阅读说明：本技术 金属有机框架、药物制剂及其在制备药物中的用途 (Metal organic framework, pharmaceutical preparation and use thereof in preparing medicament ) 是由 林文斌 何春柏 卢旷达 于 2015-10-14 设计创作，主要内容包括：本申请提供金属有机框架、药物制剂及其在制备药物中的用途。本发明描述包含光敏剂的金属有机框架(MOF)。所述MOF还可以包括能够吸收X射线和/或闪烁光的部分。可选地,所述光敏剂或其衍生物可以形成所述MOF的桥连配位体。另外,所述MOF可以可选地在所述MOF的腔体或通道中包含无机纳米颗粒或可以与无机纳米颗粒组合使用。本发明还描述了在光动力疗法中或X射线诱导的光动力疗法中使用MOF和/或无机纳米颗粒的方法,其中伴随或不伴随一种或多种免疫治疗剂和/或一种或多种化学治疗剂的共施用。(The present invention describes Metal Organic Frameworks (MOFs) comprising photosensitizers, the MOFs may also include moieties capable of absorbing X-rays and/or scintillating light, optionally the photosensitizers or derivatives thereof may form bridging ligands for the MOFs.)

1. Use of a scintillator and a nanoparticle comprising a photosensitizer for the manufacture of a medicament for the treatment of a disease in a patient, the treatment comprising administering the scintillator and the nanoparticle comprising a photosensitizer to a patient, irradiating at least parts of the patient with X-rays, and administering an immunotherapeutic agent to the patient.

2. The use of claim 1, wherein the disease is selected from the group consisting of head tumors, neck tumors, breast tumors, gynecological tumors, brain tumors, colorectal cancers, lung cancers, mesothelioma, soft tissue sarcomas, skin cancers, connective tissue cancers, adipose cancers, lung cancers, stomach cancers, anal and genital cancers, kidney cancers, bladder cancers, colon cancers, prostate cancers, central nervous system cancers, retinal cancers, blood cancers, neuroblastoma, multiple myeloma, lymphatic cancers, and pancreatic cancers.

3. The use of claim 1, wherein the immunotherapeutic agent is selected from the group consisting of an anti-CD 52 antibody, an anti-CD 20 antibody, an anti-CD 47 antibody, an anti-GD 2 antibody, a radiolabeled antibody, an antibody-drug conjugate, a cytokine, polysaccharide K, and a neo-antigen, optionally wherein the cytokine is an interferon, an interleukin, or tumor necrosis factor α, further optionally wherein the cytokine is selected from the group consisting of IFN- α, INF- γ, IL-2, IL-12, and TNF- α.

4. The use of claim 1, wherein the immunotherapeutic agent is selected from the group consisting of: alemtuzumab, ofatumumab, rituximab, zeugalin, aldrich, trastuzumab, and dinil interleukin.

5. The use of claim 1, wherein the immunotherapeutic agent is selected from the group consisting of: PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, IDO inhibitors, and CCR7 inhibitors.

6. The use of claim 1, wherein the disease is metastatic cancer.

7. The use of claim 1, wherein irradiating the patient with X-rays comprises generating X-rays using a tungsten target.

8. The use of claim 7, wherein the X-rays generated using a tungsten target pass through a filter before irradiating the patient, optionally wherein the filter comprises an element having an atomic number of at least 20, further optionally wherein the filter comprises copper.

9. The use of claim 8, wherein the optical filter has a thickness of less than 5mm, less than 4mm, less than 3mm, less than 2mm, less than 1mm, less than 0.5mm, less than 0.4mm, less than 0.3mm, less than 0.2mm, or less than 0.1 mm.

10. The use of claim 1, wherein the X-rays are generated using a peak voltage of less than 230kVp, less than 225kVp, less than 200kVp, less than 180kVp, less than 160kVp, less than 140kVp, less than 120kVp, less than 100kVp, or less than 80 kVp.

11. The use of claim 1, wherein the X-rays are generated using peak voltages, currents and optional filters, the filters selected so as to minimize DNA damage to the patient due to X-ray exposure and maximize X-ray absorption by the scintillator.

12. The use of claim 1, wherein the X-rays are generated using a 120kVp peak voltage.

13. The use of claim 1, wherein the scintillator comprises a lanthanide.

14. The use of claim 13, wherein the scintillator comprises lanthanide nanoparticles, optionally wherein the scintillator comprises lanthanide core-shell nanoparticles, further optionally , wherein the shell of the lanthanide core-shell nanoparticles comprises a lanthanide chalcogenide.

15. The use of claim 1, wherein the scintillator comprises a metal-organic framework comprising hafnium, zirconium or cerium, optionally wherein the scintillator comprises M₆(μ₃-O)₄(μ₃-OH)₄L₆Wherein M is hafnium, zirconium or cerium, and L is 9, 10-anthracylbis-benzoic acid.

16. The use of claim 15, wherein the photosensitizer is covalently bound to the metal-organic framework, optionally wherein the covalent linkage is formed via amide coupling, ester coupling, thiourea coupling, click chemistry or disulfide coupling.

17. Use according to claim 1, wherein the scintillator comprises carbon dots.

18. The use of claim 1, wherein the scintillator comprises core-shell nanoparticles, wherein the shell comprises zinc sulfide and the core comprises a transition metal or a lanthanide metal.

19. The use of claim 1, wherein the scintillator comprises nanoparticles comprising gold, platinum, or iridium.

20. Use according to claim 1, wherein the scintillator comprises lanthanide aluminium garnet or lanthanide fluoride.

21. The use of claim 1, wherein the photosensitizer is bound to the scintillator via a coordination bond.

22. The use according to claim 21, wherein:

the photosensitizer comprises a carboxylate, thiol, hydroxyl, amino, or phosphate group;

the scintillator comprises a metal; and is

The carboxylate, thiol, hydroxyl, amino, or phosphate group is bonded to the metal.

23. The use of claim 22, wherein the photosensitizer is linked to the scintillator and the linkage comprises a cyclodextrin, a polyethylene glycol, a poly (maleic acid), or C₂-C₁₅Straight or branched alkyl chains.

24. The use of claim 23, wherein the photosensitizer comprises of the following, or a deprotonated form of of the following:

25. use according to claim 1, wherein the scintillator is encapsulated in a metal organic framework or in mesoporous silica.

Technical Field

The presently disclosed subject matter provides metallo-organic framework (MOF) material-based nanocarrier platforms for photodynamic therapy (PDT), X-ray induced photodynamic therapy (X-PDT), Radiotherapy (RT), chemotherapy, immunotherapy, or any combination thereof, including nano-scale metallo-organic framework (NMOF), for PDT, for X-ray induced photodynamic therapy (X-PDT), for example, for PDT in an embodiment , for X-PDT in an embodiment , for RT. in an embodiment , for a combination of X-PDT and 5635 in an embodiment 7, for PDT or for a combination of X-RT and immunotherapy in an embodiment , for a combination of chemotherapy, for an embodiment , for a combination of chemotherapy and immunotherapy, for a combination of PDT 365635.

Background

Photodynamic therapy (PDT) may be an effective anticancer treatment option. PDT involves the administration of a tumor-localized Photosensitizer (PS) followed by photoactivation to generate highly cytotoxic Reactive Oxygen Species (ROS), specifically singlet oxygen (R) ((R))¹O₂) Thereby causing apoptosis and necrosis. By localizing the PS and illumination to the tumor area, PDT can selectively kill tumor cells while preserving local tissue. PDT has been used to treat patients with a variety of different types of cancer, including head and neck tumors, breast cancer, gynecological tumors, brain tumors, colorectal cancer, mesothelioma, and pancreatic cancer. The use of PDT to treat head and neck cancers is particularly advantageous over traditional treatment modalities, such as surgery and irradiation, because PDT causes less damage to surrounding tissues and reduces loss of aesthetics and function. Porphyrin molecules, e.g.

And

is the PS most commonly used for PDT. However, despite the photochemical properties of these molecules to generate ROS efficiently, suboptimal tumor accumulation of these molecules after systemic administration can limit the efficacy of PDT in the clinic.

Accordingly, there is a continuing need for additional delivery vehicles (delivery vehicles) for improved delivery (e.g., targeted delivery) of PS therapeutics, in particular, delivery vehicles that can deliver combinations of PS and other therapeutics (e.g., other chemotherapeutic and immunotherapeutic agents) in order to increase therapeutic efficacy.

Abbreviations

Degree centigrade

Percent is

μ l to μ l

Micromolar concentration of

BODIPY ═ boron-dipyrromethene

bpy 2,2' -bipyridine

cm is equal to centimeter

DBBC ═ 5, 15-di (p-benzoyloxy) bacteriochlorin

DBC ═ 5, 15-di (p-benzoyloxy) chlorin

DBP ═ 5, 15-di (p-benzoyloxy) porphyrin

DLS ═ dynamic light scattering

DMF ═ dimethylformamide

DMSO ═ dimethyl sulfoxide

DOPC ═ 1, 2-dioleoyl-sn-glycerol-3-phosphate sodium salt

DOTAP ═ 1, 2-dioleoyl-3-trimethylammonium propane

DSPE-PEG_2k1, 2-distearoyl-sn-glycerol-3-phosphate ethyl ester

Alcohol amine-N- [ amino (polyethylene glycol) 2000]

g is g ═ g

h is hour

Hf is hafnium

IC₅₀Fifty percent inhibitory concentration

ICP-MS (inductively coupled plasma-mass spectrometry)

kg is kg

kVp-peak kilovolt

Ln is lanthanoid

mg ═ mg

min is minutes

mL to mL

mM to millimolar concentration

mmol ═ mmol

Mn ═ Mn

MOF ═ metal organic frameworks

MRI (magnetic resonance imaging)

m-THPC ═ tetra (m-hydroxyphenyl) chlorin

MW ═ molecular weight

NIR ═ near infrared

nm-nm

NMOF-nano-scale metal-organic framework

NMR (nuclear magnetic resonance)

PBS-phosphate buffered saline

PDI ═ polydispersity index

PDT (photodynamic therapy)

PEG ═ polyethylene glycol

PS ═ photosensitizers

Pt ═ platinum

PVP ═ polyvinylpyrrolidone

RES (reticuloendothelial system)

rpm is the number of revolutions per minute

Ru ═ ruthenium

SBU is a secondary building block

sec is second

Fluorescent probe for singlet oxygen

TEM (transmission electron microscope)

TFA ═ trifluoroacetic acid

TBC-5, 10,15, 20-tetrakis (benzoyloxy) dihydro

Porphin

TBP ═ 5,10,15, 20-tetrakis (p-benzoyloxy) -porn

Quinoline (III)

X-PDT (X-ray-induced photodynamic therapy)

Zn ═ zinc

Zr ═ zirconium

Disclosure of Invention

In embodiments, the presently disclosed subject matter provides a Metal Organic Framework (MOF) comprising a) a photosensitizer, and b) a plurality of metal-containing Secondary Building Units (SBUs) linked together at via bridging ligands, optionally wherein the SBUs are metal oxygen clusters, in embodiments or more SBUs contain metal cations capable of absorbing x-rays, in embodiments or more SBUs contain metal ions selected from the group consisting of Hf, lanthanide metals, Ba, Ta, W, Re, Os, Ir, Pt, Au, Pb, and Bi.

In embodiments, the MOF further comprises at least of a metal polyacid salt, a metal nanoparticle, or a metal oxide nanoparticle located in a cavity or channel of the MOF.

In embodiments, each bridging ligand comprises an organic compound comprising a plurality of coordination sites, optionally wherein each bridging ligand comprises between 2 and 10 coordination sites in embodiments, each bridging ligand is capable of binding to two or three sbus in embodiments, each bridging ligand comprises at least two groups, wherein the two groups are each independently selected from the group comprising carboxylate, aromatic or non-aromatic nitrogen-containing groups, phenolic groups, acetyl acetonate, phosphonate, and phosphate groups, optionally wherein the aromatic nitrogen-containing groups are pyridine groups.

In some embodiments, at least of the bridging ligands comprise a photosensitizer or photosensitizer derivative in some embodiments, at least bridging ligands comprise a porphyrin, chlorin, chlorophyll, phthalocyanine, ruthenium-bipyridine complex, or iridium-bipyridine complex in some embodiments, at least bridging ligands comprise diphenyl-bis (benzoyloxy) porphyrin, dibenzoyloxy (bipyridyl) ruthenium bis (bipyridine), tetra (benzoyloxy) porphyrin, or dibenzoyloxy (bipyridine) ruthenium bis (phenylpyridine) in some embodiments, at least bridging ligands are:

in , or more SBUs comprise ions selected from oxygen ions and OH^-The anion of (4).

In embodiments, at least bridging ligands are porphyrin-based ligands, chlorin-based ligands, bacteriochlorin-based ligands, macrocyclic pi-conjugated systems, boron-dipyrromethene (BODIPY) derivatives or bis-salicylidene-1, 2-cyclohexylidene diamine derivatives in embodiments, at least bridging ligands are selected from 5, 15-bis (p-benzoyloxy) porphyrin (DBP) or derivatives and/or metal complexes thereof, 5, 15-bis (p-benzoyloxy) chlorin (DBC) or derivatives and/or metal complexes thereof, 5, 15-bis (p-benzoyloxy) bacteriochlorin (DBBC) or derivatives and/or metal complexes thereof, 5,10,15, 20-tetrakis (p-benzoyloxy) porphyrin or derivatives and/or metal complexes thereof, 5,10,15, 20-tetrakis (p-pyridyl) porphyrin, phthalocyanine-octacarboxylic acid, optionally complexed with a metal, bis (5' -benzoyloxy) -1, 2-cyclohexylidene diamine derivatives and optionally substituted with at least one or more of the group consisting of palladium-porphyrin, palladium-bis (p-benzoyloxy) porphyrin, palladium-1, 2-cyclohexylidene diamine derivatives and lutetium- (TPO-dihydroporphyrin) derivatives and lutetium- (TPO) porphyrin derivatives, palladium-tris (p-benzoyloxy) porphyrin, palladium-phenoxide) and lutetium- (p-phenoxide) porphyrin derivatives and lutetium- (p-phenoxide) substituted in 4632) porphyrin derivatives and optionally substituted in embodiments.

In embodiments, the photosensitizer is a covalently linked dye, optionally wherein the dye is covalently linked via an amide or thiourea bond in embodiments, at least bridging ligands are a quaterphenyl dicarboxylic acid derivative in embodiments, the MOF comprises:

in some embodiments , the photosensitizer is a dye that is non-covalently entrapped within the MOF in some embodiments , the dye is a compound or compound derivative selected from the group consisting of toluidine blue, methylene blue, Nile blue (Nileblue), hypericin, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, and a chalcogenide pyran salt.

In some embodiments , the photosensitizer is selected from the group consisting of protoporphyrin IX, papporfin, tetrakis (m-THPC), NPe6, chlorin e6, lotalporfin, and derivatives thereof.

In embodiments, the MOF further comprises a non-covalently bound platinum drug, temozolomide (temozolomide), doxorubicin (doxorubicin), camptothecin (camptothecin), paclitaxel (paclitaxel), pemetrexed (pemetrexed), methotrexate (methotrexate), or an IDO inhibitor, optionally wherein the IDO inhibitor is selected from the group comprising ICBN24360, NLG-919, 1-methyl-D-tryptophan, and 1-methyl-L-tryptophan in embodiments, the MOF further step comprises a covalently or electrostatically bound polyethylene glycol (PEG) moiety or or more lipid molecules, optionally wherein or more lipid molecules are selected from the group comprising 1, 2-dioleoyl-3-trimethylammonium propane (DOTAP), 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOTAP), and 1, 2-dioleoyl-sn-glycero-3-phosphocholine (dsn- [ dsn-amino-Phosphoethanolamine (PEG) ].

In embodiments, the presently disclosed subject matter provides pharmaceutical formulations comprising a MOF comprising a photosensitizer and a plurality of SBUs linked together at via a bridging ligand, optionally wherein the SBUs are metal oxygen clusters, and a pharmaceutically acceptable carrier.

In embodiments, the presently disclosed subject matter provides a method for treating a disease in a patient, the method comprising administering to the patient a MOF comprising a photosensitizer and a plurality of SBUs linked together at via a bridging ligand, optionally wherein the SBUs are metal oxygen clusters, and irradiating the patient with visible or near infrared light, in embodiments, irradiating on portions of the patient's body structure selected from the patient's skin, blood, and gastrointestinal tract, in embodiments, the disease is selected from the group consisting of a head tumor, a neck tumor, a breast cancer, a gynecological tumor, a brain tumor, a colorectal cancer, a lung cancer, a mesothelioma, a soft tissue sarcoma, and a pancreatic cancer.

In embodiments, the presently disclosed subject matter provides a method for treating a disease in a patient, the method comprising administering to the patient a MOF comprising a photosensitizer and a plurality of SBUs linked up to via a bridging ligand, optionally wherein the SBUs are metal oxygen clusters, and irradiating at least the portion of the patient with x-rays, in embodiments or more of the bridging ligands comprise an anthracene linker, such as 9, 10-anthracenylbis (benzoic acid).

In embodiments, the disease is selected from the group consisting of a head tumor, a neck tumor, breast cancer, gynecological tumor, brain tumor, colorectal cancer, lung cancer, mesothelioma, soft tissue sarcoma, and pancreatic cancer, in embodiments, the disease is metastatic cancer.

In in some embodiments, the immunotherapeutic agent is selected from the group consisting of a PD-1/PD-L1 antibody, an IDO inhibitor, a CTLA-4 antibody, an OX40 antibody, a TIM3 antibody, a LAG3 antibody, a siRNA-targeted PD-1/PD-L1, a siRNA-targeted IDO, and a siRNA-targeted CCR 7.

In embodiments, the presently disclosed subject matter provides methods for treating a disease in a patient, the method comprising administering to the patient a scintillant and nanoparticles comprising a photosensitizer, irradiating at least a portion of the patient with X-rays, and administering to the patient an immunotherapeutic agent in embodiments, the disease is selected from the group consisting of a head tumor, a neck tumor, a breast cancer, a gynecological tumor, a brain tumor, a colorectal cancer, a lung cancer, a mesothelioma, a soft tissue sarcoma, a skin cancer, a connective tissue cancer, a adipose cancer, a lung cancer, a stomach cancer, an anal and a genital cancer, a kidney cancer, a bladder cancer, a colon cancer, a prostate cancer, a central nervous system cancer, a retinal cancer, a blood cancer, a neuroblastoma, a multiple myeloma, a lymphoma, and a pancreatic cancer.

In embodiments, the method further comprises step administering to the patient an additional cancer therapy, in embodiments, the additional cancer therapy is selected from the group consisting of surgery, radiation therapy, chemotherapy, toxin therapy, immunotherapy, cryotherapy, and gene therapy, optionally wherein the chemotherapy comprises (a) administering to the patient a drug selected from the group consisting of oxaliplatin (oxaliplatin), doxorubicin, daunorubicin (daunorubicin), docetaxel (docetaxel), mitoxantrone (mitoxantrone), paclitaxel, digitoxin (digitoxin), digoxin (digoxin), and/or a humicide (septicidin), and/or (b) administering to the patient a drug selected from the group consisting of polymeric micelle, liposomal, dendrimer, polymeric nanoparticle, silica-based nanoparticle, nanoscale coordination polymer, nanoscale metal organic framework, and inorganic nanoparticle.

in some embodiments, the immunotherapeutic agent is selected from the group consisting of anti-CD 52 antibody, anti-CD 20 antibody, anti-CD 20 antibody, anti-CD 47 antibody, anti-GD 2 antibody, radiolabeled antibody, antibody-drug conjugate, cytokine, polysaccharide K and a neo-antigen, optionally wherein the cytokine is interferon, interleukin or tumor necrosis factor α (TNF- α), and optionally wherein the cytokine is selected from the group consisting of IFN- α, INF-gamma, IL-2, IL-12 and TNF- α. in embodiments, the immunotherapeutic agent is selected from the group consisting of Alemtuzumab (Alemzumab), Ofatumumab (Ofatumumab), Rituximab (Rituximab), Zevalin (Zevalin), AddeSite Ritutricis (Adertris), tuzumab (Kadcylla), and Ontan (Takk). In. 3, the inhibitor of Onta 3884, the inhibitor of IDO-4642, the inhibitor of IDO-1.

In embodiments, the disease is metastatic cancer.

In some embodiments , irradiating the patient with X-rays comprises generating X-rays using a tungsten target in some embodiments , the X-rays generated using the tungsten target pass through a filter before irradiating the patient, optionally wherein the filter comprises an element having an atomic number of at least 20, further optionally wherein the filter comprises copper in some embodiments , the thickness of the filter is less than 5mm, less than 4mm, less than 3mm, less than 2mm, less than 1mm, less than 0.5mm, less than 0.4mm, less than 0.3mm, less than 0.2mm, or less than 0.1mm in some embodiments Vp embodiments, the X-rays are generated using a peak voltage of less than 230kVp, less than 225kVp, less than 200kVp, less than 180kVp, less than 160kVp, less than 140kVp, less than 120kVp, less than 100kVp, or less than 80 kVp.

In embodiments, the X-rays are generated using peak voltage, current, and optional filters selected to minimize patient DNA damage caused by X-ray exposure and maximize scintillator absorption of X-rays in embodiments, the X-rays are generated using 120kVp peak voltage.

In embodiments , the scintillator comprises a lanthanide, in embodiments , the scintillator comprises a lanthanide nanoparticle, optionally wherein the scintillator comprises a lanthanide core-shell nanoparticle, further optionally , wherein the shell of the lanthanide core-shell nanoparticle comprises a lanthanide chalcogenide.

In embodiments, the scintillator comprises a MOF comprising hafnium, zirconium, or cerium, optionally wherein the scintillator comprises M₆(μ₃-O)₄(μ₃-OH)₄L₆Wherein M is hafnium, zirconium or cerium and L is 9, 10-anthracenylbisbenzoic acid in embodiments, the photosensitizer is covalently bound to the MOF, optionally wherein the covalent linkage is formed via amide coupling, ester coupling, thiourea coupling, click chemistry, or disulfide coupling.

In embodiments, the scintillator comprises carbon dots (carbon dots), in embodiments, the scintillator comprises core-shell nanoparticles, wherein the shell comprises zinc sulfide and the core comprises a transition metal or lanthanide metal, in embodiments, the scintillator comprises nanoparticles comprising gold, platinum, or iridium, in embodiments, the scintillator comprises lanthanide aluminum garnet or lanthanide fluoride.

In some embodiments , the photosensitizer is bound to the scintillator via a coordination bond in some embodiments , the photosensitizer comprises a carboxylate, thiol, hydroxyl, amino, or phosphate group, the scintillator comprises a metal, and the carboxylate, thiol, hydroxyl, amino, or phosphate group is bound to the metal.

In embodiments, the photosensitizer is linked to the scintillator and the linkage comprises a cyclodextrin, a polyethylene glycol, a poly (maleic acid), or a C₂-C₁₅ embodiments, the photosensitizer comprises of the following, or a deprotonated form of of the following:

in embodiments, the scintillator is encapsulated in a MOF or mesoporous silica in embodiments, the photosensitizer is entrapped in the pores of the mesoporous silica or is covalently attached to the MOF.

In embodiments, the presently disclosed subject matter provides methods for treating a disease in a patient, the method comprising administering to the patient a nanoparticle chemotherapeutic agent and administering to the patient an immunotherapeutic agent.

In embodiments, a further step includes administering an X-ray absorbent and optionally a photosensitizer to the patient, and irradiating at least the portion of the patient with X-rays in embodiments, the nanoparticle chemotherapeutic agent is a Metal Organic Framework (MOF) comprising an X-ray absorbent, optionally wherein the MOF comprises a Secondary Bridging Unit (SBU) comprising a metal cation capable of absorbing X-rays, and wherein the MOF comprises a chemotherapeutic agent entrapped in the pores or channels of the MOF, in embodiments, the MOF comprises a bridging ligand comprising a photosensitizer or a photosensitizer derivative.

In embodiments, the method further comprises administering a photosensitizer to the patient, and illuminating the patient with visible or near infrared light, hi embodiments, the nanoparticle chemotherapeutic agent is a Metal Organic Framework (MOF) comprising a photosensitizer, optionally wherein the MOF comprises a bridging ligand comprising the photosensitizer or a derivative of the photosensitizer, and wherein the MOF comprises the chemotherapeutic agent entrapped in the pores or channels of the MOF.

In embodiments, the chemotherapeutic agent is selected from the group consisting of oxaliplatin, doxorubicin, daunorubicin, docetaxel, mitoxantrone, paclitaxel, digitoxin, digoxin, and a victimide.

It is therefore an object of the presently disclosed subject matter to provide MOFs, nanoparticles of MOFs and pharmaceutical formulations thereof comprising a photosensitizer and/or a scintillator and/or an X-ray absorbing moiety; and methods of treating diseases using such compositions and the use of such compositions for treating diseases.

The objects of the presently disclosed subject matter having been stated hereinabove, and which are achieved in whole or in part by the presently disclosed subject matter, other objects will become evident as the description proceeds when taken in connection with the accompanying drawings and examples as best described hereinbelow.

Drawings

FIG. 1 is a drawing of a 5, 15-bis (p-benzoyloxy) chlorin bridged ligand (H)₂Schematic of the synthesis of DBC).

FIG. 2-A is a powder X-ray diffraction (PXRD) pattern of a bis (p-benzoyloxy) porphyrin metal-organic framework (DBP-UiO; dotted line) and a bis (p-benzoyloxy) chlorin metal-organic framework (DBC-UiO) before (dashed line) and after (solid line) incubation in cell culture medium.

FIG. 2-B shows bis (p-benzoyloxy) chlorin (H)₂DBC; solid line), DBC-UiO (dotted line), bis (p-benzoyloxy) porphyrin (H)₂DBP; dotted line) and DBP-UiO (dotted and dashed line) in Dimethylformamide (DMF) or 0.67 millimolar (mM) Phosphate Buffered Saline (PBS).

FIG. 2-C is 1 micromolar (μ M) H₂Steady state fluorescence profiles of DBC (solid line) and DBC-UiO (dotted line) in aqueous solution.

FIG. 2-D is thisA graph of samples, the graph showing the concentration at 0.1 Watts per square centimeter (W/cm)²) Under irradiance, DBC-UiO (diamond shape), H₂DBC (triangle pointing to the left), DBP-UiO (square), H₂Graph of singlet oxygen production of DBP (circles) and protoporphyrin IX (PpIX; triangles pointing upwards). DBC-UiO and H₂DBC was illuminated with a 650 nanometer (nm) Light Emitting Diode (LED), while others were illuminated with a 640nm LED. Symbols (e.g., squares, triangles, etc.) are experimental data, and solid lines are fitted curves.

FIG. 3 is a graph showing bis (p-benzoyloxy) chlorin metal organic frameworks (DBC-UiO), bis (p-benzoyloxy) porphyrin metal organic frameworks (DBP-UiO), bis (p-benzoyloxy) chlorin (H) at different Photosensitizer (PS) concentrations in CT26 colon cancer cells (left) and HT29 colon cancer cells (right)₂DBC) and bis (p-benzoyloxy) porphyrin (H)₂ vs. PDT cytotoxicity of DBP) in the left and right panels, the percentage of cell viability of DBC-UiO treatment with light illumination (triangles pointing to the left) and without light illumination (i.e., darkness; squares), H with light illumination (circles) and without light illumination (triangles pointing to the right) is shown₂Percentage of cell viability for DBC treatment; percentage of cell viability with DBP-UiO treatment under light illumination (triangles pointing up) and no light illumination (diamonds); and H under light illumination (triangle pointing down) and no light illumination (pentagon)₂Percentage of cell viability for DBP treatment.

FIG. 4 is a pair plot showing tumor growth inhibition curves after photodynamic therapy (PDT) treatment of a CT26 colon cancer model (left panel) and a HT29 colon cancer model (right panel). in both plots, the following treated tumor volumes (cubic centimeters (cm)³)): control (phosphate buffered saline (PBS); filled squares); bis (p-benzoyloxy) chlorin metal organic frameworks (DBC-UiO; open circles); higher dose of DBC-UiO (hollow star); bis (p-benzoyloxy) porphyrin metal organic framework (DBP-UiO; solid triangle pointing upwards); bis (p-benzoyloxy) chlorins (H)₂DBC; a downwardly pointing hollow triangle); and bis (p-benzoyloxy) porphyrin (H)₂DBP; point to the leftSolid triangle of (1).

FIG. 5-a is a schematic of the synthesis of hafnium metal organic framework (Hf-MOF) and zirconium metal organic framework (Zr-MOF).

FIG. 5-b is a schematic representation of X-ray induced generation of fast photoelectrons from heavy metals followed by scintillation of anthracene linker in the visible spectrum.

FIGS. 6-a, 6-b, 6-c, 6-d, 6-e show schematic diagrams of structural models of hafnium metal organic frameworks (Hf-MOFs) and zirconium metal organic frameworks (Zr-MOFs), including: (FIG. 6-a) from [100 ]]A directionally observed structure; (FIG. 6-b) from [110 ]]A directionally observed structure; (FIG. 6-c) M₆(μ₃-O)₄(μ₃-OH)₄(Carboxylic acid ester)₁₂A bat model of a Secondary Building Unit (SBU) (M ═ Hf or Zr); (FIG. 6-d) tetrahedral cavities, and (FIG. 6-e) octahedral cavities. Polyhedron: hf with eight coordinated oxygen atoms⁴⁺Or Zr^{4 +}。

FIGS. 7-a and 7-b show the following figures: (FIG. 7-a) luminescence signals from hafnium metal organic framework (Hf-MOF), zirconium metal organic framework (Zr-MOF) and control sample (from left to right): hafnium oxide (HfO)₂) And zirconium dioxide (ZrO)₂) Colloidal nanoparticles, individual bridged ligands (H)₂L)、H₂L+HfO₂Colloid, H₂L+ZrO₂Colloids, Hf-MOF and Zr-MOF; and (FIG. 7-b) the luminescence signals of the Hf-MOF and Zr-MOF at different concentrations and different emitter voltages. In FIG. 7-a, H in the sample₂The concentration of L or Hf or Zr was 1.2 millimolar (mM). The X-ray dose is 1 gray (Gy)/10 seconds (sec), with an effective X-ray energy of 18.9 kilo electron volts (keV) (40 kilo voltage (kV) tube voltage, 0.08 milli-amp (mA) tube current) and a detection gain of 200. In FIG. 7-b, data is provided for the following scenario: Hf-MOF (square) at 30 kV; Hf-MOF (circles) at 50 kV; Hf-MOF (triangle) at 80 kV; Zr-MOF (square) at 30 kV; Zr-MOF (circles) at 50 kV; and Zr-MOF (triangles) at 80 kV.

FIG. 8 is 5, 15-bis (p-benzoyloxy) porphyrin ligand (H)₂DBP).

FIG. 9 is a schematic of the synthesis of 10, 20-diphenyl-5, 15-bis (p-benzoyloxy) porphyrin ligand.

FIG. 10 is a schematic of the synthesis of 10, 20-bis (m-hydroxyphenyl) -5, 15-bis (p-benzoyloxy) porphyrin ligand.

FIG. 11 is a bridged ligand [ Ru (bipy) ] based on ruthenium bipyridine complexes₂(bpy-dc)]Cl₂Schematic of the synthesis of (RuBipyL).

FIGS. 12-A, 12-B, 12-C are sets of plots (FIG. 12-A) fitting curves for conventional photodynamic therapy (PDT) of bis (P-benzoyloxy) porphyrin metal organic framework (P-MOF), (FIG. 12-B) linear fitting of optical density change (Δ (OD)) to the irradiation dose at 439nm, and (FIG. 12-C) fitting of Δ (OD) to the irradiation dose at 439 nm.

FIG. 13-A, FIG. 13-B is a graph showing (FIG. 13-A) the concentration-dependent cytotoxicity of Nanosized Metal Organic Frameworks (NMOF) of bis (P-benzoyloxy) porphyrin metal organic frameworks (P-MOF) in human glioblastoma (U87) cells given 0.5 gray (Gy) X-ray irradiation (circles) and no X-ray irradiation (squares), and (FIG. 13-B) the cytotoxicity of human laryngeal carcinoma (SQ20B) cells treated with NMOF (P-MOF or ruthenium bipyridine type metal organic frameworks (Ru-MOF)) plus X-ray irradiation or P-MOF plus Light Emitting Diode (LED) irradiation with beef jerky as the mask or without the mask.

FIG. 14-A, 14-B, 14-C, 14-D, 14-E, 14-F sets of charts show cytotoxicity of tetra (benzoyloxy) porphyrin-hafnium (TBP-Hf) Metal Organic Framework (MOF) against GL261 glioma cells (FIG. 14-A), U251 glioblastoma cells (FIG. 14-B), U87 primary glioblastoma cells (FIG. 14-C), CT26 colon carcinoma cells (FIG. 14-D), TUBO breast cancer cells (FIG. 14-E), and TRAMP-C2 prostate cancer cells (FIG. 14-F) after X-ray irradiation. the Hf dose is 10 micromolar (. mu.M) of TBP-Hf NMOF was incubated with the cells for 4 hours (H), followed by X-ray irradiation at different doses.72 hours, cell viability was assessed by (3- (4, 5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium) (MTS).

Figure 15 is a schematic showing the synthesis of amino-triphenyldicarboxylic acid (amino-TPDC) ligands and UiO Nanosized Metal Organic Frameworks (NMOFs).

FIG. 16 is a pair chart showing (left panel) UiO-66 (open bar), UiO-67 (bar with line from bottom left to top right), amino UiO-68 (bar with line from top left to bottom right), and HfO₂Cell uptake after 4H incubation of nanoparticles (bars with squares) with SQ20B head and neck cancer cells, where hafnium (Hf) concentration was determined by inductively coupled plasma-mass spectrometry (ICP-MS), and (right panel) UiO-66 (open bars), UiO-67 (bars with lines from bottom left to top right), amino UiO-68 (bars with lines from top left to bottom right) and P-MOF (bars with squares) cytotoxicity against SQ20B cells incubated with NMOF with hafnium concentration of 10 micromolar (. mu.M) and treated with different doses of X-ray irradiation.

FIG. 17 is a graph showing the residual concentration of bis (P-benzoyloxy) porphyrin metal organic framework (P-MOF) at the tumor site at different times after intratumoral injection of P-MOF in mice bearing CT26 tumors, expressed as hafnium (Hf; open circles) and bis (P-benzoyloxy) porphyrin (DBP) ligand amounts, respectively.

FIG. 18-A, 18-B, 18-C, 18-D, 18-E sets of diagrams showing (FIG. 18-A) tumor growth curves of mice having SQ20B tumors treated with phosphate buffered saline (PBS; filled squares), bis (P-benzoyloxy) porphyrin metal organic framework (P-MOF, 2.0 gray (Gy)/irradiation dose of open circles, or 0.5 Gy/irradiation dose of closed triangles), or ligand dose of 10 micromoles/kg (μmol/kg) ruthenium-bipyridyl metal organic framework (Ru-MOF; open triangles), (FIG. 18-B) tumor growth curves of mice having SQ20B tumors treated with PBS (filled squares) or P-MOF (open circles) having a ligand dose of 10 μmol/kg and irradiated with X-rays (FIG. 18-C) tumor growth curves of mice having SQ20 μmol/35 tumors treated with PBS (filled squares) (MOF-MOF) or MOF) X-MOF) doses of 10 μmol/kg and irradiated with X-ray (filled squares) tumors of mice having MOF-MOF) tumor growth curves of open circles and irradiatedTumor growth curves for mice with PC3 tumor; and (FIG. 18-E) tumor growth curves of mice bearing CT26 tumor treated with P-MOF treated with PBS (filled squares) or ligand at a dose of 10. mu. mol/kg (open circles) or 1. mu. mol/kg (filled triangles) and irradiated with X-rays. In FIG. 18-A, when the tumor reached 100 cubic millimeters (mm)³) Treatment is initiated. In FIG. 18-B, when the tumor reached 250mm³Treatment is initiated. In FIG. 18-C, when the tumor reached about 100mm³Treatment is initiated. In FIG. 18-D, when the tumor reached 100mm³Treatment is initiated. In FIG. 18-E, when the tumor reached 150mm³Treatment is initiated. For FIGS. 18-A, 18-B, 18-C, 18-D, 18-E, mice were X-rayed 12 hours after intratumoral injection of PBS or NMOF for three consecutive days.

FIG. 19 is a graph showing the tumor growth curves of mice bearing CT26 tumors treated with phosphate buffered saline (PBS; squares) or a bis (P-benzoyloxy) porphyrin metal organic framework (P-MOF) and an IDO1 inhibitor immunotherapeutic agent (INCB24360) (P-MOF/INCB 24360; open circles) at a ligand dose of 7 micromoles per kilogram (μmol/kg) and irradiated with X-rays when tumors reached about 100 cubic millimeters (mm/kg)³) Treatment is initiated. Mice were X-ray irradiated (0.5Gy each) 12 hours (h) after intratumoral injection of PBS or nanoscale metal-organic frameworks (NMOFs) for three consecutive days. The growth curve in the right panel is the treated tumor (right side of the mouse), while the growth curve in the left panel is the untreated distal tumor on the left side of the mouse.

FIG. 20 is a graph of showing the tumor growth curves of mice bearing TUBO tumors treated with phosphate buffered saline (PBS; filled squares) at a ligand dose of 7 micromoles per kilogram (μmol/kg) of bis (P-benzoyloxy) porphyrin metal organic framework (P-MOF; open circles) or P-MOF and IDO1 inhibitor immunotherapeutic agent INCB24360(P-MOF/INCB 24360; filled triangles.) when tumors reached about 100 cubic millimeters (mm) when tumors were irradiated with X-rays³) Treatment is initiated. Mice were X-ray irradiated (0.5Gy each) 12 hours (h) after intratumoral injection of PBS or Nanoscale Metal Organic Frameworks (NMOFs) for three consecutive days. The growth curve in the right panel is the treated tumor (right side of the mouse),while the growth curve in the left panel is the untreated distal tumor on the left side of the mouse.

FIG. 21 is a graph of showing the tumor growth curves of TRAMP-C2 tumor-bearing mice treated with P-MOF and IDO1 inhibitor immunotherapeutic agent INCB24360(P-MOF/INCB 24360; filled triangles) treated with X-rays treated with Phosphate Buffered Saline (PBS) at a ligand dose of 3.5 micromoles per kilogram (μmol/kg), or P-benzoyloxy) porphyrin metal organic framework (P-MOF; open circles; or P-MOF and IDO1 inhibitor the tumor growth curves when tumors reach 200 cubic millimeters (mm/kg)³) Treatment is initiated. The growth curve in the right panel is the treated tumor (right side of the mouse), while the growth curve in the left panel is the untreated distal tumor on the left side of the mouse.

FIG. 22 is a graph of pairs showing the tumor growth curves of mice bearing MC38 tumors treated with X-ray radiation and treated with either bis (P-benzoyloxy) porphyrin metal organic framework (P-MOF, open circles) or P-MOF and IDO1 inhibitor immunotherapeutic agent INCB24360(P-MOF/INCB 24360; closed triangles) in a 3.5 micromole/kilogram (μmol/kg) dose of phosphate buffered saline (PBS; closed squares). The tumors reach 250 cubic millimeters (mm) when irradiated with X-ray³) Treatment is initiated. The growth curve in the right panel is the treated tumor (right side of the mouse), while the growth curve in the left panel is the untreated distal tumor on the left side of the mouse.

FIG. 23 is a pair plot showing the tumor growth curves of mice bearing MC38 tumors treated with X-ray radiation and treated with either bis (P-benzoyloxy) porphyrin metal organic framework (P-MOF; open circles) or P-MOF and IDO1 inhibitor immunotherapeutic agent INCB24360(P-MOF/INCB 24360; closed triangles) in a 3.5 micromole/kilogram (μmol/kg) dose of phosphate buffered saline (PBS; closed squares). The tumors reach 200 cubic millimeters (mm/kg)³) Treatment is initiated. The growth curve in the right panel is the treated tumor (right side of the mouse), while the growth curve in the left panel is the untreated distal tumor on the left side of the mouse.

FIG. 24, , is a graph showing phosphate buffered saline (PBS; filled squares) at a ligand dose of 3.5 micromoles per kilogram (. mu.mol/kg) of bis (p-benzoyloxy) porphyrin metalTumor growth curves of mice bearing TUBO tumors treated with frame (P-MOF; open circles) or P-MOF and IDO1 inhibitor immunotherapeutic INCB24360(P-MOF/INCB 24360; closed triangles), X-ray irradiation, and PD-L1 antibody (i.p.). When the tumor reaches 200 cubic millimeters (mm)³) Treatment is initiated. The growth curve in the right panel is the treated tumor (right side of the mouse), while the growth curve in the left panel is the untreated distal tumor on the left side of the mouse.

Sets of of FIGS. 25-A, 25-B, 25-C, 25-D, 25-E, 25-F show (FIG. 25-A) the fraction of X-ray photons having different energies calculated after penetration of a selected attenuator, (FIG. 25-B) the X-ray spectrum from a tungsten (W) target source at 120 peak kilovolts (kVp) calculated after filtering by a copper attenuator, (FIG. 25-C) the X-ray spectrum from a tungsten target source at 120kVp calculated after filtering by a copper attenuator, normalized to by total photon count, (FIG. 25-D) the calculated X-ray mass-energy absorption coefficients for hafnium (Hf) and water, (FIG. 25-E) the calculated X-ray mass-energy absorption coefficients for Hf and water, and (FIG. 25-F) the calculated penetration depth of X-ray photons at different energies.

pairs of FIGS. 26-A, 26-B show (FIG. 26-A) the in vivo anticancer efficacy using bis (P-benzoyloxy) porphyrin metal organic framework (P-MOF) and using different X-ray delivery parameters in a mouse model with CT26 subcutaneous tumors, and (FIG. 26-B) the in vivo anticancer efficacy using tetraphenyloxyporphyrin-hafnium metal organic framework (TBP-Hf) and using different X-ray delivery parameters in a mouse model with CT26 subcutaneous tumors Phosphate Buffered Saline (PBS) was used as a control treatment (filled squares). in FIG. 26-A, P-MOF with a ligand dose of 10 micromoles per kilogram (μmol/kg) was injected intratumorally into mice. in FIG. 26-B, TBP-Hf with a ligand dose of 10 μmol/kg or 20 μmol/kg was injected intratumorally into mice. 12 hours, two different X-ray delivery parameters were used to irradiate the tumor 1)225 peak voltage (kVp), 13mA per day, 0.2mm of light filter (120 mA), and 36 mm of light filter X-HF per day, followed by three consecutive injections of irradiation with three days of copper (26-7 mVp).

Fig. 27 is a schematic diagram showing the chemical structure of an exemplary photosensitizer according to an embodiment of the presently disclosed subject matter.

Fig. 28 is a schematic diagram showing the chemical structure of other exemplary photosensitizers according to an embodiment of the presently disclosed subject matter.

FIG. 29 is a schematic diagram showing the chemical structures of exemplary porphyrin, chlorin, and bacteriochlorin-type photosensitizers and/or bridging ligands according to an embodiment of the presently disclosed subject matter.

Fig. 30 is a schematic diagram showing the chemical structures of some other exemplary photosensitizers and/or bridging ligands according to an embodiment of the presently disclosed subject matter.

FIG. 31 is a schematic showing the chemical structures of an exemplary boron dipyrromethene (BODIPY) derivative and a salpinyl-1, 2-cyclohexylidene diamine complex photosensitizer and/or bridging ligand according to the presently disclosed subject matter.

FIG. 32 is a schematic diagram showing the chemical structure of an exemplary dye-based photosensitizer for use in accordance with the presently disclosed subject matter.

Detailed Description

In some embodiments , the presently disclosed subject matter provides a Metal Organic Framework (MOF) comprising a photosensitizer, the MOF can further comprise a moiety capable of absorbing X-rays and/or scintillation light (scintillation). optionally, the photosensitizer or derivative thereof can form a bridging ligand of the MOF. additionally, the MOF can optionally comprise or can be used in combination with inorganic nanoparticles in the cavities or channels of the MOF. in some embodiments , the presently disclosed subject matter provides methods of using the MOF and/or inorganic nanoparticles in photodynamic therapy or X-ray induced photodynamic therapy, with or without co-administration of or more immunotherapeutic agents and/or or more chemotherapeutic agents.

The presently disclosed subject matter will now be described more fully hereinafter with reference to the accompanying examples, in which representative embodiments are shown. The presently disclosed subject matter may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of these embodiments to those skilled in the art.

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 the subject matter described herein belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are now described. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

Throughout the specification and claims, where optical and stereoisomers and racemic mixtures are present, a given chemical formula or name will encompass all optical isomers and stereoisomers and racemic mixtures.

I. Definition of

While the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are set forth to aid in the description of the presently disclosed subject matter.

Following long established patent law conventions, the terms "", "", and "the" when used in this application, including the claims, refer to " metal ion(s)". thus, for example, reference to " metal ions" includes a plurality of such metal ions, and the like.

Unless otherwise indicated, all numbers expressing quantities of size, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties to be obtained by the presently disclosed subject matter.

As used herein, when referring to a value or amount of size (i.e., diameter), weight, concentration, or percentage content, the term "about" is intended to include embodiments that vary by ± 20% or ± 10%, in another embodiment by ± 5%, in another embodiment by ± 1%, and in yet another embodiment by ± 0.1%, relative to the specified amount, such variations being suitable for performing the disclosed method.

As used herein, the term "and/or," when used in the context of a listing of entities, refers to the entities being present alone or in combination. Thus, for example, the phrase "A, B, C and/or D" includes A, B, C and D independently, but also includes any and all combinations and subcombinations of A, B, C and D.

The term "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional unrecited elements or method steps. "comprising" is a term of art used in claim language and means that the recited elements are present but that other elements may be added and still form a structure or method within the scope of the recited claims.

As used herein, the phrase "consisting of … …" does not include any element, step, or ingredient not specified in the claim when the phrase "consisting of … …" appears in a clause of the body of claims and does not immediately follow the preamble, the phrase only limits the elements set forth in the clause, other elements are not excluded from the claim as a whole.

As used herein, the phrase "consisting essentially of …" limits the scope of the claims to the specified materials or steps and does not materially affect those materials or steps of the basic and novel features of the claimed subject matter.

With respect to the terms "comprising," "consisting of … …," and "consisting essentially of … …," where of the three terms is used herein, the presently disclosed and claimed subject matter can include the use of any of the other two terms.

As used herein, the term "alkyl" may refer to C_1-20(inclusive) hydrocarbon chains that are linear (i.e., "straight chain"), branched, or cyclic saturated or at least partially unsaturated, and in some cases fully unsaturated (i.e., alkenyl and alkynyl) at , including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, octyl, vinyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and dienyl_1-8Alkyl), for example an alkyl group of 1,2, 3,4, 5,6, 7 or 8 carbon atoms. "higher alkyl" refers to an alkyl group having from about 10 to about 20 carbon atoms, for example 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, "alkyl" specifically refers to C_1-8A linear alkyl group. In other embodiments, "alkyl" specifically refers to C_1-8A branched chain alkyl group.

The term "alkyl substituent" includes, but is not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxy, aryloxy, alkoxy, alkylthio, arylthio, aralkoxy, aralkylthio, carboxy, alkoxycarbonyl, oxo, and cycloalkyl in embodiments or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms may be optionally inserted along the alkyl chain, where the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

Thus, as used herein, the term "substituted alkyl" includes alkyl groups as defined herein wherein or more atoms or functional groups of the alkyl group are substituted with another atoms or functional groups (including, for example, alkyl, substituted alkyl, halo, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto).

The term "aryl" is used herein to refer to an aromatic substituent which may be a single aromatic ring, or multiple aromatic rings fused at together, covalently linked or linked to a common group such as, but not limited to, a methylene or ethylene moiety.

The aryl group can be optionally substituted with or more of the same or different aryl substituents ("substituted aryl"), where "aryl substituents" include alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy, carboxy, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxy, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and-NR 'R ", where R' and R" can each independently be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl.

Thus, as used herein, the term "substituted aryl" includes aryl groups as defined herein, which aryl groups have or more atoms or functional groups substituted with another atoms or functional groups including, for example, alkyl, substituted alkyl, halo, aryl, substituted aryl, alkoxy, hydroxy, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.

Specific examples of aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, and the like.

As used herein, "heteroaryl" refers to aryl groups containing or more non-carbon atoms (e.g., O, N, S, Se, etc.) in the backbone of the ring structure.

"aralkyl" refers to-alkyl-aryl, optionally wherein the alkyl and/or aryl moieties are substituted.

"alkylene" refers to a straight or branched chain divalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1,2, 3,4, 5,6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms₂-) according to the formula (I); ethylene (-CH)₂-CH₂-) according to the formula (I); propylene (- (CH)₂)₃-) according to the formula (I); cyclohexylidene (-C)₆H₁₀-)；-CH＝CH-CH＝CH-；-CH＝CH-CH₂-；-(CH₂)_q-N(R)-(CH₂)_r-, wherein q and R are each independently an integer of 0 to about 20, such as 0,1, 2,3, 4,5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, and R is hydrogen or lower alkyl; methylenedioxy (-O-CH)₂-O-); and ethylenedioxy (-O- (CH))₂)_2-O-). The alkylene group may have about 2 to about 3 carbon atoms and may additionally have 6 to 20 carbons.

The arylene group can be optionally substituted with or more aryl substituents and/or include or more heteroatoms.

The term "amino" refers to the group-N (R)₂Wherein each R is independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, or substituted aralkyl. The terms "aminoalkyl" and "alkylamino" may refer to the group-N (R)₂Wherein each R is H, alkyl, or substituted alkyl, and wherein at least of the Rs are alkyl or substituted alkyl, "arylamine" and "aminoaryl" refer to the group-N (R)₂Wherein each R is H, aryl, or substituted aryl, and wherein at least R are aryl or substituted aryl, such as aniline (i.e., -NHC)₆H₅)。

The term "thioalkyl" may refer to the group-SR, where R is selected from H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl. Similarly, the terms "thioaralkyl" and "thioaryl" refer to the-SR group, where R is aralkyl and aryl, respectively.

As used herein, the term "halo", "halide" or "halogen" refers to fluoro, chloro, bromo and iodo.

The terms "hydroxyl" and "hydroxyl group" refer to the-OH group.

The term "mercapto" or "thiol" refers to the-SH group.

The terms "carboxylate" and "carboxylic acid" may each refer to the group-C (═ O) O^-The term "carboxy" may also refer to a-C (═ O) OH group in some embodiments of , "carboxylate" or "carboxy" may refer to a-C (═ O) O^-or-C (═ O) OH groups.

The term "acetylacetonate" refers to a compound obtained by reacting a group-C (═ O) CH₂C(＝O)CH₃Deprotonation to form the anion.

The term "phosphonate" refers to-P (═ O) (OR)₂Groups, wherein each R can independently be H, alkyl, aralkyl, aryl, or a negative charge (i.e., wherein there is effectively no R group bonded to an oxygen atom, such that there is an unshared pair of electrons on the oxygen atom). Thus, in other words, each R can be storedIn or out, and when present is selected from H, alkyl, aralkyl or aryl.

The term "phosphate group" means-OP (═ O) (OR')₂A group wherein R' is H or a negative charge.

The term "bonding" or "bonded" and variations thereof may refer to covalent or non-covalent bonding at the term "bonding" refers to bonding via coordination bonding.

As used herein, the term "metal-organic framework" refers to a solid two-or three-dimensional network structure comprising both a metal and an organic component, wherein the organic component comprises at least and typically more than carbon atoms in embodiments the material is crystalline in embodiments the material is amorphous in embodiments the material is porous in embodiments the metal-organic matrix material is a coordination polymer comprising coordination complex repeat units comprising metal-based Secondary Building Units (SBUs), such as metal ions or metal complexes, and bridging multidentate (e.g., bidentate or tridentate) organic ligands in embodiments the material comprises more than types of SBUs or metal ions in embodiments the material may comprise more than types of organic bridging ligands.

The term "nanoscale metal-organic framework" may refer to nanoscale particles comprising MOFs.

Thus, the ligand or chelate is generally an electron pair donor, molecule or molecular ion having an unshared pair of electrons available for donation to a metal ion.

The use of this term is not intended as a limitation, as certain coordination bonds may also be classified as having more or less covalent properties (in the absence of complete covalent properties) depending on the characteristics of the metal ion and electron pair donor.

As used herein, the term "ligand" generally refers to a substance, such as a molecule or ion, that interacts in some way with another substance, such as a bindingMartell,A.E.,AndHancock,R.P.metal Complexes in Aqueous solution (Metal Complexes in Aqueous Solutions), Plenum, New York (1996), incorporated herein by reference in its entirety the terms "ligand" and "chelating group" are used interchangeably the term "bridging ligand" may refer to a group that is bonded to more than Metal ions or Complexes, thereby providing a "bridge" between the Metal ions or Complexes₂H、-NO₂Amino, hydroxy, thio, thioalkyl, -B (OH)₂、-SO₃H、PO₃H. Phosphonates and heteroatoms (e.g., nitrogen, oxygen, or sulfur) in the heterocycle.

The term "coordination site" when used herein with respect to a ligand, e.g., a bridging ligand, refers to an unshared pair of electrons, a negative charge, or an atom or functional group capable of forming an unshared pair of electrons or a negative charge (e.g., via deprotonation at a particular pH).

The terms "nanoscale particles," "nanomaterials," and "nanoparticles" refer to structures having at least regions with dimensions (e.g., length, width, diameter, etc.) of less than about 1,000nm, in embodiments the dimensions are smaller (e.g., less than about 500nm, less than about 250nm, less than about 200nm, less than about 150nm, less than about 125nm, less than about 100nm, less than about 80nm, less than about 70nm, less than about 60nm, less than about 50nm, less than about 40nm, less than about 30nm, or even less than about 20nm), in embodiments the dimensions are between about 20nm and about 250nm (e.g., about 20nm, 30nm, 40nm, 50nm, 60nm, 70nm, 80nm, 90nm, 100nm, 110nm, 120nm, 130nm, 140nm, 150nm, 160nm, 170nm, 180nm, 190nm, 200nm, 210nm, 220nm, 230nm, 240nm, or 250 nm).

In some embodiments , the nanoparticles are substantially spherical, when the nanoparticles are substantially spherical, the characteristic dimension can correspond to the diameter of a sphere, and the nanomaterials can be disk-shaped, plate-shaped (e.g., hexagonal plate-shaped), oblong, polyhedral, rod-shaped, cubic, or irregularly shaped in addition to being spherical.

Nanoparticles can include a core region (i.e., the space between the outer dimensions of the particle) and an outer surface (i.e., the surface that defines the outer dimensions of the particle). in embodiments, the nanoparticles can have or more coatings that coat or partially coat the nanoparticle core.

In embodiments, the disclosed nanoparticles may comprise a solid Metal Organic Framework (MOF) matrix that is a two-dimensional or three-dimensional network of SBUs linked by bridging ligands to . the MOF may comprise or more pores or hollow interior regions. the MOF matrix may be amorphous or crystalline. in embodiments, the nanoparticle core further comprises or more PS, X-ray absorber, scintillator and/or other therapeutic agents (e.g., anti-cancer agents or immunotherapeutic agents) that may be physically trapped within the matrix, form coordination bonds with metal ions of the matrix, or chemically bonded via covalent or ionic bonds (e.g., bonded to organic bridging ligands in the matrix or dispersed in a layer on the nanoparticle core). in embodiments, the photosensitizer or derivative thereof may be an organic bridging ligand or linked to an organic bridging ligand forming a core of the nanoparticle within a metal organic matrix material, while the metal of the SBU acts as a scintillator, X-ray absorber, and/or covalent attachment to MOF.

"embedding" may refer to agents being bound (e.g., covalently bound or bound via coordination bonds) to the interior of the core of the particle (e.g., to the coordination sites of bridging ligands or metal ions of SBUs).

The terms "polymer" and "polymerized" refer to a chemical structure having repeating units (i.e., multiple copies of a given chemical substructure.) the polymer may be formed from polymerizable monomers the polymerizable monomers are molecules that contain or more moieties that can react with moieties on other molecular polymerizable monomers to form bonds (e.g., covalent or coordinative bonds.) in embodiments, each polymerizable monomer molecule may be bonded to two or more other molecules/moieties.

As used herein, the term "inorganic" means that a compound or composition contains at least atoms in addition to carbon, hydrogen, nitrogen, oxygen, sulfur, phosphorus, or halides.

As used herein, "organic polymers" are those that do not include silica or metal atoms in the repeating units. some organic polymers contain biodegradable linkages, such as esters or amides, thereby enabling their degradation over time under biological conditions.

As used herein, the term "hydrophilic polymer" generally refers to hydrophilic organic polymers such as, but not limited to, polyvinylpyrrolidone (PVP), polyvinylmethyl ether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxyethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, Polyethyleneimine (PEI), polyethylene glycol (i.e., PEG) or another hydrophilic poly (alkylene oxide), polyglycerol, and polyasparagine.

The term "photosensitizer" (PS) refers to a compound or moiety that can be excited by light of a specific wavelength, typically visible or Near Infrared (NIR) light, and generates Reactive Oxygen Species (ROS). For example, in the excited state, the photosensitizer may undergo intersystem transition and transfer energy to oxygen (O)₂) (e.g., in tissue treated with PDT) to generate ROS, e.g., singlet oxygen (C¹O₂) In in the photosensitizer may have or more functional groups such as carboxylic acids, amines or isothiocyanates, for example, for linking the photosensitizer to another molecule or moiety such as an organic bridging ligand or SBU, and or for providing or more additional sites to promote coordination or form a coordinate bond with or more additional metals, in in embodiments the photosensitizer is a porphyrin or a derivative or analog thereofPorphyrin analogs include, but are not limited to, extended porphyrin family members (e.g., porphyrins quarternary (texaphyrin), thialines dihydrothialines and hexaporphyrins), porphyrin isomers (e.g., porphyrins, inverted porphyrins, phthalocyanines and naphthalocyanines), and TPP substituted with or more functional groups.

As used herein, the term "cancer" refers to a disease caused by the ability of uncontrolled cell division and/or cell metastasis, or the ability to build new growth at another site. The terms "malignant," "malignant disease," "neoplasm," "tumor," "cancer," and variants thereof refer to a cancer cell or a population of cancer cells.

Specific cancer types include, but are not limited to, skin cancer (e.g., melanoma), connective tissue cancer (e.g., sarcoma), adipose cancer, breast cancer, head and neck cancer, lung cancer (e.g., mesothelioma), stomach cancer, pancreatic cancer, ovarian cancer, cervical cancer, uterine cancer, anal , and genital cancer (e.g., testicular cancer), kidney cancer, bladder cancer, colon cancer, prostate cancer, Central Nervous System (CNS) cancer, retinal cancer, blood cancer, neuroblastoma, multiple myeloma, and lymphoid cancers (e.g., hodgkin's lymphoma and non-hodgkin's lymphoma).

The term "metastatic cancer" refers to a cancer that has spread from an initial site (i.e., primary site) within a patient's body.

The terms "anticancer drug," "chemotherapeutic agent," and "anticancer prodrug" refer to drugs (i.e., compounds) or prodrugs known to be capable of treating or suspected of being capable of treating cancer (i.e., killing cancer cells, preventing cancer cell proliferation, or treating symptoms associated with cancer.) in the embodiments, as used herein, the term "chemotherapeutic agent" refers to non-PS molecules useful for treating cancer and/or having cytotoxic capabilities such more traditional or conventional chemotherapeutic agents may be described by mechanism of action or by class of compounds and may include, but are not limited to, alkylating agents (e.g., melphalan (mellan)) anthracyclines (e.g., doxorubicin), cytoskeleton disrupting agents (e.g., paclitaxel), epothilones (epithilones), histone deacetylase inhibitors (e.g., vorinostat), topoisomerase I or II inhibitors (e.g., irinotecan or etoposide)), inhibitors (e.g., bortezomib (bortezomib)), or siderite (e.g., vincristine), or vincristine analogs such as vincristine (e.g., vinblastine), or vincristine (e.g., a), or a), a bioplatin (e.g., a), or a bioplatin).

The term "scintillator" refers to a moiety or compound that exhibits luminescence (emission of light, e.g., in the visible or NIR range) when excited by ionizing radiation, e.g., x-rays.

II, general description

Most -widely recognized PDT mechanisms involve the transfer of energy from a photo-excited PS to oxygen molecules in the tissue to produce Reactive Oxygen Species (ROS), specifically singlet oxygen (singlet oxygen)¹O₂) Thereby inducing cytotoxicity. PDT can cause local destruction of diseased tissue via selective uptake of PS and/or local exposure, thereby providing minimally invasive cancer therapy.

Selective delivery of chemotherapeutic agents to tumors is preferred for successful chemotherapy. Similarly, PS localization in tumors is preferred for effective PDT. However, many PS are hydrophobic, which not only results in insufficient tumor localization, but also causes PS aggregation, thereby reducing PDT efficacy. Therefore, in order to make these PS more effective PDT agents in vivo, significant synthetic modification is preferred.

An alternative approach is to use nanocarriers to selectively deliver therapeutic or PDT agents to tumors via high permeation and retention Effects (EPR) and sometimes via targeting of active tumors with small molecules or biological ligands that bind to overexpressed receptors in cancers.

Porphyrins NMOF for photodynamic therapy

In exemplary embodiments according to the presently disclosed subject matter (described in further in the examples below), Hf-porphyrin NMOF is prepared and used as PDT for drug-resistant head and neck cancer PS., without wishing to be bound by any theory, it is believed that the incorporation of porphyrin-derived bridging ligands into stable and porous uo (University of Oslo in norway) NMOF structures with suitable morphology and size may provide various advantages over other nanoparticle PDT agents molecules or moieties may be sufficiently separated in the NMOF framework to avoid aggregation and excited state self-quenching (self-quenching) secondly, the formation of coordination bonds between porphyrin ligands and heavy metal (e.g., Hf) centers may facilitate intersystem transitions to increase ROS generation efficiency¹O₂) Conveniently diffuse out of the interior of NMOF to exert cytotoxic effects on cancer cells. In addition, extremely high PS loading can be achieved to provide effective PDT for difficult to treat cancers.

Thus, in embodiments, the presently disclosed subject matter provides MOFs comprising SBUs linked together at via porphyrin-like bridging ligands, e.g., porphyrins, porphyrin derivatives, and/or metal complexes thereof.

Chlorins NMOF for photodynamic therapy of colon cancer

In another exemplary embodiment, the presently disclosed subject matter provides chlorins NMOFs having photophysical properties suitable for treating tumors, such as DBC-UiO, for example, DBC-UiO can be used to treat colon cancer in two colorectal adenocarcinoma mouse models, as described in the examples below.

Porphyrins to bleed have been developedThe derivative is used as th generation PS, so that kinds of PDT reagent are clinically applied

However, for some applications, the photophysical properties of porphyrins are not preferred, with absorption peaks typically near the high energy edge of the tissue penetration window (600-900nm) and with smaller extinction coefficient (. epsilon.) values it has been shown that reduction of porphyrins to dihydroporphins shifts absorption to longer wavelengths with an increase in ε.for example, reduction of 5,10,15, 20-M-tetra (hydroxyphenyl) porphyrins to their dihydroporphin derivatives red-shifts the last Q bands from 644nm to 650nm with ε from 3400M^-1·cm^-1Sharply increased to 29600M^-1·cm^-1。

Thus, in embodiments, the presently disclosed subject matter provides MOFs comprising SBUs linked via a dihydroporphin-like bridging ligand or other porphyrin-based reduced form, e.g., bacteriochlorin ligand, to .

Synergistic assembly of heavy metal clusters and light-emitting organic bridging ligands in metal-organic frameworks for X-ray scintillation (scintillation)

X-ray scintillators have been developed by for general use in X-ray dosimetry and imaging₂O₂S Tb and M' -YTaO₄As a highly efficient X-ray-to-light converter. Nanophosphors have also been used as molecular probes for bimodal X-ray and optical imaging, known as X-ray luminescence computed tomography (XLCT). XLCT can provide a very sensitive molecular imaging technique by taking advantage of the long penetration depth of X-rays and the low optical autofluorescence background. Furthermore, solid state scintillator-based nanoparticles have been combined with singlet oxygen sensitizers for X-ray induced PDT (X-PDT).

Organic crystals, such as anthracene, can also function as radiation scintillators, particularly for detecting low energy β rays and neutrons, due to their high scattering cross-sections for electrons and neutrons and low backscattering rates, however, organic scintillators cannot effectively detect X-rays (<100keV) due to their small X-ray scattering cross-sections, Metal Organic Frameworks (MOFs) can provide -class crystalline materials constructed from well-defined molecular bridging ligands and metal/metal cluster connecting nodes, thus MOFs can serve as an adjustable platform for co-assembling organic scintillator molecules and high atomic number (Z) metal cluster nodes within a highly ordered structure, for example, Zn MOFs for emission luminescence induced by fast protons, neutrons, electrons, and gamma rays have been reported in U.S. patent No. 7,985,868, which is incorporated herein in its entirety by reference.

exemplary embodiments according to the presently disclosed subject matter, are described herein with high Z metal clusters, such as M₆(μ₃-O)₄(μ₃-OH)₄(Carboxylic acid ester)₁₂(M ═ Hf or Zr) MOFs having anthracene-based emitters as bridging ligands as connecting nodes. Since Z72 for Hf and Z40 for Zr, Hf and Zr clusters act as efficient X-ray absorbers. Hf in the photoelectric absorption of X-rays in the range of 20-200keV⁴⁺And Zr⁴⁺The shell electrons of the ions are ejected as fast electrons, which interact with the anthracene linker to produce a luminescent signal from its electronically excited state. Thus, the high-Z metal clusters act synergistically with the emitting bridging ligands to cause very efficient X-ray induced luminescence in the visible spectrum which is easy to detect.

NMOF for very efficient X-ray induced photodynamic therapy

In the case of cancer radiotherapy, tumors are irradiated with high-energy radiation (e.g., X-rays) to destroy malignant cells in the treated volume NMOF can be treated by a combination of radiotherapy and PDT for deep cancers, according to embodiments of the presently disclosed subject matter NMOF with SBUs containing high Z metal ions (e.g., Zr or Hf) can act as efficient X-ray receivers by absorbing X-ray photons and converting them into fast electrons via the photoelectric effectExciting multiple PS in MOF, thereby efficiently generating hydroxyl radical¹O₂. Further embodiments include NMOFs that may have SBUs with: lanthanide metals (e.g., La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu), Ba, Ta, W, Re, Os, Ir, Pt, Au, Pb, and Bi, or any metal ion that strongly absorbs x-ray radiation.

in some embodiments, the subject matter disclosed herein provides heavy metals (e.g., Hf and Bi) as metal attachment points and porphyrin derivatives, chlorin derivatives, or metal-containing dyes, including Ru (bpy)₃ ²⁺And Ir (pph)₂(bpy)⁺(bpy is 2,2' -bipyridine and pph is 2-phenylpyridine) NMOF constructed as bridging ligand the use of such NMOF in X-ray induced PDT/RT is further demonstrated in the examples below at step . these NMOF's are capable of exciting photosensitizers with X-ray energy followed by singlet oxygen generation and thus act as highly effective therapeutic agents for X-ray induced PDT the advantages of such NMOF's may include: 1) combining two effective treatments (radiotherapy and PDT), 2) being capable of being used efficiently in deep cancer treatment modes, 3) low risk of radiation damage to healthy tissue, and 4) simple, relatively inexpensive and highly effective treatments.

In certain embodiments, the disclosed nanoscale metal-organic frameworks can comprise or further comprise a metal polyacid salt (POM), such as a tungsten, molybdenum, or niobate metal polyacid salt, a metal nanoparticle, such as a gold, palladium, or platinum nanoparticle, or a metal oxide nanoparticle, such as a hafnium oxide or niobium oxide nanoparticle, located in a MOF cavity or channel.

NMOF for radiotherapy

As further described below in step , three Hf NMOF's are synthesized, including UiO-66, UiO-67 and amino UiO-68, these NMOF's are constructed from Hf metal clusters and ligands with negligible photosensitizing properties, the ability of the Hf metal clusters to absorb X-rays, combined with the rapid outward diffusion of ROS (specifically, hydroxyl radicals) from the MOF channels, enabling high efficiency radiotherapy₂Nanoparticles were used for comparison.

II.F. combined PDT and immunotherapy

PDT can selectively kill tumor cells while retaining adjacent normal tissue. PDT does not cross-resist radiation therapy or chemotherapy and therefore can be used to treat cancer patients that do not respond significantly to traditional radiation therapy and/or chemotherapy. PDT can stimulate a strong acute inflammatory response, such as localized edema observed at the target site. Inflammation caused by PDT is a non-tumor antigen-specific process caused by the innate immune system. Specifically, PDT effectively and rapidly generates a large number of alert/risk signals, such as damage-related molecular patterns (DAMPs), at the treatment site that can be detected by the intrinsic immunological warning elements. It is believed that PDT-mediated enhancement of anti-tumor immunity is caused by stimulation of dendritic cells by dead and dying tumor cells, and is accompanied by recruitment and activation of CD8+ cytotoxic T Cells (CTLs), and subsequent formation of immune memory cells and resistance to subsequent tumor growth.

A variety of inorganic, organic and hybrid materials are known to strongly absorb near infrared light to generate singlet oxygen₄(e.g., doped at a ratio of Y: Yb: Er ═ 78%: 20%: 2%), with chlorin e6 or MC 540; photosensitizers embedded in silica-based nanoparticles, such as silica nanoparticles loaded with 2-devinyl-2- (1-hexyloxyethyl) pyropheophorbide (HPPH); photosensitizers loaded with polymeric micelles, e.g. on DSPE-PEG_5kZn (II) phthalocyanine in polymer micelles; liposomal photosensitizer delivery systems, such as liposomes encapsulated with 5,10,15, 20-tetrakis (m-hydroxyphenyl) chlorin and 5-aminolevulinic acid (ALA); human serum albumin based photosensitizer delivery systems, e.g. HSA-pheophorbide a couplingParticles of matter; dendrimer-based photosensitizer delivery systems, such as PEG-linked poly (propyleneimine) or poly (amidoamine) loaded with rose bengal (rose bengal) and PpIX; phospholipid bilayer delivery systems coupled to porphyrins, to chlorins or to bacteriochlorins, such as porphyrin-lipid conjugates (pyrolipids) self-assembled nanovesicles (porphyrosomes) and NCP @ pyrolipids.

Combined X-PDT and immunotherapy

According to embodiments of the presently disclosed subject matter, X-ray induced PDT can be combined with inhibitor-based immunotherapy using adaptive immune responses, such as cytotoxic T-cells to elicit systemic rejection of established tumors when combined with immunotherapeutic agents, not only can effective eradication of primary tumors be achieved, but also distal metastatic tumors can be inhibited/eradicated using NMOF-based X-PDT action, in embodiments, anti-tumor efficacy can be enhanced by the addition of chemotherapeutic agents known to cause immunogenic cell death.

A variety of inorganic materials are known to strongly absorb X-rays and convert the absorbed X-ray energy into visible and near-infrared light. Next, the near infrared light emitted by these X-ray scintillating nanomaterials is absorbed by nearby photosensitizers to achieve X-ray induced PDT effect. Other types of materials may also achieve X-ray induced PDT. When this X-ray induced PDT is combined with immune checkpoint inhibitors, superior radioimmunotherapy can be obtained. Examples of X-ray scintillating nanomaterials include, but are not limited to: LnO₃Ln' nanoparticles, LnO₂S Ln' nanoparticles or LnX₃Ln' nanoparticles, where Ln ═ Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Ln ═ Ce, Pr, Eu, Tb, and the like, and X ═ F, Cl, Br, and I; x-ray scintillator MOFs, e.g. M₆(μ₃-O)₄(μ₃-OH)₄L₆Wherein M ═ Hf, Zr, or Ce; and L ═ 9, 10-anthracenedibenzoic acid and other formulations of MOFs containing heavy metal secondary building units; lanthanide-based MOFs, SBUs include, but are not limited to: ln₄(μ₄-OH₂)(CO₂)₈(SO₄)₄、[Ln(OH₂)(CO₂)₃]_n(infinite 1-D chain), [ Ln (OH)₂)(CO₂)₄]_n(infinite 1-D chain), [ Ln (CO)₂)₃-Ln(OH₂)₂(CO₂)₃]_n(infinite 1-D chain) wherein Ln ═ La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu and/or mixtures thereof in combination; bridged ligands include, but are not limited to, [1, 4-benzoic acid biscarboxylate][2, 5-dimethoxy-1, 4-benzenedicarboxylic acid ester ]][1,3, 5-benzenetricarboxylic acid ester]And [1,3, 5-benzenetricarboxylic acid ester]And [5- (pyridin-4-yl) isophthalic acid][4,4' -S-triazine-2, 4, 6-Triphenyl Ether-formate][ Biphenyl-3, 4', 5-tricarboxylic acid ester ]]And [4,4' - [ (2, 5-dimethoxy-1, 4-phenylene) di-2, 1-ethenediyl]Bis (benzoic acid)]Etc.; quantum dots such as ZnS, M quantum dots (M ═ Cu, Co, Mn, Eu, etc.) or carbon dots; gold nanoparticles, or platinum or other third row of metal particles thereof; and other X-ray scintillators, e.g. SrAl₂O₄:Eu²⁺；NaYF₄:Tb³⁺、Er³⁺。

Examples of photosensitizers coupled to X-ray scintillating nanoparticles for X-ray induced PDT include, but are not limited to: photosensitizers that form coordinate bonds to the surface of the particle, where coordination methods include, but are not limited to, carboxylate or phosphate coordination (e.g., via carboxylate or phosphate groups on PS to open metal sites on the nanoparticle (e.g., Ln)³⁺、Zn²⁺、Al³⁺Etc.) coordination; the thiol group coordinates to the nanoparticle (coupled to the nanoparticle through the thiol group-containing PS by forming a coordination bond with Au (in gold nanoparticles) or, for example, Zn, Cd in quantum dots); polymer coupling and surface coating, such as via covalent coupling of PS to oligomers or polymers having functional groups (e.g., cyclodextrins, polyethylene glycol (PEG), poly (maleic acid) derivatives, etc.) and coupling of scintillator particles via coordination bonds of additional functional groups (e.g., formate, thiol, hydroxyl, amine, etc.) to metals on the particle surface, such as using photosensitizers, such as, but not limited to, those shown in FIGS. 27 and 28Any of the photosensitizers shown are covalently bonded to the MOF ligands, e.g., via amide coupling, ester coupling, thiourea coupling, "click chemistry", disulfide coupling, and the like, surface modification and entrapment of porous materials, mesoporous silica coating and entrapment, and MOF coating and entrapment, e.g., utilizing photosensitizers entrapped in the pores of the silica layer.

Improvement of X-ray settings for X-ray induced photodynamic therapy.

In some embodiments of of the presently disclosed subject matter, the X-ray source may be modified to enhance X-PDT action to achieve more effective cancer cell killing, the X-ray illuminator may comprise a panoramic illuminator containing at least X-ray sources inside a protective housing, each of the or more sources being operable to emit X-ray flux in an area equal to the directly facing surface area of the tumor, see U.S. patent application publication 2010/0189222 and WO 2011/049743, each of which is incorporated herein by reference in its entirety, an X-ray generator based on tungsten target emission is suitable for the present application, the output energy is typically in the range of 100 to 500 kV.

Metal Organic Frameworks (MOFs)

According to embodiments of the presently disclosed subject matter, photosensitizers and/or X-ray absorbing moieties/scintillators can be combined in MOF or NMOF carrier platforms, such as for PDT, radiotherapy, X-ray induced PDT or combined RT and X-PDT, thus, in embodiments, the presently disclosed subject matter provides MOFs comprising a Photosensitizer (PS) and a plurality of metal-containing Secondary Building Units (SBUs) connected together via bridging ligands, in embodiments the PS is incorporated into the MOF, i.e., via bridging ligands covalently linked to the MOF, by forming coordinate bonds with a metal in the SBUs of the MOF (including embodiments where the PS or their derivatives are bridging ligands), or where the PS is non-covalently isolated within pores or cavities in the MOF, thus, in embodiments, the presently disclosed subject matter can provide nanoparticles (i.e., NMOFs) comprising nanoparticles having their inner side groups linked to other MOFs (e., where the MOF is linked to a core MOF).

For example, the SBU of the MOF may contain any suitable SBU, including, but not limited to, Zr-oxygen clusters, Hf-oxygen clusters, Zn-oxygen clusters, Ti-oxygen clusters, Cu-carboxylate paddle wheels, and the like, however, the SBU is not limited to these groups in embodiments, the SBU includes a metal cation capable of absorbing x-rays in embodiments, the SBU may contain a metal ion selected from the group consisting of Hf, lanthanide metals (i.e., La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu), Ba, Ta, W, Re, Os, Ir, Pt, Au, Pb, and Bi. in embodiments, the SBU may include a metal ion selected from the group consisting of oxygen ions and OH^-In embodiments, the MOF comprises Hf oxygen cluster SBU.

In some embodiments of , each bridging ligand is an organic compound comprising multiple coordination sites that may each comprise a group capable of forming a coordination bond with a metal cation or a group capable of forming such a group.

In embodiments, each bridging ligand is contained between 2 and 10 coordination sites (i.e., 2,3, 4,5, 6, 7, 8, 9, or 10 coordination sites). in embodiments, each bridging ligand is capable of binding to two or three SBUs.

In embodiments each bridging ligand comprises at least two groups wherein the two groups are each independently selected from the group comprising carboxylate groups, aromatic or non-aromatic nitrogen-containing groups (e.g., pyridine, piperidine, indole, acridine, quinolone, pyrrole, pyrrolidine, imidazole, pyrimidine, pyridazine, pyrazine, triazole, and oxazole), phenol, acetyl acetonate (acac), phosphonate groups, and phosphate groups in embodiments at least bridging ligands are carboxylate group-containing ligands, pyridine-containing bridging ligands, phenol-containing ligands, acetyl acetonate-containing bridging ligands, phosphonate-containing bridging ligands, or phosphate-containing bridging ligands in embodiments at least bridging ligands comprise at least two carboxylate groups.

In embodiments, at least bridging ligands comprise PS or PS derivatives, for example, a bridging ligand may comprise PS., which is derivatized to include or more covalently attached groups (e.g., carboxylate-containing groups, aromatic or non-aromatic nitrogen-containing groups, phenol-containing groups, acetylacetonate-containing groups, phosphonate-containing groups, or phosphate-containing groups) to form coordinate bonds with metal ions in SBUs in embodiments, such groups being substituted directly on the PS in embodiments, the PS is derivatized by complexing with an organic compound containing a group for forming coordinate bonds with metal ions in SBUs, e.g., via an amide, ester, thiourea, or another suitable bond, in embodiments, the PS is derivatized with a derivatized organic compound containing a group for forming coordinate bonds with metal ions in SBUs in embodiments, the PS already containing a metal group for forming coordinate bonds with SBUs.

Any suitable PS may be used to bridge the ligands or as part of the bridging ligands in embodiments at least bridging ligands comprise porphyrin, chlorin, chlorophyll, phthalocyanine, ruthenium-bipyridine complexes, or iridium-bipyridine complexes in embodiments at least bridging ligands comprise diphenyl-bis (benzoyloxy) porphyrin, dibenzoyloxy (bipyridyl) ruthenium bis (bipyridine), tetra (benzoyloxy) porphyrin, or dibenzoyloxy (bipyridine) ruthenium bis (phenylpyridine) in embodiments at least bridging ligands are complexes formed from ruthenium (II) bis (2,2' -bipyridine) and 5,5' -bisphenyl-2, 2' -pyridinedicarboxylate therefore in embodiments at least bridging ligands are:

in some embodiments , at least of the bridging ligands are porphyrin-based ligands, chlorin-based ligands, bacteriochlorin-based ligands, macrocyclic pi-conjugated systems, boron-dipyrromethene (BODIPY) derivatives or bis-salicylidene-1, 2-cyclohexylidene diamine derivatives in some embodiments , at least of the bridging ligands are selected from the group consisting of, but not limited to, 5, 15-bis (p-benzoyloxy) porphyrins (DBP) or their derivatives and/or metal complexes, 5, 15-bis (p-benzoyloxy) chlorin (DBC) or their derivatives and/or metal complexes, 5, 15-bis (p-benzoyloxy) bacteriochlorin (DBBC) or their derivatives and/or metal complexes, 5,10,15, 20-tetrakis (p-benzoyloxy) porphyrins or their derivatives and/or metal complexes, 5,10,15, 20-tetrakis (p-pyridyl) porphyrins, phthalocyanine-octacarboxylic acids, complexes with metals, bis (p-benzoyloxy) porphyrins or their derivatives and/or metal complexes, optionally substituted with a substituent such as a halogen atom, as shown in the substituent at the DBP-phenyl group, optionally including but not limited to the group shown in the substituent at the DBP-phenyl group, DBP-1, DBP-aryl group, DBC, DBP-aryl group, and optionally including the substituent at the substituent of the substituent group shown in the formulas, DBP-phenyl group, DBP-1, DBBC, and DBP-1, DBP-phenyl group, and/or DBC, and DBP-phenyl-2-aryl group, and/or DBC, and optionally including the formulas, and optionally including the substituent at the substituent of the formulas, DBP-aryl group shown in the formulas, and/or the other embodiments, including the other embodiments, and optionally shown in the formulas, including the formulas, and optionally shown in the examples include the formulas, and optionally including the formulas, and optionally shown.

DBP, DBC, DBBC ligands and derivatives thereof

Scheme 1 exemplary DBP, DBC and DBBC ligands.

M＝Pt、Pd、Zn、Mn(OH)、Fe(OH)、Sn(OH)₂、⁶⁴Cu

Scheme 2. metal complexes of exemplary DBP, DBC and DBBC ligands.

some exemplary, more specific structures of DBP, DBC and DBBC ligands useful as bridging ligands according to the presently disclosed subject matter include 5,10,15, 20-tetrakis (3',5' -dibenzoyloxy) porphyrin, 5,10,15, 20-tetrakis (p-benzoyloxy) porphyrin (also known as 5,10,15, 20-tetrakis (benzoyloxy) porphyrin (TBP)), 5,10,15, 20-tetrakis (p-benzoyloxy) chlorin and 5,10,15, 20-tetrakis (p-benzoyloxy) bacteriochlorin, see fig. 29. other exemplary porphyrin-based ligands, i.e., the structures of 5,10,15, 20-tetrakis (p-pyridyl) porphyrin, and phthalocyanine ligands, and more specific exemplary ligands phthalocyanine-octacarboxylic acid and quaternary porphyrin-based mottersaflu (also known as Lutrin), as indicated in fig. 30, phthalocyanine ligands can optionally form a complex with metal ion (e.g., a carboxyl group, a metal ion such as Pt, a metal ion.

The structure of an exemplary bis- (5 'benzoyloxy salicylidene) -1, 2-cyclohexylidene diamine bridged ligand bis- (5' benzoyloxy salicylidene) -1, 2-cyclohexylidene diamine is shown on the right hand side of figure 31 as indicated in figure 31, the ligand may optionally be complexed with a metal M, such as Pt or Pd, furthermore, although not shown in figure 31, the carbon atoms of the cyclohexyl and/or phenyl ring may optionally be substituted with or more alkyl or aryl substituents.

Figure 31 also shows the structure of the bridged ligand based on BODIPY derivatives on the left hand side. Aromatic substituent R in BODIPY structure₁、R₂And R₃Any suitable aryl substituent may be included, as indicated in FIG. 31, in some embodiments of , R₁The radicals being aryl or alkylaryl radicals substituted by carboxyl groups, e.g. C₆H₄(CO₂H) Or CH ═ CH-C₆H₄(CO₂H)。

In embodiments, the PS and/or at least bridging ligands are selected from the group including, but not limited to, protoporphyrin IX, papporfin, tetra (meta-hydroxyphenyl) chlorin (m-THPC), NPe6, chlorin e6, lotalprofen, and derivatives thereof, the structures of these exemplary ligands/PS are shown in FIG. 32.

In embodiments, the PS is a covalently linked dye, such as a dye covalently linked to a di-carboxylate-containing, di-phosphonate-containing, di-phosphate-containing, or bipyridine-containing organic bridging ligand the type of covalent linkage can be determined based on the available functional groups on the dye (e.g., carboxylate groups, thiol groups, hydroxyl groups, amino groups) using conventional coupling strategies known in the art.

In embodiments, the MOF contains at least bridging ligands comprising terephthallic acid or terephthallic acid (i.e., (HO)₂C)C₆H₄-C₆H₄-C₆H₄-C₆H₄CO₂H) In embodiments, the derivative is terphthalic acid or tertraphthalic acid covalently attached to the PS at sites on the phenyl ring (e.g., at carbon atoms of the phenyl ring within the terphthalic acid or tertraphthalic acid.) in embodiments, the MOF comprises:

dyes for covalent attachment to bridging ligands or for use as non-covalently trapped PS in MOFs used in MOFs disclosed herein include, but are not limited to, toluidine blue, methylene blue, nile blue, hypericin, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, and pyran chalkoxides.

In embodiments, the MOF may further comprise steps of another therapeutic agent, e.g., non-covalently entrapped in the MOF in embodiments the another therapeutic agent is a chemotherapeutic or immunotherapeutic agent, e.g., as the therapeutic agents listed elsewhere herein in embodiments the MOF may comprise another non-covalent binding agent selected from the group comprising, but not limited to, platinum drugs (e.g., cisplatin or oxaliplatin), temozolomide, doxorubicin, camptothecin, paclitaxel, pemetrexed, methotrexate, or IDO inhibitors, optionally wherein the IDO inhibitor is selected from the group comprising ICBN24360, NLG-919, 1-methyl-D-tryptophan, and 1-methyl-L-tryptophan.

In embodiments, the MOF may additionally comprise moieties comprising covalently or electrostatically bound hydrophilic polymers, such as, but not limited to, polyethylene glycol (PEG) moieties or polyvinyl pyrrolidine (PVP) in embodiments, the MOF may additionally be coated with lipids (such as, but not limited to DOTAP, DOPC, and DSPE-PEG).

In some embodiments , the MOF is in the form of nanoparticles in some embodiments , the nanoscale particles can have an average diameter of less than about 250nm in some embodiments , the average diameter is between about 20nm and about 200nm in some embodiments , the nanoscale particles have an average diameter of between about 20nm and about 180nm (e.g., about 20nm, 25nm, 30nm, 35nm, 40nm, 45nm, 50nm, 55nm, 60nm, 65nm, 70nm, 75nm, 80nm, 85nm, 90nm, 95nm, 100nm, 105nm, 110nm, 115nm, 120nm, 125nm, 130nm, 135nm, 140nm, 145nm, 150nm, 155nm, 160nm, 165nm, 170nm, 175nm, or about 180nm) in some embodiments , the nanoscale particles have an average diameter of between about 20nm and about 140nm in some embodiments , the particles can have platelet morphology.

In embodiments, the presently disclosed subject matter comprises pharmaceutical formulations comprising of the nanoscale particles described herein and a pharmaceutically acceptable carrier in embodiments, the pharmaceutically acceptable carrier is pharmaceutically acceptable to a human.

Methods of using MOFs in photodynamic therapy and X-ray induced photodynamic therapy

In embodiments, the presently disclosed subject matter provides methods of using MOFs and/or inorganic nanoparticles in photodynamic therapy or X-ray induced photodynamic therapy with or without co-administration of or more immunotherapeutic agents and/or or more chemotherapeutic agents, for example, in embodiments, the presently disclosed subject matter provides a MOF comprising a PS for treating a disease, such as cancer or a pathogenic infection, via photodynamic therapy, thus, in embodiments, the presently disclosed subject matter provides methods for treating a disease in a patient in need of treatment of a disease, wherein the method comprises administering to the patient a MOF comprising a photosensitizer and a plurality of SBUs linked together via bridging ligands at , and irradiating the patient with visible light or Near Infrared (NIR) light, in embodiments, at least or more bridging ligands are or comprise a PS or derivatives thereof, in embodiments, are entrapped within a matrix or non-covalently entrapped in a MOF (e.g., in a MOF or non-covalent MOF cavity).

For example, portions of the patient's body structure affected by the disease may be irradiated, or irradiated at a location near the affected disease embodiments the patient's portion of the body structure selected from, but not limited to, the skin or gastrointestinal tract embodiments the patient's blood is irradiated.

In some embodiments the disease is cancer, for example, the disease can be selected from the group consisting of a head tumor, a neck tumor, a breast cancer, a gynecological tumor, a brain tumor, a colorectal cancer, a lung cancer, a mesothelioma, a soft tissue sarcoma, and a pancreatic cancer, in some embodiments the method can further comprise administering to the patient an additional cancer therapy (e.g., surgery, a conventional chemotherapeutic agent, etc.).

In embodiments, the presently disclosed subject matter provides methods of treating a disease (e.g., cancer) using X-ray induced PDT and/or RT, wherein absorption of X-rays by moieties present on the MOF can provide light required for PDT, such methods can be suitable, for example, when the site of the disease is not near the surface of a patient's body structure or otherwise is not sufficiently irradiated by visible or NIR light.

In embodiments, the disease is selected from the group consisting of a head tumor, a neck tumor, a breast cancer, a gynecological tumor, a brain tumor, a colorectal cancer, a lung cancer, a mesothelioma, a soft tissue sarcoma, and a pancreatic cancer in embodiments, the disease is a metastatic cancer in embodiments, the method may further comprise administering to the patient an additional cancer therapy.

Thus, in embodiments, the methods described above may additionally comprise administering to the patient an immunotherapeutic agent, such as, but not limited to, PD-1/PD-L1 antibody, IDO inhibitor, CTLA-4 antibody, OX40 antibody, TIM3 antibody, LAG3 antibody, siRNA targeting PD-1/PD-L1, siRNA targeting IDO and siRNA targeting CCR7, as well as any other immunotherapeutic agent stated elsewhere herein or known in the art.

In embodiments, the presently disclosed subject matter provides methods of treating a disease (e.g., cancer) that combine X-ray induced PDT with immunotherapy, thus, in embodiments, the presently disclosed subject matter provides methods comprising administering to a patient a scintillant and nanoparticles comprising a photosensitizer, irradiating at least portions (e.g., to fifty fractions) of the patient with X-rays, and administering to the patient an immunotherapeutic agent.

in some embodiments, the disease is, for example, a cancer selected from the group consisting of head tumor, neck tumor, breast cancer, gynecological tumor, brain tumor, colorectal cancer, lung cancer, mesothelioma, soft tissue sarcoma, skin cancer, connective tissue cancer, adipose cancer, lung cancer, stomach cancer, anal and genital cancer, kidney cancer, bladder cancer, colon cancer, prostate cancer, central nervous system cancer, retinal cancer, blood cancer, neuroblastoma, multiple myeloma, lymphatic cancer, and pancreatic cancer, in some embodiments, the disease is metastatic cancer.

In embodiments, the additional cancer treatment may comprise administering to the patient a conventional chemotherapeutic agent, such as, but not limited to, oxaliplatin, doxorubicin, daunomycin, docetaxel, mitoxantrone, paclitaxel, digitoxin, digoxin, and virucin, or another conventional chemotherapeutic agent known in the art. in embodiments, the additional cancer treatment may involve administering to the patient a pharmaceutical formulation selected from the group consisting of polymeric micelle formulations, liposomal formulations, dendrimer nanoparticle formulations, silica-based nanoparticle formulations, nanoscale metal oxide nanoparticle formulations, and other organic metal oxide nanoparticle formulations (including, but not limited to, nanoscale iron oxide nanoparticle formulations).

Immunotherapeutic agents used according to the presently disclosed subject matter may be any suitable immunotherapeutic agent known in the art, that is, compositions that inhibit or alter the function, transcription, transcriptional stability, translation, modification, localization, or secretion of polynucleotides or polypeptides encoding a target or target-associated ligand, such as anti-target antibodies, small molecule antagonists of the target, peptides that block the target, siRNA/shRNA/microrna/pdna that block fusion proteins or inhibit the target, antibodies that may be used according to the presently disclosed subject matter include, but are not limited to, anti-CD 2 antibodies (alemtuzumab), anti-CD 20 antibodies (alfuzumab), anti-CD 20 antibodies (rituximab), anti-CD 47 antibodies, anti-GD 2 antibodies, etc. monoclonal antibodies used according to the presently disclosed subject matter include, but are not limited to, radiolabeled antibodies (e.g., radiolabeled antibodies such as interferon-interleukin-2 (e), antibodies (e.g., interferon-gamma), antibodies (e.g., interferon-gamma), antibodies (interferon- α), antibodies (e.g., antibodies), interferon- α, interferon- α, or the like, including, as disclosed herein, as well as a pharmaceutical composition.

In embodiments, the immunotherapeutic agent may be selected from the group consisting of an anti-CD 52 antibody, an anti-CD 20 antibody, an anti-CD 20 antibody, an anti-CD 47 antibody, an anti-GD 2 antibody, a radiolabeled antibody, an antibody-drug conjugate, a cytokine, polysaccharide K, and a neo-antigen suitable cytokine immunotherapeutic agents may be, for example, Interferon (IFN), Interleukin (IL), or tumor necrosis factor α (TNF- α). in embodiments, the cytokine immunotherapeutic agent is selected from IFN- α, INF- γ, IL-2, IL-12, and TNF- α. in embodiments, the immunotherapeutic agent is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, an IDO inhibitor, and a CCR7 inhibitor.

At the X-ray source and/or output may be modified to enhance treatment of the disease, for example, the X-rays may be generated using peak voltages, currents, and/or optionally filters selected to minimize DNA damage to the patient caused by X-ray exposure and maximize X-ray absorption by the scintillator.

In embodiments, the irradiating can include generating X-rays using a tungsten or another metal target, a cobalt-60 source (cobalt source device), a linear accelerator (linacs), an Ir-192 source, and a cesium-137 source in embodiments, irradiating includes transmitting X-rays (e.g., X-rays generated using a tungsten target) through a filter before irradiating the patient in embodiments, the filter can include an element having an atomic number of at least 20 in embodiments, the filter includes copper (Cu) in embodiments, the thickness of the filter can be less than about 5 millimeters (mm) in embodiments, the thickness of the filter can be less than about 4mm (e.g., less than about 3mm, less than about 1mm, less than about 0.5mm, less than about 0.4mm, less than about 0.3mm, less than about 0.2mm, or less than about 0.1 mm).

The X-rays may be generated using peak voltages, currents, and/or optionally filters selected to minimize patient DNA damage caused by X-ray exposure and maximize scintillator absorption of the X-rays embodiments use a peak voltage of less than about 230kVp to generate X-rays embodiments use a peak voltage of less than about 225kVp, less than about 200kVp, less than about 180kVp, less than about 160kVp, less than about 140kVp, less than about 120kVp, less than about 100kVp, or less than about 80kVp embodiments use a peak voltage of about 120kVp to generate X-rays.

In embodiments, the scintillator comprises a lanthanide (i.e., La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, or Lu). the scintillator can, for example, be a lanthanide nanoparticle (e.g., co-administered with and/or attached to a MOF comprising a photosensitizer). for example, the lanthanide nanoparticle can be captured in a cavity or pore within the MOF comprising a photosensitizer.

Other suitable scintillators include, but are not limited to, carbon dots; core-shell nanoparticles, wherein the shell layer comprises zinc sulfide and the core comprises a transition metal or lanthanide metal; and/or nanoparticles comprising gold, platinum, or iridium.

In embodiments, the scintillator can comprise a mof comprising hafnium (Hf), zirconium (Zr), or cerium (Ce) in embodiments, the scintillator comprises M₆(μ₃-O)₄(μ₃-OH)₄L₆In some embodiments, the scintillator can comprise a MOF comprising Hf, Zr, or Ce, and the photosensitizer is covalently bound to the MOF.

For example, in embodiments the photosensitizer comprises a carboxylate, thiol, hydroxyl, amino, or phosphate group, the scintillator comprises a metal (e.g., a metal of a MOF SBU), and the carboxylate, thiol, hydroxyl, amino, or phosphate group is bound to the metal via a coordination bond.

In embodiments, the photosensitizer is linked to the scintillator and the linkage may comprise, for example, cyclodextrin, polyethylene glycol, poly (maleic acid), or C₂-C₁₅ the photosensitizer comprises of the structures shown in fig. 27 or 28 or a deprotonated form of such structures.

In embodiments, the scintillator can be encapsulated in a MOF or mesoporous silica in embodiments, the photosensitizer is also trapped in the pores of the mesoporous silica or covalently attached to the MOF.

In embodiments, the presently disclosed subject matter provides additional methods of treating a disease (e.g., cancer) via a combination of a nanoparticle chemotherapeutic agent and an immunotherapeutic agent thus, in embodiments, the presently disclosed subject matter provides methods for treating a disease (e.g., cancer) in a patient, the method comprising administering a nanoparticle chemotherapeutic agent to a patient and administering an immunotherapeutic agent to a patient, in embodiments, the nanoparticle chemotherapeutic agent comprises a MOF of the presently disclosed subject matter (e.g., a MOF comprising a photosensitizer), in embodiments, an step comprises irradiating the patient with visible light or X-rays, in embodiments, a scintillant step comprises a scintillant, in embodiments, a chemotherapeutic agent, such as, but not limited to, oxaliplatin, doxorubicin, daunorubicin, docetaxel, mitoxantrone, paclitaxel, digoxin, and a MOF, or a MOF that is conventionally entrapped in the field of chemotherapy.

V. preparation

In some embodiments , the compositions of the presently disclosed subject matter comprise a composition comprising a pharmaceutically acceptable carrier any suitable pharmaceutical formulation can be used to prepare a composition for administration to a subject in some embodiments , the composition and/or carrier can be pharmaceutically acceptable to a human.

For example, suitable formulations may include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes which render the formulation isotonic with the bodily fluids of the subject, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, the formulations may be presented in unit-dose or multi-dose containers such as sealed ampoules and vials, and may be stored in a frozen or freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier immediately prior to use, such as water for injection some exemplary ingredients are Sodium Dodecyl Sulfate (SDS), in the range of 0.1 to 10mg/ml in embodiments and about 2.0mg/ml in another embodiment, and/or mannitol PBS or another sugar, such as in the range of 10 to 100mg/ml and about 30mg/ml in another embodiment, and/or phosphate buffered physiological saline (PBS).

It is to be understood that the formulations of the presently disclosed subject matter may include other agents conventional in the art, in addition to the ingredients particularly mentioned above, given the type of formulation in question. For example, sterile pyrogen-free aqueous and non-aqueous solutions may be used.

VI. subject

The methods and compositions disclosed herein can be used for in vitro (e.g., isolated cells or tissues) or in vivo samples of a subject (i.e., a living organism, such as a patient) in embodiments, the subject or patient is a human subject, although it is understood that the principles of the presently disclosed subject matter indicate that the presently disclosed subject matter is effective for all vertebrate species, including mammals, which are intended to be encompassed within the terms "subject" and "patient".

Thus, the methods of the presently disclosed subject matter are particularly suited for use in warm-blooded vertebrates. Thus, the presently disclosed subject matter relates to mammals and birds. More specifically, methods and compositions are provided for: mammals (e.g., humans) and mammals of importance to humans due to being endangered (e.g., siberian tigers), of economic significance (animals raised on farms for human consumption) and/or of social significance (animals kept as pets or in zoos), such as carnivores other than humans (e.g., cats and dogs), swine (pigs, hogs, and boars), ruminants (e.g., cows, bulls, sheep, giraffes, deer, goats, bison, and camels), and horses. Also provided are treatments for birds, including treatments for: those classes of birds that are endangered, fed in zoos or as pets (e.g., parrots), as well as flying birds, and more specifically domestic flying birds, such as poultry, e.g., turkeys, chickens, ducks, geese, guinea fowl, and the like, as these birds are also of economic interest to humans. Thus, treatments for livestock are also provided, including but not limited to domestic swine (pigs and hogs), ruminants, horses, poultry, and the like.

Administration of

Methods suitable for administering the compositions of the disclosed subject matter of the present invention include, but are not limited to, intravenous and intratumoral injection, oral administration, subcutaneous administration, intraperitoneal injection, intracranial injection, and rectal administration. Alternatively, the composition may be deposited at the site in need of treatment by any other means, for example by spraying the composition within the pulmonary tract. The particular mode of administration of the compositions of the presently disclosed subject matter depends on a variety of factors, including the distribution and abundance of the cells to be treated and the mechanism by which the composition is metabolized or removed from its site of administration. For example, relatively superficial tumors can be injected intratumorally. In contrast, internal tumors can be treated after intravenous injection.

In embodiments, the method of administration encompasses regional delivery or features that accumulate at the site to be treated in embodiments the composition is delivered intratumorally in embodiments the selective delivery of the composition to the target is achieved by intravenous injection of the composition followed by photodynamic therapy (light irradiation) of the target.

For delivery of the composition to the pulmonary route, the compositions of the presently disclosed subject matter can be formulated in aerosol or coarse spray form. Methods for preparing and administering aerosol or spray formulations can be found, for example, in U.S. patent nos. 5,858,784; 6,013,638, respectively; 6,022,737, respectively; and 6,136,295.

VIII. dosage

An effective dose of a composition of the presently disclosed subject matter is administered to a subject. An "effective amount" is an amount of the composition sufficient to produce a detectable treatment. The actual dosage levels of the ingredients in the compositions of the presently disclosed subject matter can be varied so as to administer an amount of the composition effective to achieve the desired effect for a particular subject and/or target. The selected dosage level may depend on the composition (e.g., RT, PDT or X-PDT activity or NMOF loading) and the route of administration.

After reviewing the disclosure of the presently disclosed subject matter herein, one of ordinary skill in the art can tailor the dosage for an individual subject, taking into account the particular formulation, the intended method of administration for the composition, and the nature of the target to be treated. Such adjustments or variations, and evaluations as to when and how to make such adjustments or variations, are well known to those of ordinary skill in the art.