to 100 pg*mL^_| when the radioactivity from ³H-acetate was fixed at 1000 nCi*mL^_| (FIG. 9A). Similarly, a linear scintillation response as a function of increasing radioactivity of ³H-acetate was observed with a mass concentration of Zr-UiO68-MOFs fixed at 250 pg«m L'¹ (FIG. 9B). The limit of detection (LOD) was determined to be 11 nCi nL’¹. Combined these data support the use ofZr-UiO68-MOFs for quantitative analysis of low-energy radionuclides directly in water in the most typical radioactivity levels used for biological and biochemical measurements.

[0135] To evaluate the stability of the Zr-UiO68-MOFs, a key property for long term utilization, MOFs were incubated in an aqueous solution with a fixed radioactivity of 3H-acetate, with the scintillation response measured daily (FIG. 9C). Over the course of one week, the decrease in scintillation response was less than 10%; where the response exhibited negligible change.

[0136] Many biochemical radioisotope measurements are made in solutions that result in non-specific absorption when particles are used for analytical measurements. Thus, we sought to evaluate the effect of surface passivation via non-specific absorption on the Zr- UiO68-MOFs. The scintillation response of Zr-UiO68-MOFs was evaluated in the presence of 1 mg«mL^-1 bovine serum albumin (BSA), a commonly used model for nonspecific absorption. As shown in FIG. 9D, our results suggested the scintillation of Zr- UiO68-MOFs exhibited a linear function (R² = 0.982) in the presence of BSA.

[0137] In conclusion, we prepared stable, dispersible Zr-UiO68-MOFs SPs for measurement of low-energy radioisotopes directly in aqueous solutions. The scintillation response showed a highly linear relationship between the scintillating signals and radioactivity of spiked low-energy radioisotope. Overall, given their superior long-term stability and ease of use, our results present a new, simple and feasible way for measuring the low- energy radioisotope.

[0138] Prophetic Examples 5-8

[0139] Example 5. Detection of radioisotope in water source.

[0140] We anticipate that luminescent Zr-UiO68-MOFs will find broad use for radiometric detection and radioactive isotope monitoring in wide-ranging applications.

[0141] Water sample can be collected from a water source, for example in northern Arizona and Zr-MOFs or HF-MOFs prepared as described in above Examples can be added to the sample and tested for detection of emission of visible light from the sample using an optical detector. Detection of visible light from the sample indicates the presence of radioactive materials, such as ²³⁵U in the water source.

[0142] Example 6. Detection of radioisotope in drinking water.

[0143] Drinking water sample can be collected, and Zr-MOFs or HF-MOFs prepared as described in above Examples can be added to the sample and taken for detection in an optical detector. Detection of emission of visible light from the sample indicates the presence of radioactive materials in the drinking water sample.

[0144] Example 7. Detecting radiolabeled fertilizer or radiolabeled pesticide in crop samples.

[0145] Crops can be grown in the presence of radiolabeled fertilizer or radiolabeled pesticide. Plant parts of the crop can be tested for presence of radiolabeled fertilizer or radiolabeled pesticide by collecting a plant part, homogenizing the plant part in water, adding a MOF as prepared in above Examples to the homogenized plant part in water, detecting emission of visible light in an optical detector. The detection of visible light from the MOF containing sample indicates the presence of radiolabeled fertilizer or radiolabeled pesticide in the crop.

[0146] Example 8. Tracing how radiolabeled crops are metabolized by a subject.

[0147] If the radiolabeled crops from Example 7 are consumed by a subject (mammals, human or other animals), the metabolism of the radioisotope in the subject can be tracked with the MOFs of the preceding Examples. For example, a subject can be fed a crop treated with a radiolabeled fertilizer or a radiolabeled pesticide, then a blood sample of the subject can be obtained, an MOF added to the blood sample, and the resulting sample taken for detection in an optical detector. The detection of visible light from the sample indicates that the blood sample from the subject has radioactive substances from the consumption of the crop.

[0148] Example 9. General procedure for prepare organic linker

[0149] Chemical

[0150] 4-Carboxyphenylboronic acid (97%), 9,10-dibromoanthracene (98%), bovine serum albumin (BSA, > 96%), potassium carbonate anhydrous (K2CO3, > 99.9%)

[0151] bis(triphenylphosphine) palladium (II) dichloride (PdCl^_,2(PPh3)2, 98%), concentrated hydrochloric acid (HC1), zirconium chloride (ZrC14, metals basis, > 99.5%), sodium hydroxide, acetonitrile, ethanol, methanol, N, N-dimethylformamide (DMF), tetrahydrofuran (THF), hexane, trifluoroacetic acid (TFA, 98%) were purchased from Fisher Scientific and used as received. All the solvents used were HPLC grade. Tritium-labeled sodium acetate (3H-acetate, specific activity: 1.59 CAmmol- l ) was obtained from Perkin Elmer (Waltham, MA). Ultrapure water (18.2 MQ«cm) was used throughout the experiments.

[0152] Methods

[0153] Synthesis of exemplary polyaromatic organic linker compound

[0154] As FIG. 8 shows, the DPA linker was synthesized following the reported procedures. See A. Mallick, A. M. El-Zohry, O. Shekhah, J. Yin, J. Jia, H. Aggarwal, A.-H. Emwas, O. F. Mohammed and M. Eddaoudi, J. Am. Chem. Soc., 2019, 141, 7245-7249. Initially, degas 20 mL acetonitrile and 20 mL 2 M potassium carbonate solution (add 5.585 g K2CO3 in 20 mL water) with argon for 2 hr. Then add 9,10-dibromoanthracene (1.714 g, 5 mmol, 1 eq), 4-carboxyphenylboronic acid (1.822 g, 11 mmol, 2.2 eq), PdCl^_,2(PPh3)2 (0.208 g, 0.29 mmol, 5.7 mol%) in an Ar-flushed 100 mb round- botomed flask equipped with a stirring bar, subsequently add the degassed acetonitrile and potassium carbonate solution by using syringes and refluxed under 100 °C for 48 hr, the solution turned dark grey after the completion of the reaction. After cooling to room temperature, pour 50 mb water to the reaction mixture for quenching the reaction, followed by centrifugation at 5,000 rpm for 10 min to collect the supernatant and discard the dark pellet. Transfer the pale yellowish transparent solution to a 250 mb Erlenmeyer flask, then acidified the solution by using 2 M hydrochloric acid solution until the pH was lower than 2. Collect the crude products by centrifugation at 5,000 rpm for 20 min under 15 °C, then wash the product with water for two times to remove extra acid and dried it overnight. The crude product was purified by recrystallization from THF/hexane for several times to afford an off-white solid (yield = 60%). 1H NMR (500 MHz, DMSO- d6): 5 (ppm) = 13.15 (s, 2H), 8.25 - 8.20 (m, 4H), 7.64 - 7.60 (m, 4H), 7.58 - 7.52 (m, 4H), 7.49 - 7.43 (m, 4H).

[0155] FIG. 8 provides an exemplary synthesis route for a DPA linker for the polyaromatic linker compound disclosed herein.

[0156] Synthesis of Zr-MOFs

[0157] The Zr-MOFs were prepared as described in C. Wang, O. Volotskova, K. Lu, M. Ahmad, C. Sun, L. Xing and W. Lin, J. Am. Chem. Soc., 2014, 136, 6171-6174, with minor modifications.

[0158] Typically, zirconium chloride (ZrC14, 0.05 mmol), fluorescent organic linker (0.05 mmol), and trifluoroacetic acid (TFA, 62 pL, 0.8 mmol) were dispersed in N, N- dimethylformamide (DMF, 10 mb), sealed in a vial, and then sonicated until all reactants dissolved before placed in a preheated oil bath. The temperature was kept at 100 °C for 48 hr. After cooling to room temperature, the obtained MOFs were isolated by centrifugation, and washed with methanol and water repeatedly, then dispersed in water. The synthesized MOFs were stable in water and stored at room temperature.

[0159] MOF Characterization

[0160] The fluorescent spectra of Zr-MOFs were measured under 365 nm excitation by using a PTI fluorometer using Felix software. The scintillating signals were obtained by Beckman LS 6000 IC liquid scintillation counter (LSC) by using a HDPE 7mL scintillation vial with a screw cap. The Scanning Electron Microscope (SEM) imaging was performed by FEI Inspect S SEM operating at 30 kV equipped with a Thermo Noran System Six X-ray microanalysis system as an energy-dispersive X-ray spectrometer (EDS).

[0161] All publications (including the Communication entitled: “ Low-energy radionuclide sensing with luminescent metal-organic frameworks” by Ke et al. (manuscript submitted for publication) and those mentioned herein are incorporated by reference to the extent they support the present invention.

Claims

CLAIMS We claim:

1. A composition, comprising: a radioisotope; a plurality of scintillatable metal-organic framework particles; and a liquid in which the radioisotope and the particles are disposed; wherein the metal-organic framework particles comprise a metal (specifically, a metal ion) and a polyaromatic organic linker compound; wherein the radioisotope, as it decays, emits an alpha particles-, a beta particle, or gamma photon energy.

2. The composition of claim 1, wherein the radioisotope is a free radioisotope, a radioligand, or a combination thereof.

3. The composition of claim 1, wherein the liquid comprises an organic solvent.

4. The composition of claim 3, wherein the organic solvent is selected from the group consisting of dimethylformamide (DMF), ethanol, methanol, chloroform, and a combination of any two or more of the foregoing organic solvents.

5. The composition of any one of the proceeding claims, wherein the liquid comprises water.

6. The composition of claim 5, wherein the water is present in the liquid at a concentration from about 0.01 wt% to 100 wt%; wherein, when the water is present in the liquid at 100 wt%, the liquid does not comprise an organic solvent.

7. The composition of any one of the preceding claims, further comprising a primary fluorescent additive.

8. The composition of claim 7, wherein the primary fluorescent additive is selected from the group consisting of PPD, PTP, PBD, PPO, a-NPD, pyrene, BBD, BPO, PBO, PBBO, 0415, 0408, DAT, BIBUQ, BPBD a derivative of any one of the foregoing primary fluorescent

32 additives, and a combination of any two or more of the foregoing primary fluorescent additives.

9. The composition of any one of claim 7 or embodiment 8, wherein the mixture further comprises a secondary fluorescent additive.

10. The composition of claim 9, wherein the secondary fluorescent additive is selected from the group consisting of a-NPO, BBO, DPS, POPOP, bis-MSB, DM-POPOP, BBOT, TPB, 9,10-diphenylanthracene (DPA), Coumarin 510, Coumarin 540A, Coumarin 515, Coumarin 7, DPH, BBQ, a derivative of any one of the foregoing secondary fluorescent additives, and a mixture of any two or more of the foregoing secondary fluorescent additives.

11. The composition of any one of the preceding claims, wherein the metal is selected from the group consisting ofZr, Fe, Cr, Al, Eu, Cu, Zn, Ni, Mn, Ag, Ca, Pb, Tb, Sr, Yb, Gd, Sm, Ce, and Hf.

12. The composition of any one of the preceding claims, wherein the linker compound comprises a functional group selected from the group consisting of terphenyl (e.g., p- Terphenyl), stilbene (e.g., trans-stilbene), l,4-phenylene-2,2’-bisoxazole, stilbene, dimethyl POPOP, PPD, PPO, DPA, and derivatives thereof.

13. The composition of any one of the preceding claims, wherein the beta particle emitting radioisotope is selected from the group consisting of ³H, ¹⁴C, ²²Na, ³³P, ³⁵S, ⁴⁵Ca, ¹²⁵1, ³²P, ²³⁵U, ²²⁵Ac and ⁸⁶Rb.

14. The composition of any one of the preceding claims, wherein the scintillatable metalorganic framework particles are present in the composition from about 0. 1 mg/mL to about 30 mg/mL.

15. The composition of any one of the preceding claims, wherein the metal is present in the particles from about 15 wt% to about 35 wt%.

33

16. The composition of any one of the preceding claims, wherein the gamma photon energy emitted by the isotope is weak gamma photon energy.

17. The composition of claim 16, wherein the gamma photon energy emitting radioisotope is 125j

18. The composition of any one of the preceding claims, wherein the alpha particle emitting radioisotope is selected from the group consisting of ²⁰⁹Bi, ²¹¹Bi, ²¹²Bi, ²¹³Bi, ²¹⁰Po, ²¹¹Po, ²¹²Po, ²¹⁴Po, ²¹⁵Po, ²¹⁶Po, ²¹⁸Po, ²¹⁵At, ²¹⁷At, ²¹⁸At, ²¹⁸Rn, ²¹⁹Rn, ²²⁰Rn, ²²²Rn, ²²⁶Rn, ²²¹Fr, ²²³Ra, ²²⁴Ra, ²²⁶Ra, ²²⁵ Ac, ²²⁷Ac, ²²⁷Th, ²²⁸Th, ²²⁹Th, ²³⁰Th, ²³²Th, ²³¹Pa, ²³³U, ²³⁴U, ²³⁵U, ²³⁶U, ²³⁸U, ²³⁷Np, ²³⁸Pu, ²³⁹Pu, ²⁴⁰Pu, ²⁴⁴Pu, ²⁴¹Am, ²⁴⁴Cm, ²⁴⁵Cm, ²⁴⁸Cm, ²⁴⁹Cf, and ²⁵²Cf.

19. A method of quantifying a radioisotope in a liquid, the method comprising: forming a mixture comprising a radioisotope, a plurality of scintillatable metalorganic framework particles, and a liquid; wherein the metal-organic framework particles comprise a metal and a polyaromatic organic linker compound; and quantifying luminescence of a predefined wavelength, or a predefined plurality of wavelengths, that is emitted from the mixture wherein the radioisotope is selected from the group consisting of a free radioisotope, a radioisotope bound to a radioligand, and a combination thereof.

20. The method of claim 19, wherein the liquid comprises an organic solvent.

21. The method of claim 18, wherein the organic solvent is selected from the group consisting of DMF, ethanol, methanol, chloroform, and a combination of any two or more of the foregoing organic solvents.

22. The method of any one of claims 19 through 21, wherein the liquid comprises water.

23. The method of claim 22, wherein the water is present in the liquid at 0.01 wt% to 100 wt%; wherein, when the water is present in the liquid at 100 wt%, the liquid does not comprise an organic solvent.

24. The method of any one of claims 19 through 23, wherein the mixture further comprises a primary fluorescent additive.

25. The method of claim 24, wherein the primary fluorescent additive is selected from the group consisting of PPD, PTP, PBD, PPO, a-NPD, pyrene, BBD, BPO, PBO, PBBO, 0415, 0408, DAT, BIBUQ, BPBD a derivative of any one of the foregoing primary fluorescent additives, and a combination of any two or more of the foregoing primary fluorescent additives.

26. The method of any one of claim 23 or claim 24, wherein the mixture further comprises a secondary fluorescent additive.

27. The method of claim 26, wherein the secondary fluorescent additive is selected from the group consisting of a-NPO, BBO, DPS, POPOP, bis-MSB, DM-POPOP, BBOT, TPB, DPA, Coumarin 510, Coumarin 540A, Coumarin 515, Coumarin 7, DPH, BBQ, a derivative of any one of the foregoing secondary fluorescent additives, and a mixture of any two or more of the foregoing secondary fluorescent additives.

28. The method of any one of claims 19 through 27, wherein the metal is selected from the group consisting of Zr and Hf.

29. The method of any one of claims 19 through 28, wherein the linker comprises a functional group selected from the group consisting of terphenyl, trans-stilbene, 1,4- phenylene-2,2’-bisoxazole, PPD, PPO, DPA, and derivatives thereof.

30. The method of any one of claims 19 through 29, wherein the radioisotope selected from the group consisting of ³H, ¹⁴C, ¹⁸F, ²²Na, ³³P, ³⁵S, ⁴⁵Ca, ⁶⁸Ga, ⁸⁶Rb, "Tc, ^mIn, ¹²⁵1, ¹³¹I, ¹⁷⁷Lu, ²¹¹At, ²¹³Bi, ²²³Ra, ²²⁵Ac, ²²⁷Th, ²³²Th, and ²³⁵U.

31. The method of any one of claims 19 through 30, further comprising forming the radioligand.

32. The method of any one of claims 19 through 31, wherein the gamma photon energy is weak gamma photon energy.

33. The method of any one of claims 19 through 32, further comprising using the quantified luminescence at the predetermined wavelength, or the predetermined plurality of wavelengths, to calculate a quantity of radioligand present in the mixture.

34. A method of preparing a scintillatable metal-organic framework particle, the method comprising: dispersing a metal salt, a polyaromatic organic linker and acid in a first solvent to form a mixture; heating the mixture; cooling the mixture to room temperature to obtain a solid; isolating the solid (e.g. by centrifugation); washing the solid with a second solvent (e.g., solvents such as dimethylformamide, an alcohol (such as methanol), etc.); and, drying the solid (e.g., under vacuum) to obtain the scintillatable metal-organic framework particle.

35. The method of claim 34, wherein a metal in the metal salt is selected from the group consisting of Zr, Fe, Cr, Al, Eu, Cu, Zn, Ni, Mn, Ag, Ca, Pb, Tb, Sr, Yb, Gd, Sm, Ce, and Hf.

36. The method of claim 34, wherein the linker comprises a functional group selected from the group consisting of terphenyl, trans-stilbene, l,4-phenylene-2, 2 ’-bisoxazole, PPD, PPO, DPA, and derivatives thereof.

37. The scintillatable metal-organic framework particle of claim 34 prepared by any one of the preceeding claims.

36