MOF nanoparticles

Abstract

The present invention relates to metal-organic framework (MOF) nanoparticle or nanoparticles, compositions comprising said MOF nanoparticle or nanoparticles, methods of preparing said MOF nanoparticle or nanoparticles, methods of treatment using said MOF nanoparticle or nanoparticles, and uses of said MOF nanoparticle or nanoparticles.

Description

MOF nanoparticlesField of the Invention

[0001] The present invention relates to metal-organic framework (MOF) nanoparticle or nanoparticles, compositions comprising said MOF nanoparticle or nanoparticles, methods of preparing said MOF nanoparticle or nanoparticles, methods of treatment using said MOF nanoparticle or nanoparticles, and uses of said MOF nanoparticle or nanoparticles.Background of the Invention

[0002] Photodynamic therapy (PDT) has emerged as an important tool for cancer treatment due to its non-invasive nature, high selectivity for the target tissue, and minimal side effects as compared to conventional medical treatments, such as chemotherapy and radiotherapy.

[0003] PDT typically involves the administering of a photosensitizer (PS) directly into a tumour, followed by its direct or indirect activation by electromagnetic (EM) radiation to generate highly cytotoxic reactive oxygen species (ROS), particularly singlet oxygen (1O2), within the tumour. This then triggers cell apoptosis and necrosis within the tumour. The selectivity of PDT treatments can be enhanced by the ability to simultaneously restrict the location of both the PS and the EM radiation exposure within the tumour region.

[0004] Hence, with relative safety, PDT can be used as an adjuvant therapy in combination with other treatments in recurrent tumours. The use of PDT for treating cancers in the head and neck is particularly advantageous as the high localisation of PDT causes less damage to surrounding areas and hence reduces aesthetic and functional impairments.

[0005] Most PDT processes heavily depend on an adequate oxygen supply within the target cell for the generation of ROS. Due to the rapid cell proliferation typical of tumour cells and the distance of such cells from functional blood vessels, the microenvironment within a tumour cell is typically highly hypoxic. This can then limit the therapeutic efficacy of PDTs, including those based on MOF nanoparticles, that depend on the in-situ production of ROS.

[0006] Different strategies have been developed to mitigate this issue and improve the PDT effect, for example, by increasing the intracellular O2concentration, including hyperbaric oxygen inhalation, reoxygenation using oxygen carriers, or in situ O2generation. One known approach to alleviate hypoxia is the use of MOFs with inherent catalytic sites or nanoparticle@MOF composites to catalyse the intracellular transformation of H202to O2, suchthat O2 can further be reacted to produce ROS. Another approach targets the presence of ROS scavengers, such as glutathione (GSH), within a cell so as to maximise the efficacy of the limited ROS that is produced. MOFs bearing high valence metal ions, such as Cu (II), Mn (III) and Mn (IV) have been reported to eliminate intracellular GSH.

[0007] Despite significant progress achieved with such approaches, the relatively low intracellular H2O2 levels and high expression of GSH within cells can affect the cells reoxygenation and ROS generation capability. PDTs using MOF nanoparticles have had minimal success to date. Therefore, novel strategies to improve the efficiency and efficacy of PDT treatments for treating cancer are still required.

[0008] The present invention addresses these and other problems associated with known PDT therapeutics.Summary of the Invention

[0009] Accordingly, in a first aspect, the present invention provides a metal-organic framework (MOF) nanoparticle or nanoparticles. Each nanoparticle comprises a MOF comprising a plurality of metal ions (inorganic nodes) and a plurality of organic ligands. Each MOF nanoparticle comprises a photosensitiser, and one or more moieties capable of associating to oxygen.

[0010] The one or more moieties capable of associating to oxygen may each have a molecular weight of about 1000 g / mol or less. Preferably, the one or more moieties capable of associating to oxygen each have a molecular weight of from about 200 g / mol to about 1000 g / mol, or about 300 g / mol to about 900 g / mol, or about 400 g / mol to about 800 g / mol. Most preferably, the one or more moieties capable of associating to oxygen each have a molecular weight of about 819 g / mol.

[0011] Preferably, each of the one or more moieties capable of associating to oxygen comprises a perfluorocarbon moiety. Preferably, the one or more moieties capable of associating to oxygen are one or more perfluorocarbon moieties. More preferably, each of the one or more moieties capable of associating to oxygen is a perfluorocarbon moiety. Perfluorocarbon moieties having a carbon backbone chain of about 6 to about 16 carbon atoms are preferred. Preferably, the perfluorocarbon moiety is a perfluorooctyl group.

[0012] Each of the one or more moieties capable of associating to oxygen may be a 1 ,3-diene. In some embodiments, each of the one or more moieties capable of associating to oxygen is one or more aromatic moieties selected from the group consisting of: anthracene or a derivative thereof, naphthalene or a derivative thereof, and 2-pyridone or a derivative thereof; preferably anthracene or a derivative thereof. In certain embodiments, each of the one or more moieties capable of associating to oxygen is a moiety selected from anthracene, naphthalene and 2-pyridone; preferably anthracene.

[0013] Preferably, the MOF nanoparticles have an enhanced oxygen-carrying capacity of greater than about 5 mg / mL as measured according to the Oxygen Carrying Capacity Test Method defined herein. Preferably, the MOF nanoparticles have an enhanced oxygen-carrying capacity of greater than about 6 mg / mL, greater than about 8 mg / mL, or greater than about 10 mg / mL as measured according to the Oxygen Carrying Capacity Test Method defined herein.

[0014] Accordingly, in a related aspect, the present invention provides a metal-organic framework (MOF) nanoparticle or nanoparticles wherein each MOF nanoparticle comprises: a MOF comprising a plurality of metal ions and a plurality of organic ligands; a photosensitiser; and one or more perfluorocarbon moieties. Perfluorocarbon moieties having a carbon backbone chain of about 6 to about 16 carbon atoms are preferred. Preferably, the perfluorocarbon moiety is a perfluorooctyl group. Preferably, the MOF nanoparticles have an enhanced oxygen-carrying capacity of greater than about 5 mg / mL as measured according to the Oxygen Carrying Capacity Test Method defined herein. Preferably, the MOF nanoparticles have an enhanced oxygen-carrying capacity of greater than about 6 mg / mL, greater than about 8 mg / mL, or greater than about 10 mg / mL as measured according to the Oxygen Carrying Capacity Test Method defined herein.

[0015] Accordingly, in a further related aspect, the present invention provides a metal-organic framework (MOF) nanoparticle or nanoparticles wherein each MOF nanoparticle comprises: a MOF comprising a plurality of metal ions and a plurality of organic ligands; and a photosensitiser; wherein the MOF nanoparticles have an enhanced oxygen carrying capacity of greater than about 5 mg / mL measured according to the Oxygen Carrying Capacity Test Method defined herein. Preferably, the MOF nanoparticles have an enhanced oxygen-carrying capacity of greater than about 6 mg / mL, greater than about 8 mg / mL, or greater than about 10 mg / mL as measured according to the Oxygen Carrying Capacity Test Method defined herein. Preferably, each MOF nanoparticle comprises one or more perfluorocarbon moieties.Perfluorocarbon moieties having a carbon backbone chain of about 6 to about 16 carbon atoms are preferred. Preferably, the perfluorocarbon moiety is a perfluorooctyl group.

[0016] Accordingly, in another related aspect, the present invention provides a metal-organic framework (MOF) nanoparticle or nanoparticles wherein each MOF nanoparticle comprises: a MOF comprising a plurality of metal ions and a plurality of organic ligands; a photosensitiser; and a 1 ,3-diene. In some embodiments, the 1 ,3-diene is one or more aromatic moieties selected from the group consisting of: anthracene or a derivative thereof, naphthalene or a derivative thereof, and 2-pyridone or a derivative thereof; preferably anthracene or a derivative thereof. In certain embodiments, the MOF nanoparticles comprise a moiety selected from anthracene, naphthalene and 2-pyridone; preferably anthracene. Moieties such as anthracene, naphthalene and 2-pyridone can react with oxygen in the presence of a photosensitiser and EM radiation to form endoperoxides (i.e. these moieties are “moieties capable of associating to oxygen”). These endoperoxides can then release singlet oxygen when exposed to thermal energy, such as body temperature (37 °C), when injected into a tumour. Preferably, the MOF nanoparticles have an enhanced oxygen-carrying capacity of greater than about 5 mg / mL as measured according to the Oxygen Carrying Capacity Test Method defined herein. Preferably, the MOF nanoparticles have an enhanced oxygen-carrying capacity of greater than about 6 mg / mL, greater than about 8 mg / mL, or greater than about 10 mg / mL as measured according to the Oxygen Carrying Capacity Test Method defined herein.

[0017] The present invention provides PS-containing MOF nanoparticles that may display an enhanced oxygen-carrying capability. The MOF nanoparticles may comprise a high oxygen affinity moiety, such as a perfluoro moiety. Any inclusion of a high oxygen affinity moiety may be controlled to provide improved oxygen-carrying capability.

[0018] PDT therapies that depend on the generation of ROS require an oxygen supply within the target cell. The microenvironment within a tumour cell is typically highly hypoxic, limiting the therapeutic efficacy of PDTs that depend on the in-situ production of ROS. The present invention addresses this problem by providing a MOF suitable for PDT therapy that may deliver oxygen to the tumour cell, including deeper more inaccessible tumours. The MOF may provide a source of oxygen for ROS generation by the photosensitiser, preferably even within the hypoxic microenvironment of a tumour cell.

[0019] The present invention provides improved MOF-based PDT treatments by the use of MOF nanoparticles (comprising suitable PS and metal cations) having the ability to carry oxygen to within a tumour cell. The use of the inventive MOF nanoparticles enables theincreased generation of ROS even within the hypoxic microenvironment of a tumour cell. Furthermore, the use of a modified MOF nanoparticle to deliver the PS to within the tumour cells has many advantages. The size of the nanoparticle can be tuned so as to cross a target cell membrane. The nanoparticle can be coated or treated to improve its biocompatibility. Many nanoparticles comprising PS tend to aggregate in aqueous suspension due to the hydrophobicity of the PS. The incorporation of the PS in a suitably modified MOF nanoparticle can be used to address the tendency of the nanoparticles to aggregate.

[0020] The following embodiments relate to each of the foregoing aspects.

[0021] Preferably, the plurality of organic ligands are selected from 2',3”-dimethyl- [1 ,1’:4',1 ”:4",1 ”’-quaterphenyl]-4,4”’-dicarboxylic acid (Li), tetrakis (4- carboxyphenyl)porphyrin (TCPP), 1 ,4-benzenedicarboxylic acid (BDC), 1 ,3,5- benzenetricarboxylic acid (H3BTC), 1 ,3, 5, 8- (p-benzoate)pyrene linkers (F TBAPy), 4’,4”’,4””’,4”””’-(ethene-1 ,1 ,2,2- tetrayl)tetrakis(([1 ,1'-biphenyl]-3-carboxylic acid)) (H4ETTC), a ligand of Formula I, a ligand of Formula II, a ligand of Formula III, a ligand of Formula IV, a ligand of Formula V, a ligand of Formula VI, and chlorin-based ligands.

[0022] Preferably, the plurality of metal ions are metal ions having an atomic weight of greater than about 40 g / mol. Preferably, the plurality of metal ions may (as a plurality) consist essentially of (that is to say substantially all of the metal ions within the MOF nanoparticle are the same), or consist of, ions of a metal selected from the group consisting of: zirconium, iron, thorium, hafnium, gadolinium, neodymium, ytterbium and erbium ; more preferably the plurality of metal ions may consist essentially of ions, or consist of ions, of a metal selected from the group consisting of: zirconium, hafnium and ruthenium; most preferably the plurality of metal ions may consist essentially of ions, or consist of ions, of a metal selected from the group consisting of zirconium and hafnium. In some embodiments, the plurality of metal ions consists essentially of zirconium; and the organic ligand is the photosensitiser l_2or the photosensitiser l_3, preferably wherein the organic is the photosensitiser l_2In some such embodiments, the MOF nanoparticle further comprises a phosphate-terminated mPEG according to Structure A (below), wherein m is from about 40 to about 250.

[0023] The use of high atomic number metal cations in the MOF nanoparticles means that high energy, penetrating EM radiation can be used, if required, for less accessible, deeper tumours to activate a suitable PS by a two-step process. The metal cation can be excited / activated by high energy EM radiation (e.g. Gamma rays or X-rays) so as to emit photoelectrons. The photoelectrons then excite / activate the PS to generate ROS, such assinglet oxygen. This allows treatment of tumours further away from the skin or accessible surfaces. Typically, the metals in the MOF have an atomic number greater than 40. Such metals are referred to as “high-Z metals”. Typically the metal species are biocompatible. For example, the skilled person will appreciate that a metal species such as Cadmium may be toxic and undesirable. The chemistries of some metals, such as rare earth metals (e.g. yttrium), are so different from those involved in any biological processes that the metal is essentially biologically inert. Such metals are typically also suitable for the present invention due to their high ability to absorb high-energy EM radiation. High Z metals such as zirconium, hafnium and thorium are preferred, in particular for the treatment of deep tumours (e.g. those that cannot be treated with visible light) with Gamma rays or X-rays. The MOF nanoparticles of the invention are also suitable for shallower tumours, such as skin cancer, by use of varying frequencies of EM radiation.

[0024] EM radiation includes energy which is part of the electromagnetic spectrum, such as radio waves, microwaves, infrared, (visible) light, ultraviolet, X-rays, and gamma rays. The frequency of radio waves is between 3 Hz and 1 GHz. The frequency of microwaves is between 1 GHz and 300 GHz. The frequency of infrared is between 300 GHz and 400 THz. The frequency of visible light is between 400 THz and 790 THz. The frequency of ultraviolet is between 800 THz and 30000 THz. The frequency of X-rays is between 30000 THz and 30000000 THz. The frequency of gamma rays is above 30000000 THz.

[0025] The photosensitiser may be selected from the group consisting of: porphyrins, chlorins, bacteriochlorins, phthalocyanines, boron-dipyrromethene (BODIPY) derivatives, disalycilidene-1 ,2-cyclohexylidenediamine derivatives, gemcitabine, or combinations thereof, preferably wherein the photosensitiser is a BODIPY derivative. In some embodiments, the photosensitiser is disclosed in U.S. Pat. 10,206,871 , which is incorporated herein by reference in its entirety.

[0026] The photosensitiser may also be selected from the group consisting of: 5, 15-di(p- benzoato)porphyrin (DBP) and derivatives thereof; 5,15-di(p-benzoato)chlorin (DBC) or derivatives thereof; 5, 15-di(p-benzoato)bacteriochlorin (DBBC) and derivatives thereof; 5, 10, 15, 20-tetra(p-benzoato)porphyrin and derivatives thereof; 5, 10, 15, 20-tetra(p- pyridyl) porphyrin, phthalocyanine-octacarboxylic acid and derivatives thereof and di(5'- benzoatosalycylidene)-1 ,2-cyclohexylidenediamine and derivatives thereof, and combinations thereof. The term “derivative” includes metal complexes of a species.

[0027] Preferably, the photosensitiser is selected from the group consisting of: BODIPY- based ligands of Formula I, Aza-BODIPY-based ligands of Formula II, porphyrin-based ligands of Formula III, bacteriochlorin-based ligands of Formula IV, phthalocyanine-based ligands of Formula V, M(bpy)3ligands of Formula VI, and combinations thereof. Photosensitisers of Formula I and Formula VI are particularly preferred.Formula VI

[0028] Preferably, when the photosensitiser is one of Formula I to Formula VI, each of the plurality of organic ligands is photosensitiser.

[0029] Preferably, the photosensitiser is BODIPY-based ligand or a derivative thereof.Preferably, the photosensitiser is selected from the group consisting of: l_2and l_3

[0030] The photosensitiser may be attached to or otherwise associated with the MOF nanoparticle by any appropriate means. The skilled person would be aware of attachment / association modalities. Preferably, in each MOF nanoparticle (a) at least one of the plurality of organic ligands comprises photosensitiser; (b) each of the plurality of organic ligands comprises or consists of photosensitiser; (c) the photosensitiser is attached to one or more metal ions of the nanoparticle, optionally by phosphate-metal coordination; or (d) the photosensitiser is non-covalently attached to the MOF nanoparticle. Most preferably, (a) atleast one of the plurality of organic ligands comprises photosensitiser; or (b) each of the plurality of organic ligands comprises photosensitiser. Appropriate ligands include those selected from the group consisting of: porphyrins, chlorins, bacteriochlorins, large-ring TT- conjugation systems, phthalocyanines, boron-dipyrromethene (BODIPY) derivatives or a disalycilidene- 1 ,2-cyclohexylidenediamine derivative.

[0031] In some embodiments, when the photosensitiser is selected from the group consisting of l_2 and l_3, either (a) at least one of the plurality of organic ligands comprises photosensitiser; or (b) each of the plurality of organic ligands comprises photosensitiser. Preferably, at least one of or each of the plurality organic ligands comprises photosensitiser l_2. Preferably, at least one of or each of the plurality organic ligands is photosensitiser l_2.

[0032] Preferably, each MOF nanoparticle comprises one or more hydrophilic polymers.

[0033] The moiety capable of associating to oxygen or the PFC may exhibit poor aqueous solubility, for example, PFCs may be formed as emulsions. In addition, photosensitisers can display hydrophobic properties resulting in aggregation in aqueous solution. Thus, there may be a need for moieties within the MOF nanoparticle which improve aqueous solubility and / or biocompatibility and / or reduce aggregation due to excessive hydrophobicity. The presence of a hydrophilic polymer in MOF nanoparticles comprising perfluorocarbon moieties can improve the aqueous solubility of MOF nanoparticles that may otherwise display poor aqueous solubility due to the presence of perfluorocarbon moieties. Thus, hydrophilic polymer and moiety capable of associating to oxygen or PFC moiety within the MOF can simultaneously provide oxygen-carrying capability, biocompatibility and reduce excessive hydrophobicity.

[0034] Preferably, the hydrophilic polymer is selected from the group consisting of: polyethylene glycol (PEG) or a derivative thereof, dioleoylphosphatidylcholine (DOPC) or a derivative thereof, 1 ,2-Dioleoyl-3-trimethylammonium propane (DOTAP) or a derivative thereof, polyvinyl alcohol (P A) or a derivative thereof, poly (lactic-co-glycolic acid) (PLGA) or a derivative thereof, heparin or a derivative thereof, chitosan or a derivative thereof, pluronic F-127, and phospholipids. More preferably, the hydrophilic polymer comprises polyethylene glycol or a derivative thereof. In some embodiments, the hydrophilic polymer is linear methoxy polyethylene glycol (mPEG).

[0035] Preferably, the polyethylene glycol or derivative thereof comprises from about 40 to about 250 repeating units. PEGs display good hydrophilicity and biocompatibility. Typically, the PEG may have a molecular weight of from about 2000 g / mol to about 10000 g / mol (PEG2000 to PEG 10000), preferably from about 3000 g / mol to about 9000 g / mol (PEG3000to PEG9000), from about 4000 g / mol to about 8000 g / mol (PEG4000 to PEG8000), from about 5000 g / mol to about 7000 g / mol (PEG5000 to PEG7000), from about 5000 g / mol to about 6000 g / mol (PEG5000 to PEG6000). Preferably, the PEG has a molecular weight of about 5000 g / mol (PEG5000).

[0036] The size of the hydrophilic polymer may affect the biocompatibility and stability of the MOF nanoparticle.

[0037] In embodiments, when the hydrophilic polymer comprises polyethylene glycol or a derivative thereof, preferably the polyethylene glycol is linear polyethylene glycol or a derivative thereof. Preferably the polyethylene glycol is predominantly linear polyethylene glycol or a derivative thereof, more preferably the polymer may consist essentially of, or consists of, linear polyethylene glycol or a derivative thereof. Preferably, the hydrophilic polymer is not or is free from branched polyethylene glycol or branched derivatives thereof. Preferably, the polymer comprises, or consists essentially of, a linear alkoxy polyethylene glycol (PEG), wherein the alkoxy group is preferably a Ci to C5 alkoxy, more preferably a Ci to C3alkoxy. Even more preferably, the hydrophilic polymer comprises, or consists essentially of, a phosphate-terminated linear methoxy polyethylene glycol (mPEG).

[0038] The one or more moieties capable of associating to oxygen or the one or more perfluorocarbon moieties or the one or more aromatic moieties may be attached to or otherwise associated with the MOF nanoparticle by any appropriate means. The skilled person would be aware of attachment / association modalities. Preferably, (a) at least one of the plurality of organic ligands comprises at least one of the one or more moieties capable of associating to oxygen or at least one of the one or more perfluorocarbon moieties or at least one of the aromatic moieties; or (b) each of the plurality of organic ligands comprises the one or more moieties capable of associating to oxygen or the one or more perfluorocarbon moieties or the one or more aromatic moieties; or (c) the one or more moieties capable of associating to oxygen or the one or more perfluorocarbon moieties or the one or more aromatic moieties are non-covalently attached to the MOF nanoparticle; or (d) the one or more moieties capable of associating to oxygen or the one or more perfluorocarbon moieties or the one or more aromatic moieties are attached to the one or more hydrophilic polymers; or (e) the one or more moieties capable of associating to oxygen or the one or more perfluorocarbon moieties or the one or more aromatic moieties is attached to one or more metal ions of the nanoparticle, optionally by phosphate-metal coordination.

[0039] Preferably, when the one or more moieties capable of associating to oxygen or the one or more perfluorocarbon moieties or the one or more aromatic moieties are attached to the one or more hydrophilic polymers, they form one or more polymers and each of the one or more polymers are attached to one or more metal ions of the nanoparticle. Preferably, the one or more polymers comprise a phosphate group and the one or more polymers are attached to one or more metal ions of the nanoparticle by phosphate-metal coordination.

[0040] Typically, the mPEG may have a molecular weight of from about 2000 g / mol to about 10000 g / mol (mPEG2000 to mPEG 10000), preferably from about 3000 g / mol to about 9000 g / mol (mPEG3000 to mPEG9000), from about 4000 g / mol to about 8000 g / mol (mPEG4000 to mPEG8000), from about 5000 g / mol to about 7000 g / mol (mPEG5000 to mPEG7000), from about 5000 g / mol to about 6000 g / mol (mPEG5000 to mPEG6000). Preferably, the mPEG has a molecular weight of about 5000 g / mol (mPEG5000).

[0041] Highly fluorinated compounds such as perfluorocarbons (PFCs) show high affinity for oxygen molecules and have exhibited promise as oxygen carriers. Thus, the Inventors have found that addition of a PFC group to the MOF increases the oxygen-carrying capability of the nanoparticle. As described herein, PFCs may have poor aqueous solubility and so hydrophilic polymers may be incorporated in the MOF to improve aqueous solubility.

[0042] In embodiments, the polymer is a phosphate-terminated mPEG according to Structure AStructure A wherein n is from about 40 to about 250.

[0043] F-PEG is provided as an illustration of a preferred embodiment. F-PEG allows for straightforward attachment of both the moiety capable of associating to oxygen or PFC moiety and hydrophilic polymer to the metal ions of the MOF nanoparticle by phosphate coordination chemistry. The phosphate-metal coordination bond is robust in the presence of phosphate ions, such as those in phosphate buffered saline (PBS) or in vivo.

[0044] Other PFC / PEG phosphate molecules are suitable for use in the present invention. Indeed, it is well within the skilled person’s abilities to prepare alternative PFC / PEG phosphates that display the desired oxygen carrying capacity and hydrophilicity.

[0045] In a preferred embodiment, the invention provides a polymer-coated metal organic framework (MOF) nanoparticle or nanoparticles wherein each nanoparticle comprises a MOF comprising a plurality of metal ions and a plurality of organic ligands; wherein each MOF nanoparticle comprises photosensitiser; wherein the polymer coating comprises a hydrophilic polymer and a moiety capable of associating to oxygen; and wherein the polymer coating is attached to one or more metal ions of each nanoparticle. The embodiments described herein in relation to all aspects of the invention apply mutatis mutandis to this preferred embodiment.

[0046] In a further preferred embodiment, the invention provides a polymer-coated metal organic framework (MOF) nanoparticle or nanoparticles wherein each nanoparticle comprises a MOF comprising a plurality of metal ions and a plurality of organic ligands; wherein each MOF nanoparticle comprises photosensitiser; wherein the polymer coating comprises a hydrophilic polymer and a perfluorocarbon moiety; and wherein the polymer coating is attached to one or more metal ions of each nanoparticle. The embodiments described herein in relation to all aspects of the invention apply mutatis mutandis to this preferred embodiment.

[0047] MOF nanoparticles according to the foregoing aspects of the invention are particularly advantageous as they may facilitate increased oxygen carrying within or on the MOF nanoparticles and consequently an improved ability to carry oxygen into tumours during PDT, thus providing an improved cancer treatment. The advantages of the compositions according to the first aspect of the invention are demonstrated in the Examples and Figures described herein.

[0048] Increasing the oxygen-carrying capacity of the MOF nanoparticles of the present invention has been observed to increase performance even in the hypoxic environment of a cancerous cell (tumour cell). Interestingly, such nanoparticles also exhibit generally higher performance than equivalents that do not contain oxygen carrying moieties, even when they have not been pre-oxygenated. This is believed to be due to the concentration of the low levels of oxygen available within the cell around the moiety capable of associating to oxygen or the PFC moiety and hence the proximity to the PS.

[0049] In a second aspect, the invention provides a composition comprising a metal organic framework (MOF) nanoparticle or nanoparticles as defined in the first or related aspects of theinvention. Preferably, the composition may comprise between about 0.001 wt% and about 10 wt% of the composition MOF nanoparticle by weight, or between about 0.001 wt% and about 1 wt% of the composition MOF nanoparticle by weight, or between about 0.001 wt% and about 0.1 wt% of the composition MOF nanoparticle by weight.

[0050] The composition may be a pharmaceutical composition. Preferably, the composition may comprise one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may be selected from the group consisting of: solvents, co-solvents, buffers, stabilisers, antioxidants, preservatives, chelating agents, emulsifiers, flavourings, lubricants, suspending agents, tonicity adjusting agents, surfactants, solubilisers, suspending aids, dispersion agents, humectants, thickeners, colouring agent, wetting agent, anti-foaming agent, viscosity modifier, sweeteners and combinations thereof.

[0051] The composition may be an aqueous composition, for example a saline composition.

[0052] The composition may be substantially saturated with oxygen or the composition may be saturated with oxygen.

[0053] Embodiments related to each of the first and related aspects of the invention apply mutatis mutandis to the second aspect of the invention.

[0054] Compositions according to the second aspect of the invention are particularly advantageous as they may facilitate increased oxygen carrying within or on the MOF nanoparticles and consequently an ability to carry oxygen into tumours during PDT, thus improving cancer treatment. The advantages of the compositions according to the first aspect of the invention are demonstrated in the Examples and Figures described herein.

[0055] In a third aspect, the present invention provides a MOF nanoparticle or nanoparticles as defined in the first or related aspects of the invention for use as a medicament.

[0056] In particular, the invention provides a MOF nanoparticle or nanoparticles for use as a medicament, the or each MOF nanoparticle comprising a MOF comprising a plurality of metal ions (inorganic nodes) and a plurality of organic ligands, wherein the or each MOF nanoparticle comprises photosensitiser, and wherein the or each MOF nanoparticle is configured to deliver oxygen to the photosensitiser for use therewith. The or each MOF nanoparticle may comprise one or more moieties capable of associating with oxygen as described in the first aspect or related aspect. Preferably, the or each MOF nanoparticle comprises a perfluorocarbon moiety. Additionally or alternatively, the or each MOFnanoparticle may comprise moieties selected from the group consisting of anthracene, naphthalene and 2-pyridone.

[0057] In a fourth aspect, the present invention provides MOF nanoparticle or nanoparticles as defined in the first or related aspects of the invention for use in the treatment of cancer by photodynamic therapy.

[0058] In particular, the invention provides a MOF nanoparticle or nanoparticles for use in the treatment of cancer by photodynamic therapy, the or each MOF nanoparticle comprising a MOF comprising a plurality of metal ions (inorganic nodes) and a plurality of organic ligands, wherein the or each MOF nanoparticle comprises photosensitiser, and wherein the or each MOF nanoparticle is configured to deliver oxygen to the photosensitiser for use therewith. The or each MOF nanoparticle may comprise one or more moieties capable of associating with oxygen as described in the first aspect or related aspect. Preferably, the or each MOF nanoparticle comprises a perfluorocarbon moiety.Additionally or alternatively, the or each MOF nanoparticle may comprise moieties selected from the group consisting of anthracene, naphthalene and 2-pyridone.

[0059] In a fifth aspect, the present invention provides the composition as defined in the second aspect of the invention for use as a medicament. In particular, the invention provides a composition for use as a medicament, the composition comprising a metal-organic framework (MOF) nanoparticle or nanoparticles, wherein the or each nanoparticle comprises a MOF comprising a plurality of metal ions (inorganic nodes) and a plurality of organic ligands, wherein the or each MOF nanoparticle comprises photosensitiser, and wherein the or each MOF nanoparticle is configured to deliver oxygen to the photosensitiser for use therewith. The or each MOF nanoparticle may comprise one or more moieties capable of associating with oxygen as described in the first aspect or related aspect. Preferably, the or each MOF nanoparticle comprises a perfluorocarbon moiety.Additionally or alternatively, the or each MOF nanoparticle may comprise moieties selected from the group consisting of anthracene, naphthalene and 2-pyridone.

[0060] In a sixth aspect, the present invention provides the composition as defined in the second aspect for use in the treatment of cancer by photodynamic therapy.In particular, the invention provides a composition for use in the treatment of cancer by photodynamic therapy, the composition comprising a metal-organic framework (MOF) nanoparticle or nanoparticles, wherein the or each nanoparticle comprises a MOF comprising a plurality of metal ions (inorganic nodes) and a plurality of organic ligands, wherein the oreach MOF nanoparticle comprises photosensitiser, and wherein the or each MOF nanoparticle is configured to deliver oxygen to the photosensitiser for use therewith. The or each MOF nanoparticle may comprise one or more moieties capable of associating with oxygen as described in the first aspect or related aspect. Preferably, the or each MOF nanoparticle comprises a perfluorocarbon moiety. Additionally or alternatively, the or each MOF nanoparticle may comprise moieties selected from the group consisting of anthracene, naphthalene and 2-pyridone.

[0061] The cancer may be selected from the group consisting of: breast cancer, prostate cancer, lung cancer, brain tumours (including glioblastoma), bladder cancer, cervical cancer, head and neck cancers, Hodgkin's lymphoma, Non-Hodgkin's Lymphoma, melanoma, pancreatic cancer, rectal cancer, skin cancer (including Basal Cell Carcinoma and Squamous Cell Carcinoma) esophageal cancer, thyroid cancer, testicular cancer, mesothelioma, ovarian cancer, kidney cancer, liver cancer, gastric (stomach) cancer, bone cancer (including osteosarcoma and Ewing sarcoma), soft tissue sarcomas, endometrial (uterine) cancer, spinal tumour, nasopharyngeal cancer, salivary gland cancer, childhood cancers (certain types such as some leukaemias, neuroblastoma, Wilms tumour), colon cancer. The cancer is preferably a solid cancer or tumour.

[0062] As described herein, the photodynamic therapy is carried out using EM radiation. For example, EM radiation selected from the group consisting of radio waves, microwaves, infrared, (visible) light, ultraviolet, X-rays, and gamma rays. Gamma and X-rays may be preferred for treating deep tumours (e.g. where visible light cannot be used).

[0063] The third to sixth aspects of the invention are particularly advantageous as they provide MOF nanoparticles having improved oxygen carrying capacity for use in treatment. In particular, the treatment of cancer by photodynamic therapy. Such treatments may reduce the need for invasive therapies, such as surgery. The advantages of the third to sixth aspects of the invention are demonstrated in the Examples and Figures described herein.

[0064] In a seventh aspect, the invention provides a method of preparing one or more MOF nanoparticles as defined the first aspect of the invention. The method comprising the steps of: (a) mixing a plurality of metal ions, a plurality of organic ligands, photosensitiser and one or more moieties capable of associating to oxygen in a solvent to form a suspension of one or more MOF nanoparticles, (b) optionally additionally mixing one or more hydrophilic polymers in step a., (c) optionally drying the one or more MOF nanoparticles by lyophilisation. Preferably, the one or more moieties capable of associating to oxygen are perfluorocarbon moieties. Insome embodiments, the plurality of organic ligands is the photosensitiser, wherein the photosensitiser is of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI.

[0065] In an eighth aspect, the invention provides a method of preparing one or more MOF nanoparticles as defined in the first aspect or related aspects of the invention. The method comprising the steps of: (a) mixing a plurality of metal ions and a plurality of organic ligands in a solvent to form a suspension of one or more initial MOF nanoparticles, (b) encapsulating photosensitiser within and / or locating photosensitiser on the one or more initial MOF nanoparticles to provide a suspension of one or more photosensitiser-containing MOF nanoparticles, (c) subsequently mixing the suspension of one or more photosensitisercontaining MOF nanoparticles with the polymer coating and allowing the polymer coating to attach to one or more metal ions of the one or more photosensitiser-containing MOF nanoparticles to provide a suspension of one or more polymer-coated MOF nanoparticles, and (d) optionally drying the one or more polymer-coated MOF nanoparticles by lyophilisation. The polymer is as defined in relation to the first and related aspects of the invention.

[0066] Preferably, step (c) is carried out in water at about 10 °C to about 30 °C, or about 15 °C to about 25 °C, or about 20 °C. Typically, step (c) lasts less than about 24 hours, preferably less than about 18 hours, preferably from about 1 hour to about 24 hours, preferably from about 8 hours to about 20 hours, preferably from about 10 hours to about 16 hours.

[0067] Typically, the coordination step (c) is performed for a period of time (the coating time) sufficient for the metal sites on the external surface of the MOF nanoparticles to be substantially saturated.

[0068] Preferably, the polymer coating makes up less than about 40 % by weight of the polymer-coated nanoparticle MOF, preferably less than about 30 % by weight, more preferably from about 10 % by weight to about 40 % by weight, preferably from about 20 % by weight to about 35 % by weight of the polymer-coated nanoparticle amorphous MOF.

[0069] In the methods of the seventh and eighth aspects, step a. may be carried out at a temperature of from about 80 °C to about 140 °C, or from about 100 °C to about 120 °C. Preferably, step a. is carried out at a temperature of about 120 °C. Preferably, step a. is carried out over about 12 h to about 48 h, or about 20 h to about 40 h.

[0070] The methods of the seventh and eighth aspects of the invention are particularly advantageous because the methods produce stable MOF nanoparticles having improvedoxygen affinity. The advantages of the methods according to the seventh and eighth aspects of the invention are demonstrated in the Examples and Figures described herein.

[0071] In an ninth aspect, the present invention provides a method of preparing one or more MOF nanoparticles as defined in the first aspect or related aspects of the invention, the method comprising the steps of: (a) mixing a plurality of metal ions, a plurality of organic ligands and one or more moieties capable of associating to oxygen in a solvent to form a suspension of one or more initial MOF nanoparticles, (b) mixing the suspension of one or more initial MOF nanoparticles with photosensitiser to replace one or more of the plurality of organic ligands with photosensitiser by post-synthetic ligand exchange to form the one or more MOF nanoparticles, (c) optionally additionally mixing one or more hydrophilic polymers in step a., (d) optionally drying the one or more MOF nanoparticles by lyophilisation. Preferably, the one or more moieties capable of associating to oxygen are perfluorocarbon moieties.

[0072] Step (a) may be carried out at a temperature of from about 80 °C to about 140 °C, or from about 100 °C to about 120 °C. Preferably, step (a) is carried out at a temperature of about 120 °C. Preferably, step (a) is carried out over about 12 h to about 48 h, or about 20 h to about 40 h. Preferably, step (b) is carried out at a temperature of from about 50 °C to about 120 °C, or from about 60 °C to about 100 °C. Preferably, step a. is carried out at a temperature of about 70 °C. Preferably, step (b) is carried out over about 2 days to about 8 days, or about 4 days to about 6 days. Preferably, step (b) is carried out over about 4 days.

[0073] The methods of the seventh to ninth aspects may be used to prepare one or more MOF nanoparticles of the first or related aspects of the invention. For example, the one or more moieties capable of associating to oxygen in the methods of the seventh to ninth aspects of the invention may be replaced with perfluorocarbon moieties or aromatic moieties.

[0074] The Inventors have found that BODIPY derivatives usually have a high tendency to form aggregates in aqueous solutions, creating low intersystem crossing efficiency that is detrimental in PDT. Attempts to form MOF nanoparticles, especially Zr-containing MOF nanoparticles, using BODIPY derivatives as ligands by direct solvothermal methods were unsuccessful, likely due to the limited stability of the BODIPY core in the long-term presence of the strong acids and high temperature typically required for MOF nanoparticle synthesis.

[0075] Thus, the use of BODIPY-derivatives as ligands for MOF nanoparticles has been limited. Therefore, there is a need for improved methods for the preparation of such MOF nanoparticles as part of a preferred aspect of the present invention.

[0076] The inventors have discovered that it is possible to introduce a BODIPY-derivative ligand into a MOF nanoparticle having a ligand of identical length by a post-synthetic exchange strategy. A preferred MOF is derived from Zr UiO-69 (referred to herein as 69-Me2) wherein the ligand Li (shown below and Figure 10a) of 69-Me2has been replaced by the BODIPY derivative l_2by a post-synthesis ligand exchange. The l_2BODIPY derivative ligand has a very similar length to Li and identical bidentate functionality. In a similar manner the BODIPY derivative l_3can also be used for post-synthesis ligand exchange of Li in 69-Me2to form 69- l_3. In some embodiments, in step b. the organic ligand Li is replaced with photosensitiser l_2or L3.

[0077] Other suitable MOF nanoparticles which have ligands of identical sizes to BODIPY derivatives and which could be modified to have BODIPY functionality include PCN-222. Furthermore, the method of the ninth aspect can be used to substitute any ligands having similar size to a desired photosensitiser.

[0078] Thus, the method of the ninth aspect of the invention is particularly advantageous as the method provides an alternative way of introducing ligands that are otherwise difficult to introduce into MOF nanoparticles. The advantages of the method according to the ninth aspect of the invention are demonstrated in the Examples and Figures described herein.

[0079] Preferably, the methods of the seventh, eighth and ninth aspects of the invention are carried out in medium selected from the group consisting of water, dimethylformamide (DMF),saline, dimethylsulfoxide (DMSO) or acetic acid. Preferably, the methods of the seventh, eighth and ninth aspects of the invention are carried out in an aqueous medium.

[0080] In a tenth aspect, the invention provides a MOF nanoparticle or nanoparticles manufactured according to the method as defined in seventh, eighth or ninth aspects of the invention.

[0081] In an eleventh aspect, the invention provides a method of treating cancer by photodynamic therapy, the method may comprise administering to a patient the MOF nanoparticle or nanoparticles as defined in the first or related aspects of the invention or the composition of the second aspect of the invention.

[0082] In particular, the invention provides a method of treating cancer by photodynamic therapy comprising administering to a patient a metal-organic framework (MOF) nanoparticle or nanoparticles, wherein each nanoparticle comprises a MOF comprising a plurality of metal ions (inorganic nodes) and a plurality of organic ligands, wherein each MOF nanoparticle comprises photosensitiser, and wherein each MOF nanoparticle is configured to deliver oxygen to the photosensitiser for use therewith. Each MOF nanoparticle may comprise one or more moieties capable of associating with oxygen as described in the first aspect or related aspect. Preferably, each MOF nanoparticle comprises a perfluorocarbon moiety. Additionally or alternatively, each MOF nanoparticle may comprise moieties selected from the group consisting of anthracene, naphthalene and 2-pyridone.

[0083] In a twelfth aspect, the invention provides the use of the MOF nanoparticle or nanoparticles as defined in the first or related aspects of the invention for the manufacture of a medicament for the treatment of cancer by photodynamic therapy.

[0084] For the avoidance of doubt, embodiments related to each aspect of the invention apply mutatis mutandis to the other aspects of the invention. Further aspects and embodiments of the present invention will be evident from the discussion herein.Brief Description of the DrawingsFigure 1 Illustration of a possible disordered orientation of L2.Figure 21H NMR spectrum of F-PEG.Figure 313C NMR spectrum of F-PEG.Figure 419F NMR spectrum of F-PEG.Figure 531P NMR spectrum of F-PEG.Figure 6 GPC trace of F-PEGFigure 7 a. The structures of tetrahedral cavities, and b, two-fold interpenetrated frameworks of 69-Me2, 69-1.2, and 69-L3. Hydrogen atoms are omitted for clarity.Figure 8 Optical microscope image of Me2(left) and 69-L2(right) crystalsFigure 91H NMR spectrum of the digested SC 69-L2.Figure 10 a, Illustration of the synthesis through PSE. b, Octahedral cavity, c, Tetrahedral cavity, d, Their packing mode in the non-interpenetrated feu network, e, Structure of the twofold interpenetrated network in which the parent and second interpenetrating networks are depicted as large sphere and small sphere, respectively. Hydrogen atoms, guest solvents, and disorder are omitted for clarity.Figure 11 a, Representation of the PSE and PEGylation. b, Simulated and experimental PXRD patterns, c and d, Experimental N2isotherm at 77K, inset, N2isotherm at 77 K plotted with a logarithmic x-axis to highlight the differences in the low-pressure region, e, PSD obtained with the NLDFT method, f, Intensity-average diameter, and g, Zeta potential of aqueous suspensions of 69-Me2, 69-L2, 69-L2@P, and 69-L2@F (n = 3). h, HAADF-STEM image and, i, EDS mapping of 69-L2. Scale bar 50 nm. j, TEM image of 69-L2@F. Scale bar: 500 nm. k, UV-vis (solid line) and fluorescence (dashed line, Aexc = 395 nm) spectra of the aqueous solutions of 69-L2, 69-L2@P, and 69-L2@F. I, time-dependent changes of dissolved oxygen concentrations in 69-L2@F or 69-L2@P at the same 69-L2concentrations of 2 mg mL-1. m, the DPBF degradation rate curves with 69-L2@F and 69-L2@P in MeOH.Figure 12 Synthesis of l_3Figure 131H NMR spectrum of S6Figure 141H NMR spectrum of S7Figure 1513C NMR spectrum of S7Figure 161H NMR spectrum of l_3Figure 1713C NMR spectrum of l_3Figure 18 The lengths of Li, l_2, and l_3Figure 19 SEM images and particle size analysis of a. 69-Me2, b. 69-1.2, c. 69-l_2@P and d. 69-L2@F. Scale bar 1 pmFigure 20 TEM (left) and HAADF-STEM (right) images of a. 69-Me2and b. 69-L2Figure 21 TGA profiles of a. 69-L2and 69-L2@P, b. 69-L2and 69-L2@PFigure 22 Simulated and experimental PXRD patternsFigure 23 FT-IR spectra of PEG in 69-L2@P and 69-L2@FFigure 24 TEM (left) and HAADF-STEM (right) images of a. 69-l_2@P and b. 69-l_2@F.Figure 25 Long-term dispersity of 69-L2and 69-L2@F in water or PBS (pH = 7.4).Figure 26 TEM images of a. 69-L2and b. 69-L2@F in water after 3 weeks. Scale bar: 100 nmFigure 27 Time-dependent TEM bare 69-L2and 69-L2@F in PBS (pH =7.4) monitored by TEM. Scale bar: 100 nm.Figure 28 Normalized absorbance (solid line) and emission spectra (dashed line, Aex = 395 nm) of 69-L2in different solvents with varying polaritiesFigure 29 The detection of ROS generation using DPBF as1O2indicator in water, a, 69-L2@F. b, 69-L2@P. C, DPBF.Figure 30 Cytotoxicity of 69-L2, 69-L2@P and 69-L2@F under dark conditions. MDA-MB-231 cells' viability was measured by MTS assay after 72 h incubation.Figure 31 a, CLSM images of MDA-MB-231 cells after incubating with 69-L2, 69-L2@P, and 69-L2@F for 24 h at a concentration of 100 pg / mL; scale bar, 20 pm. MDA-MB-231 cells' viability was measured using the methyl thiazolyl tetrazolium (MTT) assay, b, cells were incubated under normoxic conditions, and c, under the hypoxic condition with 1 % O2after LED light irradiation. Concentrations are based on bare 69-L2. Data are presented as mean ± SD (n=3; **** p<0.001 , *** p<0.001 , ** p<0.01 , * p<0.05, two-way ANOVA followed by a Sidak's test for multiple comparisons).Figure 32 3D z-stack CLSM of a. 69-L2, b, 69-L2@P and c, 69-L2@F. Scale bar: 10 pmFigure 33 TEM images of the stained MDA-MB-231 cells after incubation with BODIPY-MOF samples, a, Untreated, b, 69-L2@P. c, 69-L2@F. Arrows denote MOF nanoparticles.Figure 342D CLSM observation of ROS generation of MDA-MB-231 cells incubated with 69- L2, 69-L2@P, and 69-L2@F (25 pg / mL and 100 pg / mL based on the concentration of 69-L2) under dark or LED light irradiation in normoxic conditions. When exposed to ROS, thenonfluorescent DCFH-DA could be efficiently converted into fluorescent DCF. Scale bar: 10 mFigure 35 ROS generation of 69-l_2@P and 69-l_2@F. MDA-MB-231 cells were treated with 69-l_2@P or 69-l_2@F for 24 h at a concentration of 25 pg / mL based on 69-L2, followed by green LED light irradiation. ROS generation was measured by DCF fluorescence intensity using flow cytometry, a, Normalized DCF fluorescent intensity (n=5; ** p<0.01 , * p<0.05, two- way ANOVA followed by a Sidak's test for multiple comparisons), b, Overlapped histograms of DCF intensity for normoxic and hypoxic cells, c, Flow cytometry analysis of cells with MOF intensity vs DCF intensity.Figure 36 Overlapped histograms of DCF intensity for normoxic and hypoxic MDA-MB-231 cells incubated with 69-L2@P and 69-L2@F with light irradiationFigure 37 Relative cell death of MDA-MB-231 cells after incubation with the control, 69-L2, 69-L2@P or 69-L2@F a, without, and b, with LED light irradiationFigure 38 Live cell images of PDT treated MDA-MB-231 cells by IncuCyte before and after LED light treatment.Detailed Description of the Invention

[0085] References herein to a singular of a noun encompass the plural of the noun, and vice- versa, unless the context implies otherwise.

[0086] Throughout this specification the word ‘comprise’, or variations such as ‘comprises’ or ‘comprising’, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The term ‘comprising’ includes within its ambit the term ‘consisting’ or ‘consisting essentially of’.

[0087] The term ‘consisting’ or variants thereof is to be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step or group of elements, integers or steps.

[0088] The term ’consisting essentially of’ or variants thereof is to be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, and that further components may be present, but only those not materially affecting the essential characteristics of the embodiment of the invention.

[0089] The term ‘about’ herein, when qualifying a number or value, is used to refer to values that lie within ± 5% of the value specified. For the avoidance of doubt, where a number or value is specified herein in the absence of the term ‘about’, the number or value should be understood according to standard numeric rounding conventions according to the number of decimal places. For example, a whole number, such as 6, is understood to encompass values > 5.5 and < 6.5. Likewise, a number specified to one decimal place, such as 5.3, is understood to encompass values > 5.25 and < 5.35.

[0090] Where a range of values is provided, the range includes the end point values. For example, the range 20 to 28, or from 20 to 28, would include the values 20, 21 , 22, 23, 24, 25, 26, 27 and 28; the range 5 to 15, or from 5 to 15, would include the values 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 and 15.

[0091] The present invention relates to metal-organic framework (MOF) nanoparticles, methods of manufacturing said MOF nanoparticles, and uses of said MOF nanoparticles.

[0092] Metal-organic frameworks (MOFs) are crystalline materials consisting of coordination bonds between metal ions, e.g. metal cations, and multidentate organic ligands. The MOF structure is characterised by an open framework that may be porous.

[0093] MOF nanoparticles comprise metal-organic frameworks and may display 3D architectures. MOF nanoparticles disclosed herein may be generally rod-shaped, spherical, or cuboid. Polymer-coated MOF nanoparticles of the present invention may each comprise a MOF comprising a plurality of metal ions (inorganic nodes) and a plurality of organic ligands, wherein each MOF nanoparticle comprises photosensitiser and one or more moieties capable of associating to oxygen, preferably one or more perfluorocarbon moieties.

[0094] Preferred parent MOFs for the MOF nanoparticles according to the present invention may be UiO-69 (referred to as 69-Me2herein), UiO-66, UiO-68, or Mx-M(bipy)3(where bipy is 2,2'-bipyridine, Mxcan be zirconium, iron, thorium, and hafnium , ruthenium, gadolinium, neodymium, ytterbium and erbium, and M can be ruthenium (Ru), iridium (Ir), and osmium (Os)). The structure of M(bipy)3is shown below:

[0095] For example, 69-Me2 where the ligand is replaced with l_2 is denoted as 69-1.2. Nomenclature for MOF nanoparticles having polymer attached is MOF@polymer. For example, 69-L2wherein the mPEG polymer is attached via phosphate coordination is denoted as 69-L2@P. 69-1.2 wherein the mPEG polymer and perfluorooctyl group are attached via phosphate coordination is denoted as 69-L2@F.

[0096] “Hydrophilic polymer” refers to a polymer having a strong affinity for water. For example, hydrophilic polymers may interact with water via hydrogen bonding.

[0097] “Perfluorocarbon” or “perfluorocarbon moiety” or “PFC” (used interchangeably herein) refers to chemical groups composed of only carbon and fluorine atoms. All available bonding sites of the carbon atoms are occupied by fluorine atoms, one bonding site is available to associate to the or each MOF. Examples of perfluorocarbon groups suitable for use in the present invention include those having from six to 16 carbon atoms, preferably perfluorohexyl, perfluorooctyl, or perfluorononyl groups.

[0098] “Moiety” or “moieties” refers to a distinct part, structural feature, or functional group within a larger molecule, i.e. a part of a larger molecule that has its own characteristic properties. For example, a perfluorocarbon moiety refers to the part of the MOF nanoparticle composed of only carbon and fluorine atoms, such as a perfluorooctyl group.

[0099] “Photosensitiser” refers to a molecule that can be raised to an excited electronic state, either by direct excitation by the absorption of EM radiation or indirect excitation by activation of a neighbouring entity such as a metal cation absorbing EM radiation and emitting photoelectrons. When in the excited electronic state, the photosensitiser can react with molecular oxygen to form ROS, such as singlet oxygen. For example, in its excited state, a photosensitiser can undergo intersystem crossing and transfer energy to oxygen to produce ROS, such as singlet oxygen, that can absorb light and transfer its energy to other molecules.

[0100] “Hypoxia” or “hypoxic” refers to a condition in which tissue is deprived of an adequate supply of oxygen. The oxygen supply to tumour cells can be insufficient due to the rapid growth of the tumour cells without the equivalent rapid growth of blood vessels to supply oxygen to all parts of the tumour.

[0101] “Normoxia” or “normoxic” refers to cells having a normal level of oxygen availability. The concentration of oxygen within each cell is within the expected physiological range.

[0102] “Cancer” refers to a group of diseases characterised by uncontrolled growth and spread of abnormal cells.

[0103] “Photodynamic therapy” refers to a therapy involving the use of a photosensitiser and EM radiation to generate singlet oxygen from molecular oxygen to promote cell death. Photodynamic therapy typically involves the administering of a photosensitizer directly into a tumour, followed by its direct or indirect activation by electromagnetic (EM) radiation to generate highly cytotoxic reactive oxygen species, particularly singlet oxygen, within the tumour. This then triggers cell apoptosis and necrosis within the tumour.

[0104] The particle size of the one or more MOF nanoparticles may be from about 25 nm to about 500 nm. Preferably the particle size of the one or more MOF nanoparticles is from about 25 nm to about 300 nm, or from about 50 nm to about 200 nm, or from about 100 nm to about 250 nm, or from about 100 nm to about 200 nm.

[0105] The particle size of the one or MOF nanoparticles may be measured according to the dynamic light scattering (DLS) method disclosed herein. The particle size refers to the hydrodynamic diameter, which can be defined as the radius of a hypothetical sphere that diffuses at the same rate as the particle under investigation.

[0106] Typically, a MOF nanoparticle contains only a single species of the metal ion. Accordingly, the plurality of metal ions (inorganic nodes) may consist essentially of (or consist of) ions of a metal selected from the group consisting of zirconium, iron, thorium, and hafnium, ruthenium, gadolinium, neodymium, ytterbium and erbium. The plurality of metal ions (inorganic nodes) may consist essentially of (or consist of) an ion of a metal selected from the group consisting of zirconium, hafnium and ruthenium. Preferably, the plurality of metal ions consists essentially of (or consists of) an ion of a metal selected from the group consisting of zirconium and hafnium. Typically, the metal ion selected will be biocompatible / pharmaceutically acceptable.

[0107] In embodiments, the metal ions are capable of absorbing x-rays. Such metal ions comprise hafnium (Hf), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Gd), cadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), barium (Ba), tantalum (Ta), tungsten (W,) rhenium (Re), iridium (Ir), lead (Pb), and bismuth (Bi). The plurality of metal ions may consist essentially of (or consist of) ions of a metal selected from the group consisting of: hafnium (Hf), lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Gd), cadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), lutetium (Lu), barium (Ba), tantalum (Ta), tungsten (W,) rhenium (Re), iridium (Ir), lead (Pb), and bismuth (Bi).

[0108]

[0109] The organic ligands in the MOFs according to the present invention may be multidentate. A multidentate organic ligand is an organic ligand capable of donating two or more pairs of electrons in a complexation reaction to form two or more coordinate bonds. The organic ligands may comprise two or more oxygen and / or nitrogen atoms suitable for donating a pair of electrons to form the two or more coordinate bonds. Preferably, the oxygen atoms may be present as carboxylate or nitro groups. Preferably, the nitrogen atoms may be present as amine groups. Typically, the plurality of organic ligands may be an aromatic carboxylate, an aromatic amine and / or an aromatic nitro. Preferably, the plurality of organic ligands may be selected from the group consisting of: Li, tetrakis (4-carboxyphenyl)porphyrin (TCPP), 1 ,4- benzenedicarboxylic acid (BDC), 1 ,3,5-benzenetricarboxylic acid (H3BTC), 1 ,3, 5, 8- (p- benzoate) pyrene linkers (H4TBAPy), 4’,4”’,4””’,4”””’-(ethene-1 ,1 ,2,2- tetrayl)tetrakis(([1 , 1 '- biphenyl]-3-carboxylic acid)) (H4ETTC), M(bipy)3-based ligands (where bipy is 2,2'-bipyridine, and M can be ruthenium (Ru), iridium (Ir), and osmium (Os)) (photosensitiser of Formula VI), photosensitiser of Formula I, photosensitiser of Formula II, photosensitiser of Formula III, photosensitiser of Formula IV, photosensitiser of Formula V and chlorin-based ligands. Typically, the organic ligand selected will be biocompatible / pharmaceutically acceptable.

[0110] Optionally, the photosensitiser or moiety capable of associating to oxygen or perfluorocarbon moiety may be attached to the plurality of organic ligands. Optionally, the photosensitiser, as defined herein, may be one or more of the plurality of organic ligands in the MOF nanoparticle.

[0111] Moieties such as anthracene, naphthalene and 2-pyridone can react with oxygen in the presence of a photosensitiser and EM radiation to form endoperoxides. Theseendoperoxides can then release singlet oxygen when exposed to thermal energy, such as body temperature (37 °C), when injected into a tumour. The endoperoxide may be formed prior to injection into the tumour when the or each MOF nanoparticle is exposed to air and, therefore, oxygen. Additionally, or alternatively, the endoperoxide may be formed in situ in the tumour and may be formed repeatedly while a source of oxygen is available. For example, the MOF nanoparticle may be injected into a tumour comprising an endoperoxide and, when singlet oxygen is released at 37 °C, the MOF nanoparticle can again be exposed to EM radiation to regenerate the endoperoxide for release of singlet oxygen.

[0112] In embodiments, the electromagnetic radiation is X-ray radiation. MOFs and methods using X-ray radiation, which can be combined with the moiety capable of associating to oxygen disclosed herein, are described in US 10,206,871 , which is incorporated by reference in its entirety. In such embodiments, the patient can be irradiated with X-rays in any suitable manner and / or using any suitable equipment, such as that currently being used for delivering X-rays in a medical or veterinary setting. In some embodiments, the X-ray source and / or output can be refined to enhance disease treatment. For instance, the X-rays can be generated using a peak voltage, current and / or, optionally, a filter chosen to minimize DNA damage in the patient due to X-ray irradiation and maximize X-ray absorption by the scintillator.

[0113] In some embodiments, the irradiating can comprise generating X-rays using a tungsten or another metal target, Cobalt-60 sources (cobalt unit), linear accelerators (linacs), lr-192 sources, and Cesium-137 sources. In some embodiments, the irradiating comprises passing the X-rays (e.g., the X-rays generated using a tungsten target) through a filter prior to irradiation the patient. In some embodiments, the filter can comprise an element with an atomic number of at least 20. In some embodiments, the filter comprises copper (Cu). In some embodiments, the filter can have a thickness that is less than about 5 millimeters (mm). In some embodiments, the filter can have a thickness of less than about 4 mm (e.g., less than about 3 mm, less than out 1 mm, less than about 0.5 mm, less than about 0.4 mm, less than about 0.3 mm, less than about 0.2 mm, or less than about 0.1 mm).

[0114] The X-rays can be generated using a peak voltage, current and / or, optionally, a filter chosen to minimize DNA damage in the patient due to X-ray irradiation and maximize X-ray absorption by the scintillator. In some embodiments, the X-rays are generated using a peak voltage that is less than about 230 kVp. In some embodiments, the peak voltage is less than about 225 kVp, less than about 200 kVp, less than about 180 kVp, less than about 160 kVp, less than about 140 kVp, less than about 120 kVp, less than about 100 kVp, or less than about80 kVp. In some embodiments, the X-rays are generated using a peak voltage that is about 120 kVp.

[0115] Any suitable scintillator can be used. In some 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 be, for example, a lanthanide nanoparticle (e.g., co-administered with the MOF nanoparticles disclosed herein comprising the photosensitizer moiety capable of associating to oxygen). For example, the lanthanide nanoparticles can be trapped in cavities or pores within the MOF comprising the photosensitizer. In some embodiments, the lanthanide is the metal of the SBUs of the MOF comprising the photosensitizer. In some embodiments, the lanthanide nanoparticle can be a lanthanide core-shell nanoparticle, further optionally wherein the shell of the lanthanide core-shell nanoparticle comprises a lanthanide chalcogenide. In some embodiments, the scintillator comprises a lanthanide aluminum garnet or a lanthanide fluoride.

[0116] Other suitable scintillators include, but are not limited to, carbon dots; core-shell nanoparticles wherein the shell comprises zinc sulfide and the core comprises a transition metal or lanthanide metal; and / or nanoparticles comprising gold, platinum, or iridium.

[0117] Lyophilisation (also known as freeze drying or cryodesiccation) is a drying process carried out at low temperature. Lyophilisation generally involves reducing temperature and pressure to below the substance's triple point and removing the frozen solvent (e.g. water ice) by sublimation. For aqueous compositions, such as those disclosed herein, lyophilisation may be carried out at temperatures of from about -50 °C to -80 °C, preferably about -70 °C, and pressures of from about 1000 Pa (0.01 bar) to about 100 Pa (0.001 bar), preferably about 800 Pa (0.008 bar).

[0118] The composition may be provided as a solid, a suspension, for example a dry powder, or an aqueous suspension. Suspensions herein include colloidal suspensions. Preferably the suspension(s) is(are) a colloidal suspension(s). This may be confirmed by using a red laser to observe the Tyndall effect.

[0119] The composition of the invention may be an aqueous composition. Preferably, the composition comprises dissolved oxygen. The composition may comprise dissolved oxygen levels greater than those found at atmospheric temperature and pressure. The dissolved oxygen level may be from about 12 mg / L to about 25 mg / L, or from about 21 mg / L to about25 mg / L for the fluorinated and non- fluorinated MOFs. Dissolved oxygen levels may be measured using Hanna Instruments HI-2004-02 Edge® Dissolved Oxygen Meter. Compositions comprising PFC-containing MOF nanoparticles displayed a slower decrease in dissolved oxygen concentrations relative to compositions comprising non-PFC-containing MOF nanoparticles.

[0120] The lyophilised MOF nanoparticles of the invention may be dispersed in an aqueous medium to provide the compositions of the invention.

[0121] Methods of administration of a pharmaceutical composition according to the present invention include oral, parenteral (for example, intravenous, subcutaneous, intramuscular or intraarticular, intratumoral), cutaneous (for example, topical) or inhalation administration. Intratumoral administration is particularly preferred. The pharmaceutical composition may be a liquid composition, preferably an aqueous composition.

[0122] The MOF nanoparticles and compositions of the invention may be used in conjunction with other cancer therapies. For example, the MOF nanoparticles and compositions may be used in conjunction with chemotherapy or radiotherapy. For example, gemcitabine may be used as both photosensitiser and chemotherapy.

[0123] The MOF nanoparticles of the invention may comprise a pharmaceutically active ingredient located on and / or within the MOF nanoparticles. For example, the pharmaceutically active ingredient may be encapsulated within the MOF nanoparticle. The pharmaceutically active ingredient may be a chemotherapeutic agent.Examples

[0124] The invention will now be demonstrated by reference to the following non-limiting examples.

[0125] Unless otherwise mentioned, room temperature and pressure are 20 °C (293.15 K, 68 °F) and 1 atm (14.696 psi, 101.325 kPa), respectively.Experimental MethodsPowder X-ray diffraction (PXRD)

[0126] PXRD data were collected on a Bruker D8 DAVINCI diffractometer at 298 K (24.85 °C) using Cu Ka radiation. The calculated PXRD patterns were produced using the Mercury program and single crystal reflection data.Thermogravimetric analysis (TGA)

[0127] TGA measurements were carried out using a TA Instruments Discovery SDT650. Measurements were collected from room temperature to 800 °C with a heating rate of 5 °C / min under nitrogen.Fourier-transform infrared spectroscopy (FT-IR)

[0128] FT-IR was carried out using a Bruker Tensor 27 FTIR with the attenuated total reflectance (ATR) method.Gas uptake

[0129] N2adsorption isotherm measurements were performed on a Micromeritics 3-Flex analyzer at 77 K (-196.15 °C). Around 80 mg samples were used for each measurement. Prior to the measurement, all the samples were degassed under vacuum at 50 °C for 24 hours using the internal turbopump. Gas uptakes were performed on the air-dried samples. The BET areas were estimated by applying the Brunauer-Emmett-Teller (BET) equation.Dynamic light scattering (DLS) and zeta potential

[0130] Measurements were recorded in an aqueous solution with the sample concentration of around 0.2 mg / mL by a Zetasizer Nano ZS, (Malvern Instrument Ltd., U.K.) equipped with a He-Ne laser operating at 633 nm at 25 °C. Zeta potential was measured in a folded capillary Zeta cell DTS1070. The Smoluchowski equation was used to calculate the zeta potential. Measurements were performed three times with over 10 subruns for each sample. Error bars represent the standard deviation of three measurements.Inductively coupled plasma-optical emission spectroscopy (ICP-OES)

[0131] ICP-OES was performed using a Perkin Elemer ICP-OES Optima 2100DV. Samples were dispersed in 2 mL of nitric acid and 6 mL of hydrochloric acid (CAUTION!) and left to stand at room temperature in the fume cupboard for at least 2 h until all reactions have ceased. After that, samples were heated at 120 °C for 10 h to digest the sample completely. After this time, the clear solution was obtained, which was then diluted 50 times with Millipore water and analyzed for P and Zr content by comparing it to the standard P and Zr solutions. 3 repeats were performed for each sample.UV-Vis spectroscopy

[0132] UV-vis and fluorescence spectra were recorded using a Tecan Spark® Multimode Microplate Reader.Liquid nuclear magnetic resonance spectroscopy (NMR)

[0133] Liquid NMR was carried out using a Bruker 400 MHz Avance III HD Smart Probe Spectrometer.Scanning electron microscopy (SEM)

[0134] The samples for SEM tests were coated with Pt or Au for 40 seconds and imaged using a FEI Nova Nano SEM 450.Transmission electron microscopy (TEM)

[0135] The samples were prepared by dispersing the samples in ethanol using ultrasonication. After that, a small number of suspensions were drop-casted on a copper grid with a carbon support film. A Thermo Scientific (FEI) Talos F200X G2 TEM operating at 200 kV was utilized for TEM, HAADF-STEM and EDS analysis. TEM images were acquired using a Ceta, 4k x 4k CMOS camera. EDS data was collected in STEM mode using the HAADF detector with EDS spectra and maps collected using the Super-X EDS detector system, which consists of 4 windowless silicon drift detectors.Transmission electron microscopy (TEM) of the stained cells

[0136] MDA-MB-231 cells were fixed in 2% glutaraldehyde / 2% formaldehyde in 0.05 M sodium cacodylate buffer pH 7.4 containing 2 mM CaCI2 at 4 °C for at least 4 h . Samples were washed 3x in 0.05 M sodium cacodylate buffer pH 7.4 and osmicated for 2h at room temperature with 1% osmiumtetroxide / 1 .5% potassium ferricyanide in 0.05 M sodium cacodylate buffer pH 7.4. Samples were washed 3x in deionized water and dehydrated in a series of ethanol solutions (50% / 70% / 95% / 100% / 100% dry ethanol), 2x in each, followed 2x with acetonitrile. The samples were resin embedded in Quetol resin, with fresh resin each day for 5 days. The resin mix was: 12 g Quetol 651 , 15.7 g nonenyl succinic anhydride (NSA), 5.7 g methyl nadic anhydride (MNA) and 0.5 g benzyldimethylamine (BDMA) (all from TAAB). The resin was cured in an embedding oven at 60 °C for 2 days. Thin sections (~ 70 nm) were cut using an ultramicrotome (Leica Ultracut E) and placed on bare 300 mesh copper TEM grids. Samples were post-stained with 2% uranyl acetate / 50% methanol for 3 min, followed by Reynold's lead citrate for 6 min. Samples were imaged in a Tecnai G20 TEM (FEI / Thermo Fisher Scientific) run at 200 keV using a 20 urn objective aperture to improve contrast. Images were acquired using an ORCA HR high-resolution CCD camera (Advanced Microscopy Techniques Corp, Danvers USA).Single crystal X-ray diffraction

[0137] Single crystal X-ray diffraction was performed on the PROXIMA 2A micro-focused beamline in SOLEIL synchrotron (A = 0.729319 A) using an EIGER X9M 2D hybrid photon counting detector. Data were collected at 100 K. Data integration and reduction were undertaken with Xia21. No corrections for solvent scattering have been made. The structure suffers from a significant amount of disorder, some of which is included in the presented model and some which could not be modelled with standard tools. The conformation for the L2 modelled in the structure represents the majority contributions, as evidenced by the acceptable R1 value. It is possible that, beyond the currently modelled orientations of L2, it also exists in reverse orientation, slightly offset from the modelled position. An illustration of this possibility is given in Figure 1. Due to the pseudo-symmetry of the core of L2, it is not possible to distinguish this from the modelled orientation at the resolution obtainable at the beamline PROXIMA 2A (approximately 0.7 A). In addition, it is possible to identify two weak residual electron density peaks at (0.353, 0.652, 0.152) and (0.318, 0.625, 0.125), which may represent the two fluorine atoms in this reverse orientation. When only the reverse orientation is modelled, the R1 and wR2 values are higher than the presented model. This kind of disorder cannot be modelled at the same time as the two existing orientations using the standardSHELX tools. This explains the combination of poor refinement statistics and thermal ellipsoids with very good integration statistics, a stable and chemically sensible model and an absence of confidently identifiable electron density peaks for the other orientations or ligands. The structure was solved using the direct method and refined by full-matrix least-squares on F2 by the SHELXTL-2014 software package. The disorder was modelled using standard crystallographic methods, including constraints, restraints and rigid bodies where necessary. All carbon-bound hydrogen atoms were added in idealized positions and refined using a riding model. DFIX, DELU, SIMU, SADI and SIMU restraints were used to obtain reasonable parameters. H-atoms were refined isotropically, while the other atoms were refined anisotropically. All the phenyl rings are constrained to the ideal six-membered ring. Crystal data and details of the data collection are given in Table 1 , while the selected bond distances and angles are presented in Tables 2-3.Table 1. Crystal data and structure refinement for 69-L2 and 69-L3Table 2 Selected bond lengths [A] and angles [°] for 69-L2Table 3 Selected bond lengths [A] and angles [°] for 69-L3Size exclusion chromatography with multi-angle light scattering (SEC-MLAS)

[0138] SEC-MLAS was performed on a Shimadzu HPLC system consisting of an LC-20AD Pump, SIL-20A autosampler, CTO-20A column oven and CBM-20A control unit. The column set was made up of 1 x PSS SUPREMA analytical 100 A (8 x 300 mm) and 2 x PSS SUPREMA analytical 3000A (8 x 300 mm). Dual detection was achieved via a Wyatt DAWN HELEOS-II multiangle light scattering (MALS) detector (laser at A = 658 nm), and Wyatt Optilab rEXdifferential refractive index (DRI) detector with a 658 nm light source. MilliQ Water containing 0.1 mol / L sodium nitrate and 0.01 mol / L sodium azide was used as the eluent at a flow rate of 1.0 mL / min. The column temperature and the detector temperature were kept at 30 °C. All data analysis was performed using Wyatt Astra 6.1.1 software. A literature value for the dn / dc of polyethylene glycol) in water (0.134 ml_ / g)2 was used to determine the molecular weight of all samples.Cell culture

[0139] MDA-MB-231 cells were chosen as our in vitro cellular system to evaluate the PDT efficacy of 69-L2@P and 69-L2@F against breast cancer cells. MDA-MB-231 cells were maintained at 37°C, and 5% CO2in high-rich glucose (4500 mg / L) DMEM (Gibco Dulbecco's Modified Eagle Medium, Gibco® 41965039) supplemented with 10% (v / v) fetal bovine serum (Sigma-Aldrich F9665), 100 units / mL penicillin, and 100 pg / mL streptomycin (Life Technologies 15140122). The supplemented medium is then named the 'complete' medium. PBS (Sigma D8537) and trypsin-EDTA (Life Technologies 25300054) were used to maintain the cell line. For hypoxic cultures, cells were split and incubated under normal conditions (with approximately 18.6% O2concentration) for at least 8 h to allow cells to adhere to the bottom of the plates before they were put in a designated hypoxic incubator with 1% O2concentration.MTS cytotoxicity assay

[0140] The concentration (based on 69-L2)-dependent viability of 69-L2, 69-L2@P and 69- L2@F on MDA-MB-231 cell line were evaluated using MTS assay (Promega, USA). Cells were seeded into 96-well plates at a density of 10 000 cells / well in 100 pL of complete growth medium and incubated at 37 °C, 5% CO2for 24 h. Subsequently, 69-L2, 69-L2@P and 69- L2@F were dispersed and diluted in complete medium in a range of concentrations accordingly, of which 100 pL were added to each well and incubated for 72 h at 37 °C, 5% CO2in the dark. At the end of the incubation period for 72 h, cells were washed once with PBS followed by 2 h incubation of diluted MTS solution that was prepared according to manufacturer protocol. The absorbance of each well was measured at 490 nm using a Spark plate reader (TECAN, CH). Control measurements included negative control of cells with DMEM, cells with DMEM containing 1% of water, and cell-free cultured media (blank). All experiments were conducted in biological triplicates.MTT cytotoxicity assay

[0141] The concentration-dependent viability of 69-L2@P and 69-L2@F was investigated using the Thiazolyl Blue Tetrazolium Bromide (Sigma, M2128-5G, dissolved as 40 mg / mL stock in DMSO). Briefly, MDA-MB-231 cells were seeded on a 96-well plate at a density of 5000 cells / well for approximately 24 h. 69-L2@P and 69-L2@F were dispersed in a complete medium, and a range of concentrations was prepared accordingly, of which 100 pL were added to each well and incubated at either normoxic or hypoxic condition for 24 h. Then, plates were treated with LED light irradiation (525 nm high-power LED, 3.1 W, SOLIS-525C, ThorLabs) for 10 min. Following a further incubation of 48 h, the treatment solutions were removed, and cells were washed once with PBS. 2 mg / mL of final MTT working solution was added to each well, and the contents were incubated for 4 h at 37°C / 5% CO2. After the incubation, the supernatant was removed, and 150 pL of DMSO was added to dissolve the formazan crystals. The resulting solution was then transferred to a clean 96-well plate, and the absorbance was recorded by UV-Vis SPECTROstar Nano at 570 nm. All experimental results were independently carried out three times with five technical repeats in each experiment.Live cytotoxicity assay

[0142] The time-dependent cytotoxicity of 69-L2, 69-L2@P, and 69-L2@F (100 pg / mL based on 69-L2) in MDA-MB-231 cell line was evaluated using the lncuCyte®S3 Live Cell Analysis System (Sartorius). Cells were seeded into two 96-well plates at a density of 10000 cells / well in 100 pL of complete growth medium and incubated at 37 °C, 5% CO2for 24 h. Subsequently, different concentrations of 69-L2, 69-L2@P, and 69-L2@F were diluted in a complete medium containing 250 nM of Incucyte® Cytotox Dye and incubated at 37 °C, 5% CO2. After 24h, one plate was treated with LED light irradiation using Lumidox® Gen II 96- Well LED Arrays at 527 nm wavelength for 10 minutes. Both light and non-light-treated plates were imaged every 3 h for 7 days under cell culture conditions with 10* objective using the brightfield and the red channels. Mean cell confluence was calculated using the images taken from 3 random fields of view per well using the IncuCyte S3 v2022A software. All Incucyte experiments were performed in triplicate. Relative confluence values were obtained by dividing the Cytotox red signal by the total confluence and normalizing each value to the time zero value in each sample.Flow cytometry

[0143] MDA-MB-231 cells were seeded on to 6-well plate the day before they were treated with 69-l_2@P and 69-l_2@F at a concentration of 25 pg / mL (based on 69-L2) to each well for 24 h. Then, 10 pM of DCF-DA were added to each well and incubated for 2 h before their LED light (3.1 W, SOLIS-525C, ThorLabs) irradiation for 10 min. Following their light irradiation, cells were washed with PBS and detached from the plate using trypsin for 3 min at 37°C / 5% CO2. The cell pellets were then collected and washed with PBS twice by centrifugation and fixed on ice with 4% paraformaldehyde (PFA) for immediate acquisition on the same day. Unstained and single stain compensation tubes, with and without MOFs treatment, were also prepared for spectral overlap compensation. The samples are then acquired using BD LSRFortessa which is equipped with three lasers (405, 488 and 642 nm) in standard configuration and standard filter sets. FlowJo v10.8.1 was used for analysis.Confocal microscopy

[0144] MDA-MB-231 Cells were seeded into an 8-well Nunc™ Lab-Tek™ II Chamber Slide™ System Measurements at a concentration of 100 000 cells / mL and incubated at 37 °C overnight. Subsequently, the cells were treated with water (control) or 69-L2, 69-L2@P and 69- L2@F at a concentration of 100 pg / mL based on 69-L2for 24 h. For the internalization experiment, cells were then washed twice with 1xPBS and stained with CellMask™ Red (Thermo Fischer) Plasma membrane stain and Hoechst 33342 (Thermo Fisher) according to the manufacturer's instructions. For the ROS generation confocal experiment, cells were washed with 1xPBS and incubated with DCF for 2 h. Subsequently, one plate was left in dark conditions for the duration of the experiment, while another plate was treated with LED light irradiation for 10 minutes. Cells were washed three times with 1xPBS, left in growth media, and imaged using a confocal microscope (Axio Observer Z1 LSM 800, Zeiss). The 405 nm, 488 nm, 561 nm, and 640 nm lasers were used to excite MOFs and stains. Images were collected using an oil immersion 63X / 1.4NA lens. Zen software (Zeiss) was used for acquisition and image processing.Oxygen Carrying Capacity Test Method

[0145] The oxygen-carrying capacity of MOF nanoparticles was measured as follows.

[0146] Ultra-pure water, Milli-Q water (18.2 MO. cm resistivity at 25 °C), was saturated with oxygen at 20 °C by extended bubbling of pure oxygen through the water until the oxygencontent as measured by a dissolved oxygen probe shows no further change. Suitable equipment includes the Hanna Instruments HI-2004-02 Edge® Dissolved Oxygen Meter.

[0147] The MOF nanoparticles being tested were then dispersed into a volume of water saturated with oxygen to form a MOF nanoparticle suspension having a solids concentration of 0.2 wt%. Water volumes of 200 mL are preferred, but other volumes are suitable. Oxygen was bubbled through the suspension to keep the oxygen level saturated.

[0148] The suspension was then exposed to the atmosphere and the oxygen content of the MOF nanoparticle suspension monitored over time at 20 °C with gentle agitation at 500 rpm. Free oxygen will diffuse out from the suspension to the surrounding atmosphere. The oxygencarrying capacity of the MOF nanoparticles is the difference in dissolved oxygen level after 30 minutes at 20 °C between the test MOF nanoparticle suspension and a sample of pure water saturated with oxygen and prepared and tested in an identical manner.

[0149] The more oxygen is associated with the nanoparticles, the less oxygen will be lost to the surrounding atmosphere and the higher the measurement of dissolved oxygen in the suspension.Materials and Synthesis

[0150] All reagents unless otherwise stated were obtained from commercial sources and were used without further purification. 2',3”-dimethyl-[1 ,1 ’:4',1 ”:4",1 ”’-quaterphenyl]-4,4”’- dicarboxylic acid (Li) was synthesised according to the procedure reported in Lippke et al., Inorg. Chem. 2017, 56, 748-761. S1 was synthesised according to the procedure reported in Nepomnyashchii et al. J. Am. Chem. Soc. 2011 , 133, 8633-8645 Milli-Q water (18.2 MQ.cm resistivity at 25 °C) was used throughout the experiment. Dialysis tubing (Molecular Weight Cut-off; MWCO 3,500 and 12,000 - 14,000 Daltons) was obtained from Medicell Membranes Ltd. 525 nm high-power LED (3.1 W, SOLIS-525C, ThorLabs) was used for light irradiation. The concentrations of MOF samples used in the in vitro studies were calculated based on the amount of bare 69-L2.Synthesis of mPEG5K-phosphate (P-PEG)

[0151] To a flame-dried two-neck flask, phosphorus oxychloride (POCh) (100 mmol) in 10 mL of dry dichloromethane (DCM) was added, followed by the addition of dry triethylamine (300 mmol) at 0 °C. After that, polyethylene glycol) methyl ether (Mn = 5000, 30 mmol) was addedto the mixture in 100 mL of dry DCM over 30 min. The resulting solution was stirred at room temperature for 10 h, then 40 mL of water was added, the mixture was reacted for an additional 3 h. DCM was removed under a vacuum, and the raw product was purified by dialysis (MWCO 3,500) followed by removing the residual water with lyophilization to give mPEG-PO3as a white solid (127.5 g, 25.5 mmol, 85%).1H NMR (D2O, 400 MHz), 5: 3.63 (s, 448H, -CH2OCH2-), 3.31 (s, 3H, -OCH3)31P NMR 5: (D2O, 162 MHz) 5: 0.22.Synthesis of Zr6cluster

[0152] The Zr3cluster was synthesized according to the reported procedure (Noh et al., Chem. Mater. 2018, 30 (7), 2193-2197). 15 ml of a 80 % solution of Zr(OBu)4(5 mmol) in n-Butanol was added into a solution of 100 g (818.8 mmol) benzoic acid in 300 ml of n-propanol, resulting in a clear mixture solution. The mixture is further refluxed for overnight and white solid precipitation appears. After filtration, 10.2 g (yield: 63 %) solid was separated, washed by anhydrous n-propanol five times and dried under vacuum.Synthesis of l 2Synthesis of S2

[0153] To a flame-dried flask was added with S1 (1.05 g, 4 mmol), NIS (1.8 g, 8 mmol), and anhydrous DCM (120 mL). The mixture was stirred at room temperature for 24 h. Afterward, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (DCM / cyclohexane, 1 :1 v / v) to give compound S2 as a red solid (1.75 g, 85%).1H NMR (400 MHz, CDCI3): 52.62 (s, 3H), 2.60 (s, 6H), 2.46 (s, 6H).Synthesis of S4

[0154] A 100 mL flame-dried round-bottom flask was charged with S2 (1.29 g, 2.5 mmol), S3 (1.94 g, 8.75 mmol, 3.5 equiv), K2CO3(2.07 g, 15 mmol, 6 equiv) and Pd(PPh3)4(289 mg, 0.25 mmol), followed by addition of the degassed dioxane (30 mL) and H2O (6 mL). The resulting suspension was heated at 90 °C for 24 h. After cooling to room temperature, water was added. The resulting mixture was then extracted with DCM 3 times and washed with water. The combined organic extracts were dried over Na2SO4and then concentrated under reduced pressure. The crude solid was purified by column chromatography on silica gel (EtOAc / cyclohexane, 1 :10, v / v) to afford S4 as a red solid (936 mg, 61%).1H NMR (400 MHz, CDCI3): 5 8.07 (d, J = 8.3 Hz, 4H), 7.29 (d, J = 8.4 Hz, 4H), 2.73 (s, 3H), 2.49 (s, 6H), 2.35 (s, 6H), 1.62 (s, 18H). 13C NMR (101 MHz, CDCI3): 5 165.56, 152.36, 142.27, 138.15, 137.30, 132.87, 132.40, 130.79, 130.22, 129.52, 81.12, 28.23, 17.35, 15.52, 13.28. HRMS-ESI (m / z): Calculated for S4: C36H4I BN2O4F2: 614.3127, Found: 614.3148.Synthesis of L2

[0155] To a solution of S4 (660 mg, 1.07 mmol) in dry CH2CI2(35 mL) was added trifluoroacetic acid (15 mL) at 0 °C. The reaction mixture was allowed to stand at 0 °C for 5 h, and then stirred at room temperature overnight. Afterward, the solvent was removed with flowing nitrogen. The resulting residue was then washed with Et2O (30 mL) two times, affording L2as a red solid (483 mg, 90 %).1H NMR (400 MHz, DMSO-d6): 6 8.04 (d, J = 8.3 Hz, 4H), 7.45 (d, J = 8.3 Hz, 4H), 2.79 (s, 3H), 2.43 (s, 6H), 2.39 (s, 6H). 13C NMR (126 MHz, DMSO- d6): 5 167.55, 151.68, 144.48, 138.36, 138.04, 132.40, 132.23, 130.82, 129.93, 129.90, 17.68, 15.62, 13.57. HRMS-ESI (m / z): Calculated for [L2+ H]+, C28H26BF2N2O4: 503.1954, Found: 503.1954.Synthesis of LnSynthesis of S6

[0156] To a flame-dried flask was added with S5 (648 mg, 2 mmol), NIS (900 mg, 4 mmol), and anhydrous DCM (80 ml_). The mixture was stirred at room temperature for 24 h. Afterward, the mixture was concentrated under reduced pressure, and the crude product was purified by column chromatography on silica gel (DCM / cyclohexane, 1 :2 v / v) to give compound S6 as a red solid (933 mg, 81%).1H NMR (700 MHz, CDCI3): 6 7.56 - 7.53 (m, 3H), 7.28 - 7.26 (m, 2H), 2.67 (s, 6H), 1.41 (s, 6H).Synthesis of S7

[0157] A 150 mL flame-dried round-bottom flask was charged with S6 (1.29 g, 4.3 mmol), S3 (5.3 g, 4 equiv), K2CO3(3.6 g, 6 equiv) and Pd(PPh3)4(497 mg, 0.43 mmol), followed by addition of the degassed dioxane (60 mL) and H2O (12 mL). The resulting suspension was heated at 90 °C for 36 h. After cooling to room temperature, water was added. The resulting mixture was then extracted with DCM two times and washed with water. The combined organic extracts were dried over Na2SO4and then concentrated under reduced pressure. The crude solid was purified by column chromatography on silica gel (EtOAc / DCM / cyclohexane, 1 :1 :30, v / v / v) to afford S7 as a red solid (1 .42 g, 49%).1H NMR (700 MHz, CDCI3): 5 8.04 (d, J = 8.0 Hz, 4H), 7.52 (dd, J = 13.1 , 7.1 Hz, 3H), 7.39 - 7.37 (m, 2H), 7.25 (d, J = 8.0 Hz, 4H), 2.57 (s, 6H), 1.63 (s, 18H), 1.34 (s, 6H). 13C NMR (176 MHz, CDCI3): 5 165.56, 154.21 , 142.59, 139.47, 138.04, 135.13, 133.00, 131.46, 130.72, 130.23, 129.99, 129.45, 129.36, 129.23, 127.92, 81.10, 28.21 , 13.40, 12.74. HRMS-ESI (m / z): Calculated for S7: C4I H43BF2N2O4: 676.3284, Found: 676.3273.Synthesis of l_3

[0158] To a solution of S7 (846 mg, 1.5 mmol) in dry CH2CI2(50 mL) was added trifluoroacetic acid (20 mL) at 0 °C. The reaction mixture was allowed to stand at 0 °C for 5 h, and then stirred at room temperature overnight. Afterward, the solvent was removed with flowing nitrogen. The resulting residue was then washed with Et2O (50 mL) two times, affording L3as a red solid (719 mg, 85 %).1H NMR (500 MHz, DMF-d7): 13.33 (s, 2H), 8.11 (d, J = 8.0 Hz, 4H), 7.66 (dd, J = 14.7, 7.1 Hz, 3H), 7.62 - 7.58 (m, 2H), 7.48 (d, J = 8.0 Hz, 4H), 2.59 (s, 6H), 1 .42 (s, 6H).13C NMR (126 MHz, DMF-d7) 5 167.41 , 154.18, 143.60, 139.74, 138.02, 134.98, 132.92, 131.50, 130.53, 130.11 , 129.82, 129.81 , 129.76, 128.44, 13.19, 12.64. HRMS-ESI (m / z): Calculated for [L3+ H]+, C33H28BF2N2O4: 565.2110, Found: 565.2082.Synthesis of F- PEG

[0159] The synthesis of F-PEG was adapted from a reported method with slight modification (Keiper et al., J. Am. Chem. Soc. 2002, 124, 1834-5). To a flame-dried two-neck flask, phosphorus oxychloride (1 .6 ml_, 17.2 mmol) in 40 mL of dry DCM was added, and the mixture was cooled to 0 °C. Afterward,1H,1H,2H,2H-perfluoro-1-decanol (7.89 g, 17.0 mmol) and dry triethylamine (51.6 mmol) in 20 mL DCM were slowly added via syringe, leading to the formation of white precipitate. The mixture was then stirred at 0 °C for 1.5 h. After that, polyethylene glycol) methyl ether (Mn = 5000, 17 mmol) in dry DCM (20 mL) was added. The resulting solution was allowed to warm to room temperature and stirred under N2overnight. The white precipitate was filtered and washed with dry DCM (50 mL). Water (20 mL) was added to the filtrate and then was stirred at 40 °C overnight. Afterward, DCM was removed using flowing N2, and purified by dialysis (MWCO: 1 ,000), followed by removing the residual water with lyophilization. The crude solid was purified by column chromatography on silica gel (DCM / MeOH, 10:1 , v / v) to afford F-PEG as a white solid (10 mmol, 59%).1H NMR (400 MHz, CDCh): 5 4.20 (q, J = 7.0 Hz, 2H), 3.55 (s, 471 H), 3.28 (s, 3H), 2.45 (ddd, J = 18.4, 12.2, 6.5 Hz, 2H).13C NMR (CDCh, 101 MHz): 5 70.54.31P NMR (CDCh, 162 MHz): 5 -4.04.19F NMR (CDCh, 376 MHz): 5 -85.53, -118.33, -126.58, -127.47, -128.37, -130.86. NMR spectra and size exclusion chromatography with multi-angle light scattering (SEC-MALS) confirm the formation and purity of F-PEG (Figures 2 to 6).Synthesis of BO DIPY-based MOFsSynthesis of UiO-69 (69-Me2) single crystal (SC 69-Me2)

[0160] 69-Me2was synthesized following a previously reported procedure (Lippke et al., Inorg. Chem. 2017, 56, 748-761). To a 20 mL vial was added with Li (36 mg), ZrOCI28H2O (28 mg), acetic acid (0.982 mL) and DMF (5 mL). The resulting mixture was sonicated for 10 min and then heated at 120 °C for 48 h. After cooling down to room temperature, colourless crystals of 69-Me2were harvested by filtration.

[0161] 69-Me2 is a two-fold interpenetrated feu network with identical ligand-metal node connectivity to that of the UiO-66 to UiO-68 series MOFs (Figure 7).Synthesis of 69-Me2nanoparticle (69-Me2)

[0162] To a 20 mL vial was added with Li (18 mg), ZreOa cluster (30 mg), acetic acid (150 pL) and DMF (8 mL). The resulting mixture was sonicated for 10 min and then heated at 120 °C for 12 h. After cooling to room temperature, the obtained sample was collected by high-speed centrifugation (15,000 rpm, 35 min), followed by washing with hot DMF 3 times and exchanging with ethanol 3 times. The final product was dried or re-dispersed in ethanol for further use.Synthesis of 69-L2and 69-L3

[0163] 69-L2and 69-L3were synthesised by post-synthetic ligand exchange. Briefly, crystals or powders of 69-Me2(30 mg) were incubated in the DMF solution (4 mL) of L2or L3(100 mg) at 70°C for 4 days. SC 69-Me2was used to prepare SC 69-L2or SC 69-L3. 69-Me2nanoparticle was used to prepare 69-L2nanoparticle or 69-L3nanoparticle. The supernatant was exchanged with the fresh solution of L2or L3(100 mg) in DMF (4 mL) every 12 h. 69-L2and 69-L3in red colour was harvested by centrifugation (Figure 8). The colour change from colourless 69-Me2(denoted as SC 69-Me2) to red after incubation in a DMF solution of L2at 70 °C (Figure 8), indicates the successful incorporation of L2.

[0164] An1H NMR study on a digested sample shows that L2entirely replaced Li in 69-Me2after 4 days (Figure 9). This new material is denoted as 69-L2and its crystals as SC 69-L2. Most importantly, this transformation process takes place in a SC-SC manner, where the single-crystal X-ray diffraction (SCXRD) analysis clearly shows the successful replacement of Li by L2. Identical to the parent 69-Me2, SCXRD reveals that 69-L2, formulated as [Zr6O4(OH)4(L2)6], is also a two-fold interpenetrated network, and crystallises in the cubic space group Fd-3m with a = 38.395 A. Each hexanuclear [Zre(p3-O)4(3-OH)4] cluster is connected to twelve bidentate carboxylate groups from twelve independent L2, where the neighbouring [Zr6(p3-O)4(p3-OH)4] clusters are linked by one L2ligand, thereby forming an independent 3D framework in feu topology with two types of cavities (Figure 10d): 128 octahedral (2.26 nm, pale yellow, Figure 10b) and tetrahedral (1.31 nm, cyan, Figure 10c).

[0165] Notably, each L2is disordered on the crystallographic symmetry axis. Two such identical networks are staggered with respect to one another, affording the final 69-L2, in whichthe [Zre(|J3-O)4(|J3-OH)4] clusters and three L2ligands within the same trigonal face of the second network partially interpenetrate the tetrahedral and octahedral cavities of the first network, respectively (Figure 10e); 69-L2possesses compromised cavities with diameters of 1.31 nm (Figure 7a). Despite the presence of two-fold interpenetration, PLATON calculation (http: / / www.platonsoft.nl / platon / ) suggests a 54.5% void volume available for guest inclusion in 69-L2. Figures 11 b-11e show the powder X-ray diffraction (PXRD) patterns, 77 K N2isotherms, and DFT pore size distribution (PSD) of SC 69-Me2and SC 69-L2.

[0166] Further to the utilisation of the meso-methyl BODIPY-based ligand L2, this SC-SC transformation methodology was successfully extended to incorporate the comparably bulky meso-phenyl BODIPY-based ligand L3, obtaining the single crystal, termed 69-L3(Figure 12, Figures 7, 13 to 17, 18 and Tables 1 and 3). To the best of the Inventors’ knowledge, this represents the first example of Zr-based MOFs constructed exclusively from BODIPY-derived ligands through a SC-SC process, since most of the reported BODIPY-containing Zr-based MOFs have been prepared via post-synthetic modification.

[0167] PXRD shows good agreement within 69-L2, 69-Me2, their single crystal analogues, and the simulated pattern, indicating the phase purity (Figure 11 b). Figures 11 c-11 d show typical Type I isotherms of microporous materials, with a sharp uptake at low relative pressure (P / Po < 0.01) for SC 69-L2and the related nanoparticles, 69-L2, consistent with their parent 69-Me2material. It was noted that N2uptake at P / Po= 0.8 decreases from 428 to 393 cm3g-1(SC 69- Me2to SC 69-L2) and from 407 to 327 m3g-1(69-Me2to 69-L2nanoparticles) for micro-and nanosized MOFs in each case after the PSE process with Brunauer-Emmett-Teller (BET) areas - calculated using BETSI54 as described in Osterrieth, J. W. M. et al., Advanced Materials, 2022, 34, 2201502 - decreasing from 1639 to 1522 m2g-1and from 1388 to 1197 m2g-1, respectively. The lower N2uptakes and BET areas are attributed to the slightly increased volume and molecular weight of L2ligands (Figure 18), which could be further confirmed by the decrease in PSD from 1.38 to 1.20 nm (Figure 11 e). Additionally, dynamic light scattering (DLS) of an aqueous suspension of 69-L2indicates z-average size and zeta potential of 171 ± 5 nm and -26 ± 5 mV, respectively, identical to the parent 69-Me2(Figures 11f and 11g).

[0168] It is also noted that the particle size obtained through DLS is 2~3 times larger than the transmission electron microscopy (TEM) and the scan electron microscopy (SEM) sizes, due to the presence of aggregates (Figures 11 h, 19 and 20). Specifically, TEM shows that 69-L2nanoparticles exist in the form of aggregation consisting of a few nanoparticles, and each particle exhibits distorted octahedral morphology with a diameter of around 80 nm (Figure 11 h).Moreover, high-angle annular dark-field scanning transmission electron microscopy (HAADF- STEM) imaging reveals the existence of highly oriented channels with a lattice spacing of 1.2 nm (Figure 20b), which is slightly smaller than 1.3 nm of the parent 69-Me2(Figure 20a), consistent with the single-crystal structure and the decreased PSD obtained by 77 K N2isotherm (Figures 7a, 10e, 11e). Further energy-dispersive X-ray spectroscopy (EDS) mapping analysis confirms the uniformly distributed B and F elements within the 69-L2nanoparticles (Figure 11 i).Synthesis of 69-L2@P

[0169] A PEGylation strategy was pursued, for translational feasibility, and to improve the colloidal stability of the MOF system. The introduction of a phosphate-functionalized methoxy polyethylene glycol (P-PEG) onto Zr-based MOFs can simultaneously enhance their colloidal and chemical stability (WO 2022 / 122983 incorporated by reference herein in its entirety). P- PEG was synthesised as described herein and 69-L2@P was prepared as a control using P- PEG.

[0170] P-PEG solution (15 ml_, 25 mg / mL in H2O) was added into the aqueous suspension of 69-L2(5 ml_, 10 mg / mL). After stirring at room temperature overnight, the reaction mixture was centrifuged (25 min, 16,000 rpm) to remove the unreacted P-PEG, and washed with fresh water three times. The final product, denoted as 69-L2@P, was kept in water. The amount of P-PEG (wt %) = mass of encapsulated P-PEG / 69-L2@P x 100. The amount of P-PEG in 69- L2@P is 21.7 wt%, determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) through measuring the ratio of P to Zr (Table 4), and confirmed using thermogravimetric analysis (TGA) (Figure 21).Table 4 ICP-OES analysis for 69-L2@P and 69-L2@FSample P Zr PEG loading(ppm) (ppm) (wt%)69-L2@P batch 1 0.037549096 3.833998622 19.469-L2@P batch 2 0.029658185 2.563730218 22.169-L2@P batch 3 0.025422343 2.011467253 23.769-L2@F batch 1 0.021017144 2.594717573 16.969-L2@F batch 2 0.019827533 1.95927668 20.269-L2@F batch 3 0.02381091 3.101977208 16.1PEG loading = Mass of PEG loaded / (Mass of MOF + Mass of PEG loaded)

[0171] The crystallinity of 69-1.2 is preserved after performing the PEGylation using P-PEG, with a new peak centred at 29 = 19° (Figures 11 b and 22). In addition, 77 K N2isotherms show that 69-L2@P adsorbs 24 cm3g-1N2at P / Po= 0.8, with BET area decreasing from 1197 to 38 m2g-1, suggesting the blockage of nitrogen at 77 K towards the internal porosity of 69-L2. Fourier-transform infrared (FT-IR) spectra indicate the existence of PEG within 69-L2@P (Figure 23). TEM images show the well-preserved morphology after PEGylation with P-PEG, consisting of a few aggregated nanoparticles with diameters of 170 nm, consistent with the parent 69-L2(Figure 11j and 24). Moreover, HAADF-STEM imaging demonstrates the preservation of highly ordered mesopores after PEGylation (Figure 24). The z-average size of 69-L2@P is 188 ± 3 nm, obtained by DLS analysis (Figure 11f). Furthermore, 69-L2@P displays a more negative zeta potential of -41 ± 1 mV compared to the parent 69-L2(Figure ng).Synthesis of 69-L2@F

[0172] Given the high oxygen affinity of fluorinated polymers, it was envisioned that integrating fluorinated polymer into P-PEG would combine the merits of fluorinated polymers and P-PEG. To validate this hypothesis, a perfluorooctyl segment was introduced into the P-PEG, yielding a double-tailed phosphate known as F-PEG.

[0173] PEGylation of 69-L2was then performed using F-PEG under the protocol reported in (WO 2022 / 122983 incorporated by reference herein in its entirety) and described herein.

[0174] F-PEG was synthesised as described herein. F-PEG solution (15 ml_, 25 mg / mL in H2O) was added into the aqueous suspension of 69-L2(5 ml_, 10 mg / mL). After stirring at room temperature overnight, the reaction mixture was centrifuged (25 min, 16,000 rpm) to remove the unreacted F-PEG, and washed with fresh water three times. The final product, denoted as 69-L2@F, was kept in water. The amount of F-PEG (wt %) = mass of encapsulated F-PEG / 69- L2@F x 100. The amount of F-PEG in and 69-L2@F is 17.7 wt%, determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) through measuring the ratio of P to Zr (Table 4), and confirmed using thermogravimetric analysis (TGA) (Figure 21).

[0175] The crystallinity of 69-L2is preserved after performing the PEGylation using F-PEG, with a new peak centred at 29 = 23° (Figures 11 b and 22). In addition, 77 K N2isotherms show that 69-L2@F adsorbs 37 cm3g-1N2at P / Po= 0.8, respectively, with BET area decreasing from 1197 to 104 m2g-1, suggesting the blockage of nitrogen at 77 K towards the internal porosity of 69-L2. Fourier-transform infrared (FT-IR) spectra indicate the existence of PEG within 69-I_2@F (Figure 23). TEM images show the well-preserved morphology after PEGylation with F- PEG, consisting of a few aggregated nanoparticles with diameters of 170 nm, consistent with the parent 69-L2(Figures 11j and 24). Moreover, HAADF-STEM imaging demonstrates the preservation of highly ordered mesopores after PEGylation (Figure 24). The z-average sizes of 69-l_2@F are 171 ± 1 nm, obtained by DLS analysis (Figure 11f). Furthermore, 69-L2@F displays more negative zeta potential of-45 ± 1 mV compared to the parent 69-L2(Figure 11g).

[0176] Following the surface modification of 69-L2with F-PEG, its impact on the colloidal stability of 69-L2was assessed. Briefly, bare 69-L2and 69-L2@F were treated in water and PBS (pH = 7.4), then hydrodynamic size changes were monitored using DLS. As shown in Figure 25, 69-L2@F remained stable for up to 8 days, with negligible changes in hydrodynamic size. Although the size of 69-L2@F began to increase after 8 days, they still outperformed the untreated 69-L2, which experienced a rapid increase in size to approximately 400 nm within just 1 day. When treated in PBS (pH = 7.4), 69-L2@F maintained its hydrodynamic sizes for up to 30 h, after which it underwent rapid aggregation. In contrast, the bare 69-L2aggregated dramatically under identical conditions. Morphological changes for MOF particles were examined using TEM. Both bare 69-L2and 69-L2@F retained their morphologies when suspended in water for up to 3 weeks (Figure 26). However, when exposed to PBS (pH = 7.4), the bare 69-L2decomposed rapidly after 4 h and degraded completely at 16 h, while the morphologies of 69-L2@F remained intact for up to 48 h before particles began to degrade or aggregate (Figure 27). These findings highlight the pronounced improvement in both colloidal stability and chemical stability conferred by F-PEG.The digestion of 69-L2samples

[0177] To a 6 mL vial, the activated 69-L2(10 mg) was stirred with 10X PBS (4 mL) at 50 °C for 7 days. Afterward, the solvent was removed under the vacuum. The residue was then incubated with 5M NH4F (5 mL) at 50 °C for another 3 days. DMSO-de (0.7 mL) was added after removing the water, and the mixture was sonicated until fully dissolved, which was used for 1 H NMR measurement.Evaluation of the Oxygen Loading Capability of 69-L2@P and 69-L2@F

[0178] Milli-Q water was firstly bubbled with the flowing O2to saturate the content of O2. 69- L2@P and 69-L2@F were then diluted with the above Milli-Q water to 220 mL with a concentration of 2 mg / mL in terms of 69-L2. It was assumed that 69-L2@F, 69-L2@P, and water had the same initial amount of O2, which decreases over time due to the diffusion ofdissolved O2 into the air. The capped suspensions were then stabilized for 1 min. Afterward, the diluted suspensions were uncapped and stirred mildly, where the O2concentration was monitored using a portable dissolved oxygen meter (Hanna Instruments HI-2004-02 Edge® Dissolved Oxygen Meter) for 30 min. The values were recorded automatically every 30 s.Evaluation of ROS Generation Capability of 69-L2@P and 69-L2@F

[0179] The time-dependent ROS generation capabilities of 69-L2@P, 69-L2@F, and the control group were determined by a chemical acceptor, 1 ,3-diphenylisobenzofuran (DPBF, 97%, Acros Organics), under the LED light treatment (525 nm high-power LED, 3.1 W, SOLIS- 5250, ThorLabs). The solvents were bubbled with flowing oxygen for 30 min before sample preparation. Briefly, DPBF (50 pM) was irradiated with stirring at 525 nm in the presence of the sample (20 pM based on 69-L2) in MeOH (20 mL) at room temperature with the reaction vial open to the air. Aliquots of the reaction (100 pL) were taken every 30 s and measured by UV-Vis spectroscopy. The decrease of the Amax of DBPF (410 nm) was then evaluated and plotted according to A / A0 vs. time.

[0180] As shown in Figure 28, solvents have negligible influence on the position of the absorbance spectra of 69-L2, which possess identical absorbance bands in DMF, EtOH, and H2O, with two typical peaks centred at 530 and 380 nm, originating from the TT-TT* transitions and the charge-transfer transitions of the BODIPY ligands. In comparison, solvents appear to have a minor impact on the emission spectra, where the related emission maximum exhibits slight shifts depending on the solvent used (Figure 28). In addition, 69-L2, 69-L2@P, and 69- L2@F have nearly identical absorbance and fluorescence spectra (Figure 11k), suggesting the negligible effect of the PEGylation process on emission.

[0181] Considering the excellent oxygen affinity of the perfluorooctyl segment, the oxygencarrying ability of 69-L2@F in water was then evaluated, using water and 69-L2@P as controls. The changes in dissolved oxygen concentration were monitored using a dissolved oxygen meter. Figure 111 shows the time-resolved dissolved O2concentration as a function of the increased time. 69-L2@F suspension exhibited a noticeably higher O2concentration compared to those of 69-L2@P and pure water, where the presence of PEG component has a negligible effect on O2solubilisation. More specifically, the initial dissolved O2concentration of around 25 mg / mL decreases, after 30 minutes, to 21.46, 12.36, and 11.31 mg / mL for 69- L2@F, 69-L2@P, and 69-L2, respectively (Figure 111). The dissolved oxygen content of water was 9.61 mg / mL. Thus, the oxygen carrying capacities of 69-L2@F, 69-L2@P, and 69-L2, were 11.85 mg / mL, 2.75 mg / mL and 1.7 mg / mL, respectively. These results demonstrate theexcellent oxygen-carrying capability of 69-l_2@F and MOFs containing perfluorocarbon moieties, which can potentially enhance the therapeutic effect of PDT.

[0182] The ROS generation ability of 69-L2@F and 69-L2@P in air-saturated MeOH was assessed using a commercial trapping agent, 1 ,3-diphenylisobenzofuran (DPBF). Figure 29 shows the degradation rate curves of DPBF, a common ROS quencher, when exposed to 69- L2@F and 69-L2@P in MeOH under continuous LED light irradiation (525 nm, high-power LED, 3.1 W, SOLIS-525C, 257 ThorLabs), whereas 69-L2@F shows enhanced ROS generation capability with a 80% decrease in the relative absorbance at 410 nm after 120s (Figure 11 m). For comparison, 69-L2@F takes 270 s to achieve an 80% decrease, whereas the control group exhibits a negligible decline of DPBF absorbance under the same irradiation treatment (Figure 29c). Overall, these results demonstrate that 69-L2@F could act as an efficient PS for PDT applications while simultaneously holding the capability of carrying O2.In Vitro Study

[0183] Cytotoxicity of 69-L2, 69-L2@P and 69-L2@F was assessed under dark conditions. MDA-MB-231 cells viability was measured by MTS cytotoxicity assay after 72 h incubation. Cell culture of MDA-MB-231 cells and MTS cytotoxicity assay methods are described herein.

[0184] Breast cancer is one of the most commonly diagnosed cancers worldwide. Triplenegative breast cancer, a subset of breast cancer, is considered the most aggressive and invasive. Here, the PDT effect of BODIPY-based MOFs was investigated in the triple-negative breast cancer cells MDA-MB-231. First, the biocompatibility and intracellular uptake of 69-L2, 69-L2@P, and 69-L2@F was examined. As shown in Figure 30, 69-L2@P and 69-L2@F exhibit negligible cytotoxicity after incubation for 24 h in dark conditions, even at concentrations of 500 pg / mL. In comparison, bare 69-L2shows a reduction of over 30% in viability under the same concentration of 500 pg / mL. Altogether, this is consistent with the knowledge that the presence of PEG around the nanosized MOFs could significantly improve their biocompatibility due to the limited aggregation of the nanoparticles.

[0185] To validate the cellular uptake of the BODIPY-based MOFs, confocal laser scanning microscopy (CLSM) imaging was performed. Figure 31a shows increased fluorescence signals of the BODIPY core in MDA-MB-231 cells after incubation cells with 69-L2, 69-L2@P or 69-L2@F for 24 h; Figure 32 show the 3D z-stack CLSM, where 69-L2, 69-L2@P, and 69- L2@F are internalized and accumulated inside the cells. Figure 33 shows the TEM imaging of the heavy-metal-stained MDA-MB-231 cells where the presence of the cell membrane and the nucleus was observed, as well as the internalized 69-L2@P and 69-L2@F nanoparticles.Taken together, these results suggest excellent biocompatibility and successful internalization of 69-l_2@P and 69-L2@F required for PDT.

[0186] Next, the PDT efficacy of 69-L2@F under both normoxia and hypoxia conditions in vitro was evaluated, using 69-L2@P as a control. Figure 31 b shows that, upon light irradiation, MDA-MB-231 cells incubated with 69-L2@P and 69-L2@F exhibit more than 40% reduction in viability at MOF concentrations as low as 10 pg / mL under normoxic conditions. When increasing the concentration to 25-100 pg / mL, 69-L2@F shows a significant reduction in cell viability compared to 69-L2@P, suggesting its superior in vitro PDT efficacy. The difference in cell viability could be attributed to the O2enrichment of fluorous tags around 69-L2, which would attract the O2within the media, thus improving the ROS generation and PDT effect. Unlike in normoxia, 69-L2@P and 69-L2@F show a similar trend in viability but to a lesser extent at low concentrations under hypoxic conditions - with 69-L2@F having a consistently higher efficacy than 69-L2@P. Cell viabilities under hypoxic conditions are slightly higher than the same concentrations under normoxia (Figure 31c). This finding is attributed to the insufficient O2supply in hypoxia for ROS generation. Notably, at concentrations over 25 pg / mL, 69-L2@F shows higher toxicity against MDA-MB-231 cells in hypoxia than those treated with 69-L2@P. Again, the excellent oxygen-carrying capability provided by perfluorooctyl- containing 69-L2@F could lead to higher concentrations of oxygen and hence higher PDT efficacy against MDA-MB-231 cells in vitro when irradiated by LED light, favouring PDT treatment with deep-seated tumours.

[0187] To assess the intracellular ROS generation capability of 69-L2@P and 69-L2@F, 2', 7’- dichlorodihydrofluorescein diacetate (DCF-DA) was selected as a probe to detect intracellular ROS levels. Briefly, MDA-MB-231 cells were incubated with 25 and 100 pg / mL of either 69- L2@P or 69-L2@F for 24 h before being irradiated with LED light for 10 min. Figure 34 shows how all the MDA-MB-231 cells treated with 69-L2, 69-L2@P, or 69-L2@F at 25 and 100 pg / mL concentrations exhibit dim-green fluorescence from DCF before light irradiation. After 10 minutes of LED light treatment, the intracellular fluorescence becomes bright-green, demonstrating successful generation of ROS. Figure 35a shows the intracellular ROS level when treated with 69-L2@P and 69-L2@F, quantified by the fluorescence intensity of DCF; ROS levels are 3.5- and 4-fold higher than the control group in normoxia. This further suggests that the photocytotoxicity observed in normoxia was due to the significant increase in intracellular ROS generated by the BODYIPY-core (Figure 35b), leading to enhanced oxidative toxicity.

[0188] Figure 35a shows the normalized DCF fluorescent intensity of approximately 175 and 225 for 69-l_2@P and 69-L2@F in the case of hypoxic cells. A ca. 1 .8- and 2.3-fold increase for 69-L2@P and 69-L2@F compared to the control was observed, but to a lesser extent when compared to normoxia. Again, it is noted that 69-L2@F generated more intracellular ROS than 69-L2@P under both normoxia and hypoxia conditions (Figures 35a, 35b, and 36). Indeed, the difference in ROS generation between 69-L2@F and 69-L2@P under hypoxia is approximately 12% higher than normoxia, possibly due to a slight increase in O2concentration caused by the oxygen-carrying 69-L2@F at the cellular level. Figure 35c shows the DCF intensity as a function of BODIPY-MOFs intensity quantified by flow cytometry; 69-L2@P and 69-L2@F had similar cellular uptakes under both normoxia and hypoxia compared to the related controls. In addition, IncuCyte was used to perform real-time monitoring of the live MDA-MB-231 cells, which were treated with 69-L2, 69-L2@P or 69-L2@F (see Supporting Information for full details). As shown in Figures 37 and 38, the untreated cells proliferated throughout the observation period, regardless of light irradiation. Similar trends were also found in the treated cells without light irradiation (Figures 37 and 38). In contrast, MDA-MB-231 cells exhibited significant changes in morphology and movement after light treatment (Figure 38). All these solidly showcase the promising potential of 69-L2@F for PDT against hypoxic tumours in real setups.

[0189] Every document cited herein, including any cross-referenced or related patent or application, is hereby incorporated by reference in its entirety unless expressly excluded or otherwise limited.

[0190] It will be appreciated that various modifications may be made to the embodiments shown without departing from the spirit and scope of the invention as defined by the accompanying claims.

[0191] The project leading to this application has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 726380).The invention is further described with reference to the following numbered embodiments:1 . A metal-organic framework (MOF) nanoparticle or nanoparticles wherein the or each nanoparticle comprises a MOF comprising a plurality of metal ions and a plurality of organic ligands wherein the or each MOF nanoparticle comprises a photosensitiser and one or more perfluorocarbon moieties.2. The or each MOF nanoparticle according to embodiment 1 , wherein the or each MOF nanoparticle has an enhanced oxygen carrying capacity of greater than about 5 mg / mL measured according to the Oxygen Carrying Capacity Test Method defined herein.3. A metal-organic framework (MOF) nanoparticle or nanoparticles wherein the or each nanoparticle comprises a MOF comprising a plurality of metal ions and a plurality of organic ligands; wherein the or each MOF nanoparticle comprises photosensitiser; wherein the or each MOF nanoparticle has an enhanced oxygen carrying capacity of greater than about 5 mg / mL measured according to the Oxygen Carrying Capacity Test Method defined herein.4. The or each MOF nanoparticle according to embodiment 3 wherein the or each MOF nanoparticle comprises one or more perfluorocarbon moieties.5. The or each MOF nanoparticle according to any one of embodiments 1 to 4, wherein the or each MOF nanoparticle comprises one or more hydrophilic polymers, preferably wherein the hydrophilic polymer is selected from the group consisting of: polyethylene glycol (PEG) or a derivative thereof, polyvinyl alcohol (PVA) or a derivative thereof, poly (lactic-co-glycolic acid) (PLGA) or a derivative thereof, Heparin or a derivative thereof, Chitosan or a derivative thereof, pluronic F-127, and phospholipids, dioleoylphosphatidylcholine (DOPC) or a derivative thereof, and 1 ,2-Dioleoyl-3- trimethylammonium propane (DOTAP) or a derivative thereof, more preferably wherein the hydrophilic polymer is linear methoxy polyethylene glycol (mPEG).6. The or each MOF nanoparticle according to any one of embodiments 1 , 2, 4 or 5, wherein a. at least one of the plurality of organic ligands comprises at least one of the one or more perfluorocarbon moieties; or b. each of the plurality of organic ligands comprises the one or more perfluorocarbon moieties; orc. the one or more perfluorocarbon moieties are non-covalently attached to the or each MOF nanoparticle; or d. the perfluorocarbon moieties are attached to the one or more hydrophilic polymers to form one or more polymers. The or each MOF nanoparticle according to embodiment 6, wherein each of the one or more polymers are attached to one or more metal ions of each nanoparticle, preferably wherein the one or more polymers comprises a phosphate group and wherein the one or more polymers are attached to one or more metal ions of each nanoparticle by phosphate-metal coordination, more preferably wherein the polymer is a phosphate-terminated mPEG according to Structure AStructure A wherein n is from about 40 to about 250. The or each MOF nanoparticle according to any one of embodiments 1 to 7, wherein a. at least one of the plurality of organic ligands comprises photosensitiser, or b. each of the plurality of organic ligands comprises photosensitiser, or c. the photosensitiser is non-covalently attached to the or each MOF nanoparticle; The or each MOF nanoparticle according to any one of embodiments 1 to 8, wherein the photosensitiser is selected from the group consisting of: chlorin-based ligands, BODIPY-based ligands of Formula I, Aza-BODIPY-based ligands of Formula II, porphyrin-based ligands of Formula III, bacteriochlorin-based ligands of Formula IV, phthalocyanine-based ligands of Formula V, M(bpy)3ligands of Formula VI, and combinations thereofFormula IFormula VI preferably wherein the photosensitiser is a BODIPY-based ligand, more preferably wherein the photosensitiser is selected from the group consisting of: L2 and L3The or each MOF nanoparticle according to any one or embodiments 1 to 9, wherein the plurality of metal ions are metal ions having an atomic weight of greater than 40, preferably wherein the plurality of metal ions consist essentially of a metal ion selected from the group consisting of: zirconium, iron, thorium, hafnium, ruthenium, gadolinium, neodymium, ytterbium, and erbium. A composition comprising a metal-organic framework (MOF) nanoparticle or nanoparticles as defined in any one of embodiments 1 to 10, preferably wherein the composition comprises between about 0.001 wt% and about 0.1 wt% of the composition MOF nanoparticle by weight. The MOF nanoparticle or nanoparticles as defined in embodiments 1 to 10 or the composition as defined in embodiment 11 for use as a medicament. The MOF nanoparticle or nanoparticles as defined in embodiments 1 to 10 or the composition as defined in embodiment 11 for use in the treatment of cancer by photodynamic therapy, preferably wherein cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, brain tumours (including glioblastoma), bladder cancer, cervical cancer, head and neck cancers, Hodgkin's lymphoma, NonHodgkin's Lymphoma, melanoma, pancreatic cancer, rectal cancer, skin cancer (including Basal Cell Carcinoma and Squamous Cell Carcinoma) esophageal cancer, thyroid cancer, testicular cancer, mesothelioma, ovarian cancer, kidney cancer, livercancer, gastric (stomach) cancer, bone cancer (including osteosarcoma and Ewing sarcoma), soft tissue sarcomas, endometrial (uterine) cancer, spinal tumour, nasopharyngeal cancer, salivary gland cancer, childhood cancers (such as leukaemia, neuroblastoma, Wilms tumour), colon cancer. A method of preparing one or more MOF nanoparticles as defined in any one of embodiments 1 to 10, the method comprising the steps of: a. mixing a plurality of metal ions, a plurality of organic ligands, photosensitiser and one or more perfluorocarbon moieties in a solvent to form a suspension of one or more MOF nanoparticles, b. optionally additionally mixing one or more hydrophilic polymers in step a., c. optionally drying the one or more MOF nanoparticles by lyophilisation. A method of preparing one or more MOF nanoparticles as defined in any one of embodiments 1 to 10, the method comprising the steps of: a. mixing a plurality of metal ions, a plurality of organic ligands and one or more perfluorocarbon moieties in a solvent to form a suspension of one or more initial MOF nanoparticles, b. mixing the suspension of one or more initial MOF nanoparticles with photosensitiser to replace one or more of the plurality of organic ligands with photosensitiser by post-synthetic ligand exchange to form the one or more MOF nanoparticles, c. optionally additionally mixing one or more hydrophilic polymers in step a., d. optionally drying the one or more MOF nanoparticles by lyophilisation.

Claims

Claims1. A metal-organic framework (MOF) nanoparticle wherein the nanoparticle comprises a MOF comprising a plurality of metal ions and a plurality of organic ligands, and wherein the MOF nanoparticle comprises a photosensitiser and one or more moieties capable of associating to oxygen.

2. The metal-organic framework (MOF) nanoparticle according to claim 1, wherein the one or more moieties capable of associating to oxygen are one or more perfluorocarbon moieties.

3. The MOF nanoparticle according to claim 2, wherein the one or more perfluorocarbon moieties have a carbon backbone chain of about 6 to about 16 carbon atoms.

4. The MOF nanoparticle according to claim 3, wherein the perfluorocarbon moiety is a perfluorooctyl group.

5. The MOF nanoparticle according to claim 1, wherein the one or more moieties capable of associating to oxygen is a 1,3-diene.

6. The MOF nanoparticle according to claim 5, wherein the one or more moieties capable of associating to oxygen are one or more aromatic moieties selected from the group consisting of anthracene or a derivative thereof, naphthalene or a derivative thereof, and 2-pyridone or a derivative thereof.

7. The MOF nanoparticle according to claim 6, wherein the one or more moieties capable of associating to oxygen are selected from anthracene, naphthalene and 2-pyridone.

8. The MOF nanoparticle according to claim 7, wherein the one or more moieties capable of associating to oxygen are anthracene or a derivative thereof.

9. The MOF nanoparticle according to claim 7 or 8, wherein each of the one or more moieties capable of associating to oxygen are anthracene.

10. The MOF nanoparticle according to any one of claims 1-9, wherein the MOF nanoparticle has an enhanced oxygen carrying capacity of greater than about 5 mg / mL measured according to the Oxygen Carrying Capacity Test Method defined herein.

11. The MOF nanoparticle according to any one of claims 1-10, wherein a. at least one of the plurality of organic ligands comprises at least one of the one or more moieties capable of associating to oxygen; or b. each of the plurality of organic ligands comprises the one or more moieties capable of associating to oxygen; or c. the one or more moieties capable of associating to oxygen are non-covalently attached to the MOF nanoparticle.

12. The MOF nanoparticle according to any one of claims 1 to 11, wherein the MOF nanoparticle comprises one or more hydrophilic polymers.

13. The MOF nanoparticle according to claim 12, wherein the hydrophilic polymer is selected from the group consisting of: polyethylene glycol (PEG) or a derivative thereof, polyvinyl alcohol (PVA) or a derivative thereof, poly (lactic-co-glycolic acid) (PLGA) or a derivative thereof, Heparin or a derivative thereof, Chitosan or a derivative thereof, pluronic F-127, and phospholipids, dioleoylphosphatidylcholine (DOPC) or a derivative thereof, and 1,2-Dioleoyl- 3-trimethylammonium propane (DOTAP) or a derivative thereof.

14. The MOF nanoparticle according to claim 13, wherein the hydrophilic polymer is linear methoxy polyethylene glycol (mPEG).

15. The MOF nanoparticle according to anyone of claims 12-14, wherein the one or more moieties capable of associating to oxygen are attached to the one or more hydrophilic polymers to form one or more polymers.

16. The MOF nanoparticle according to claim 15, wherein each of the one or more polymers are attached to one or more metal ions of the nanoparticle.

17. The MOF nanoparticle according to claim 16, wherein the one or more polymers comprises a phosphate group and wherein the one or more polymers are attached to one or more metal ions of the nanoparticle by phosphate-metal coordination.

18. The MOF nanoparticle according to claim 17, wherein the polymer is a phosphate-terminated mPEG according to Structure AStructure A wherein n is from about 40 to about 250.

19. The MOF nanoparticle according to any one of claims 12-18, wherein the MOF nanoparticle is coated with a polymer coating comprising the hydrophilic polymer and a moiety capable of associating to oxygen; and wherein the polymer coating is attached to one or more metal ions of the MOF nanoparticle.

20. The MOF nanoparticle according to claim 19, wherein the polymer coating comprises the hydrophilic polymer and a perfluorocarbon moiety.

21. The MOF nanoparticle according to any one of claims 1 to 20, wherein the photosensitiser is selected from the group consisting of porphyrins, chlorins, bacteriochlorins, phthalocyanines, boron-dipyrromethene (BODIPY) derivatives, disalycilidene-l,2-cyclohexylidenediamine derivatives, gemcitabine, and combinations thereof.

22. The MOF nanoparticle according to any one of claims 1 to 21, wherein a. at least one of the plurality of organic ligands comprises photosensitiser, or b. each of the plurality of organic ligands comprises photosensitiser, or c. the photosensitiser is non-covalently attached to the or each MOF nanoparticle.

23. The MOF nanoparticle according to any one of claims 1 to 22, wherein the photosensitiser is selected from the group consisting of: chlorin-based ligands, BODIPY-based ligands of Formula I, Aza-BODIPY-based ligands of Formula II, porphyrin-based ligands of Formula III, bacteriochlorin-based ligands of Formula IV, phthalocyanine-based ligands of Formula V, M(bpy)3ligands of Formula VI, and combinations thereofFormula IFormula VI24. The MOF nanoparticle according to claim 23, wherein the photosensitiser is a BODIPY-based ligand.

25. The MOF nanoparticle according to claim 24, wherein the photosensitiser is selected from the group consisting of: L2and L326. The MOF nanoparticle according to any one of claims 23-25, wherein when the photosensitiser is of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VI, each of the plurality of organic ligands is photosensitiser.

27. The MOF nanoparticle according to any one of claims 1-26, wherein the plurality of organic ligands are selected from 2',3"-dimethyl-[l,l':4',l":4",l"'-quaterphenyl]-4,4"'-dicarboxylic acid (Li), tetrakis (4-carboxyphenyl)porphyrin (TCPP), 1,4-benzenedicarboxylic acid (BDC),1,3,5-benzenetricarboxylic acid (H3BTC), 1,3, 5, 8- (p-benzoate)pyrene linkers (H4TBAPy), 4',4"',4""',4"""'-(ethene-l,l,2,2- tetrayl)tetrakis(( [l,l’-biphenyl]-3-ca rboxylic acid)) (H4ETTC), a ligand of Formula I, a ligand of Formula II, a ligand of Formula III, a ligand of Formula IV, a ligand of Formula V, a ligand of Formula VI, and chlorin-based ligands.

28. The MOF nanoparticle according to any one or claims 1 to 27, wherein the plurality of metal ions are metal ions having an atomic weight of greater than 40, preferably wherein the plurality of metal ions consist essentially of a metal ion selected from the group consisting of: zirconium, iron, thorium, hafnium, ruthenium, gadolinium, neodymium, ytterbium, and erbium.

29. The MOF nanoparticle according to claim 27, wherein the plurality of metal ions consists essentially of zirconium; and the organic ligand is the photosensitiser L2 or the photosensitiser L3.

30. The MOF nanoparticle according to claim 2, wherein the organic ligand is the photosensitiser L2.

31. The MOF nanoparticle according to claim 29, further comprising a phosphate-terminated mPEG according to Structure AStructure A wherein n is from about 40 to about 25032. A composition comprising a metal-organic framework (MOF) nanoparticle as defined in any one of claims 1 to 31, preferably wherein the composition comprises between about 0.001 wt% and about 0.1 wt% of the composition MOF nanoparticle by weight.

33. The MOF nanoparticle as defined in claims 1 to 31 or the composition as defined in claim 32 for use as a medicament.

34. The MOF nanoparticle as defined in claims 1 to 31 or the composition as defined in claim 32 for use in the treatment of cancer by photodynamic therapy.

35. The MOF nanoparticle or composition for use according to claim 34, wherein the cancer is selected from the group consisting of: breast cancer, prostate cancer, lung cancer, brain tumours (including glioblastoma), bladder cancer, cervical cancer, head and neck cancers, Hodgkin's lymphoma, Non-Hodgkin's Lymphoma, melanoma, pancreatic cancer, rectal cancer, skin cancer (including Basal Cell Carcinoma and Squamous Cell Carcinoma) esophageal cancer, thyroid cancer, testicular cancer, mesothelioma, ovarian cancer, kidney cancer, liver cancer, gastric (stomach) cancer, bone cancer (including osteosarcoma and Ewing sarcoma), soft tissue sarcomas, endometrial (uterine) cancer, spinal tumour, nasopharyngeal cancer, salivary gland cancer, childhood cancers (such as leukaemia, neuroblastoma, Wilms tumour), and colon cancer.

36. A method of preparing one or more MOF nanoparticles as defined in any one of claims 2 to 31, the method comprising the steps of: a. mixing a plurality of metal ions, a plurality of organic ligands, photosensitiser and one or more moieties capable of associating to oxygen in a solvent to form a suspension of one or more MOF nanoparticles, b. optionally additionally mixing one or more hydrophilic polymers in step a., c. optionally drying the one or more MOF nanoparticles by lyophilisation.

37. The method of claim 36, wherein the one or more moieties capable of associating to oxygen are one or more perfluorocarbon moieties.

38. The method of claim 36 or 37, wherein the plurality of organic ligands is the photosensitiser, and wherein the photosensitiser is of Formula I, Formula II, Formula III, Formula IV, Formula V or Formula VIFormula IFormula VI39. A method of preparing one or more MOF nanoparticles as defined in any one of claims 2 to 31, the method comprising the steps of: a. mixing a plurality of metal ions, a plurality of organic ligands and one or more moieties capable of associating to oxygen in a solvent to form a suspension of one or more initial MOF nanoparticles, b. mixing the suspension of one or more initial MOF nanoparticles with photosensitiser to replace one or more of the plurality of organic ligands with photosensitiser by post-synthetic ligand exchange to form the one or more MOF nanoparticles, c. optionally additionally mixing one or more hydrophilic polymers in step a., d. optionally drying the one or more MOF nanoparticles by lyophilisation.

40. The method of claim 39, wherein the one or more moieties capable of associating to oxygen are one or more perfluorocarbon moieties.

41. The method of claim 39 or 40, wherein in step b. the organic ligand 2',3"-dimethyl- [l,l':4',l":4",l"'-quaterphenyl]-4,4"'-dicarboxylic acid (Li) is replaced with photosensitiser L2or L3:

2. A method of preparing one or more MOF nanoparticles as defined in any one of claims 19-31, the method comprising the steps of: a. mixing a plurality of metal ions and a plurality of organic ligands in a solvent to form a suspension of one or more initial MOF nanoparticles, b. encapsulating photosensitiser within and / or locating photosensitiser on the one or more initial MOF nanoparticles to provide a suspension of one or more photosensitiser-containing MOF nanoparticles, c. subsequently mixing the suspension of one or more photosensitisercontaining MOF nanoparticles with the polymer coating and allowing the polymer coating to attach to one or more metal ions of the one or more photosensitisercontaining MOF nanoparticles to provide a suspension of one or more polymer-coated MOF nanoparticles, and d. optionally drying the one or more polymer-coated MOF nanoparticles by lyophilisation.

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