WO2023160700A1

WO2023160700A1 - Colloidal mof for arteriosclerosis treatment

Info

Publication number: WO2023160700A1
Application number: PCT/CN2023/078423
Authority: WO
Inventors: Sebastian Beyer OLDENBURG; Chung Yin TSANG; Chee Man CHU; Chung Yin CHEUNG
Original assignee: The Chinese University Of Hong Kong
Priority date: 2022-02-28
Filing date: 2023-02-27
Publication date: 2023-08-31

Abstract

Provided herein are compositions and methods for treating cardiovasculardisease, particularly those known to be caused by endothelial dysfunctions due to nitricoxide (NO) deficiency in patients.The colloidal coordination compounds, including, for example,copper doped Zeolitic Imidazolate Framework 8(ZIF-8), can convert blood borne s-nitrosothiols into nitric oxide.The disintegration of the colloidal coordination compounds, including copper doped ZIF-8, can occur slowly into blood plasma, which causes a sustained and controlled conversion of s-nitrosothiols into nitric oxide. Since the Zeolitic Imidazolate Frameworks (ZIFs) disintegrates under acidic pH, the slowly-degrading copper-doped ZIF-8 can also be used as a targeted and sustained colloidal drug carrier for acidic atherosclerotic plaques.The colloidal coordination compounds can be used for targeted delivery of metal ions,organic molecules, or a pay Load, including drugs or formulations with intrinsic bioactivity resulting from structural features.

Description

COLLOIDAL MOF FOR ARTERIOSCLEROSIS TREATMENT

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the benefit of U.S. Provisional Application Serial No. 63/268,681, filed February 28, 2022, which is hereby incorporated by reference herein in its entirety, including any figures, tables, nucleic acid sequences, amino acid sequences, or drawings.

BACKGROUND OF THE INVENTION

Arteriosclerosis is a condition that occurs when arteries narrow and become stiff, which can sometimes restrict blood flow. Atherosclerosis is a type of arteriosclerosis that is a cardiovascular disease marked by a build-up of atherosclerotic plaque comprising lipids, followed by inflammatory infiltration of cells and even calcification in some cases. These atherosclerotic plaques affect the blood flow, which may include blockage in severe cases. Subsequently, this leads to ischemic conditions, such as cardiac infarction. Current treatment options focus on prevention of atherosclerotic build-up using cholesterol lowering drugs, such as statins and similar pharmaceutical strategies, or the implantation of cardiac stents to expand vessels and enable blood flow for prolonged periods of time. A current bottleneck in atherosclerosis treatment is to target reversal of atherosclerotic plaque build-up during early or advanced stages. Despite the knowledge that certain metal ions such as zinc, copper, and cobalt have the potential to reduce atherosclerotic plaques, few suitable formulations exist for targeting atherosclerotic plaques. Another aspect is the role of nitric oxide that is known to stabilize inflamed endothelial lining of blood vessels under certain conditions and therefore have a potentially beneficial effect on relieving symptoms of atherosclerosis.

Zeolitic Imidazolate Framework 8 (ZIF-8) is one polymorph of zinc (II) 2-methylimidazolate and one of the most prominent members of the ZIF subclass of Metal-organic Frameworks (MOFs) . MOFs are highly crystalline and porous materials that comprise of metal ions and organic ligands¹, which have been evaluated as enabling materials in gas storage and separation^2, 3, catalyst research⁴, electronic materials, and for biomedical applications^5-7. The latter can be briefly grouped into theragnostic applications⁸, biomaterials⁹ and MOF-based drug delivery¹⁰. In particular, ZIF-8 has received much attention for intrinsic bone growth¹¹, antibacterial properties¹² and its ability to encapsulate differently sized and charged substances, including MRI contrast agents, drugs with low molecular weights and biomacromolecules^7, 10, 13. In addition, colloidal carrier with a particle size of 10-1000 nm can be synthesized tailored to specific purposes¹⁴. In biocompatibility evaluations, ZIF-8 was shown to have minimal cytotoxicity. This assessment is based on the observation that only ZIF-8 concentrations above 30 μg/mL or Zn²⁺ concentrations above 4 μg/mL induce a significant reduction in cell viability attributed to Zn²⁺ mediated ROS generation, while lower concentrations did not exceed homeostatic conditions¹⁵. This makes biomedical application of ZIF-8 possible. One specific biomedical application of ZIF-8 that has received comparably little attention is the treatment of atherosclerosis, a condition where lipid rich inflammatory plaques occlude blood vessels, often leading to cardiovascular events such as infarction¹⁶. Colloidal ZIF-8 and in particular copper-doped ZIF-8 presents itself as an exceptionally promising material for this purpose for several reasons. Firstly, the size distribution of colloidal ZIF-8 can be accurately controlled, and colloidal particles are known to accumulate in atherosclerotic plagues due to the destruction of endothelial barrier¹⁷. Secondly, ZIF-8 is an ideal drug carrier, with a pore size ofand small apertures ofdiameter between the cages, which allows it to capture small molecules into the pores¹⁸. In addition, it also allows encapsulation of non-steroidal¹⁹ as well as steroidal²⁰ anti-inflammatory drugs with potential release in atherosclerotic plaques. Thirdly, zinc ions and copper ions, which make up a large fraction of copper doped ZIF-8 material, are known to alleviate and slow down the progression of atherosclerosis²¹ _, ²². In addition, ZIF-8 based materials are known to have a pH-based disintegration switch at pH 7.2²³. The disintegration trigger is thus conveniently positioned between that of physiological blood (pH 7.35) values and that of acidified atherosclerotic plagues that reach to pH 5.5²⁴. Additionally, endogenous production of nitric oxide can alleviate atherosclerotic plaques by providing additional NO²⁵ and promoting vasodilation²⁶. The endogenous generation of NO is brought about by the conversion of blood-borne s-nitrosothiols into NO and their corresponding thiols²⁷. This is remarkable because targeted delivery of NO is exceptionally challenging due to its very small size, and short half-life of just several minutes in biological environments²⁸.

Therefore, compositions that treat arteriosclerosis and/or atherosclerosis are urgently needed.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a method and manufacturing strategies for colloidal formulations to target delivery of metal ions, drugs and other biologically active agents to atherosclerotic plaques. Another embodiment is that these formulations generate increased nitric oxide levels at their targeted side of action. The present innovation offers treatment to affect reversal of atherosclerotic plaque formation.

Provided are compositions and methods using colloidal coordination compounds for treating of arteriosclerosis and/or atherosclerosis. The colloidal coordination compounds of the invention comprise, for example, copper minerals, coordination compounds and/or salts of pharmaceutical drugs, or metal organic frameworks (MOFs) . In certain embodiments, the MOFs can be copper-doped Zeolitic Imidazolate Framework 8 (ZIF-8) , which can be described as sodalite zeolitic crystal topology where metal atoms are primarily zinc and occasionally replaced by copper, or copper benzene-1, 3, 5-tricarboxylate (Cu-BTC) . In certain embodiments, zinc can be preferentially incorporated over copper within the ZIF-8 framework. Copper-doped ZIF-8 can offer a more sustained conversion of s-nitrosothiols into free nitric oxide, and copper doped ZIF-8 can exhibit sufficient stability in blood plasma. In certain embodiments, the ZIF can comprise a vitamin B12 co-factor and zinc and/or copper.

Further provided are methods of treating arteriosclerosis and/or atherosclerosis in subjects, which methods comprise administering at least one therapeutically effective amount of at least one colloidal coordination compound to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing (s) will be provided by the Office upon request and payment of the necessary fee.

FIGs. 1A-1I Copper-doped ZIF-8 (FIG. 1A) exhibits sodalite crystal topology at various targeted copper percentages as shown with PXRD, which is identical to that of ZIF-8. SEM images of (FIG. 1B) 1%copper-doped ZIF-8, (FIG. 1C) 5%copper-doped ZIF-8, (FIG. 1D) 10%copper-doped ZIF-8 and (FIG. 1E) 20%copper-doped ZIF-8 indicate that copper-doped ZIF-8 retains a rhombic dodecahedron crystal shape. Size distributions of (FIG. 1F) 1%copper-doped ZIF-8, (FIG. 1G) 5%copper-doped ZIF-8, (FIG. 1H) 10%copper-doped ZIF-8 and (FIG. 1I) 20%copper-doped ZIF-8 confirm the uniform size distribution of crystal sizes, with the peak size of around 70 nm. The curve generated is fit into a normal distribution.

FIG. 2 provides a calibration graph showing the relationship between light absorption of solutions containing different concentrations of copper (II) ions (0.10%, 0.50%, 1%, 2.50%, 5%, 7.50%Cu: Zn mole ratio) . The light absorption is measured at 642 nm. Based on the calibration graph, the actual copper percentages and incorporation efficiencies for 1%, 5%, 10%and 20%copper-doped ZIF-8 are calculated. With higher doping ratio, the incorporation efficiency increases and levels off at around 12%.

FIG. 3 shows the conversion rate of s-nitrosoglutathione to nitric oxide by 20%copper-doped ZIF-8, copper (II) sulfate and without any catalysts. The conversion rate is calculated by tracking the decrease in light absorption of the reaction mixture at 334 nm.

FIGs. 4A-4D Assessing the stability of ZIF-8 and copper-doped ZIF-8 in water for a potentially therapeutically relevant period up to 5 days. Stability of colloidal (FIG. 4A) copper-doped ZIF-8 with targeted doping percentage of 20%and (FIG. 4B) ZIF-8 in water over 5 days, and the stability of (FIG. 4C) colloidal copper-doped ZIF-8 with targeted doping percentage of 20%and (FIG. 4D) ZIF-8 in FBS over 5 days as measured by PXRD and SEM. In water, ZIF-8 appeared to disintegrate slightly faster over the period of 5 days as indicated by PXRD, and SEM images indicate a slight degradation of crystal surface. In FBS, both ZIF-8 and copper-doped ZIF-8 retained crystalline peaks in PXRD over the period of 5 days as indicated by PXRD, and SEM images indicate a slight degradation of crystal shape and surface.

FIG. 5 Comparing crystallinities of ZIF-8 and copper-doped ZIF-8 when immersed in water and Fetal Bovine Serum (FBS) . ZIF-8 and copper-doped Zif-8 showed great chemical stability in FBS, but decreasing crystallinity in water with increasing contact time. Chemical stability of copper-doped ZIF-8 in water is greater than that of ZIF-8.

FIG. 6 shows a schematic representation of the envisioned application of colloidal copper-doped ZIF-8 for atherosclerosis treatment. Colloidal copper-doped ZIF-8 particles are injected into the blood stream where the particles accumulate in atherosclerotic plaques and constantly release copper and zinc ions. Copper in solution as well as within the ZIF framework liberates nitric oxide (NO) from blood borne s-nitrosothiols.

DETAILED DISCLOSURE OF THE INVENTION

Selected Definitions

As used herein, the singular forms “a” , “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms “including” , “includes” , “having” , “has” , “with” , or variants thereof are used in either the detailed description and/or the claims, such terms are intended to be inclusive in a manner similar to the term “comprising” . The transitional terms/phrases (and any grammatical variations thereof) “comprising” , “comprises” , “comprise” , “consisting essentially of” , “consists essentially of” , “consisting” and “consists” can be used interchangeably.

The phrases “consisting essentially of” or “consists essentially of” indicate that the claim encompasses embodiments containing the specified materials or steps and those that do not materially affect the basic and novel characteristic (s) of the claim.

The term “about” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured, i.e., the limitations of the measurement system. In the context of compositions containing amounts of ingredients where the terms “about” is used, these compositions contain the stated amount of the ingredient with a variation (error range) of 0-10%around the value (X ± 10%) . In other contexts the term “about” is provides a variation (error range) of 0-10%around a given value (X ± 10%) . As is apparent, this variation represents a range that is up to 10%above or below a given value, for example, X ± 1%, X ± 2%, X ± 3%, X ± 4%, X ± 5%, X ± 6%, X ± 7%, X ± 8%, X ± 9%, or X ± 10%.

In the present disclosure, ranges are stated in shorthand to avoid having to set out at length and describe each and every value within the range. Any appropriate value within the range can be selected, where appropriate, as the upper value, lower value, or the terminus of the range. For example, a range of 0.1-1.0 represents the terminal values of 0.1 and 1.0, as well as the intermediate values of 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges encompassed within 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc. Values having at least two significant digits within a range are envisioned, for example, a range of 5-10 indicates all the values between 5.0 and 10.0 as well as between 5.00 and 10.00 including the terminal values. When ranges are used herein, combinations and subcombinations of ranges (e.g., subranges within the disclosed range) and specific embodiments therein are explicitly included.

As used herein, the terms “therapeutically-effective amount, ” “therapeutically-effective dose, ” “effective amount, ” and “effective dose” are used to refer to an amount or dose of a compound or composition that, when administered to a subject, is capable of treating, preventing, or improving a condition, disease, or disorder in a subject. In other words, when administered to a subject, the amount is “therapeutically effective. ” The actual amount will vary depending on a number of factors including, but not limited to, the particular condition, disease, or disorder being treated, prevented, or improved; the severity of the condition; the weight, height, age, and health of the patient; and the route of administration.

As used herein, the term “treatment” refers to eradicating; reducing; ameliorating; abatement; remission; diminishing of symptoms or delaying the onset of symptoms; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; and/or improving a subject's physical or mental well-being or reversing a sign or symptom of a health condition, disease or disorder to any extent, and includes, but does not require, a complete cure of the condition, disease, or disorder. Treating can be curing, improving, or partially ameliorating a disorder. “Treatment” can also include improving or enhancing a condition or characteristic, for example, bringing the function of a particular system in the body to a heightened state of health or homeostasis.

As used herein, “preventing” a health condition, disease, or disorder refers to avoiding, delaying, forestalling, or minimizing the onset of a particular sign or symptom of the condition, disease, or disorder. Prevention can, but is not required, to be absolute or complete; meaning, the sign or symptom may still develop at a later time. Prevention can include reducing the severity of the onset of such a condition, disease, or disorder, and/or inhibiting the progression of the condition, disease, or disorder to a more severe condition, disease, or disorder.

In some embodiments of the invention, the method comprises administration of multiple doses of the compounds of the subject invention. The method may comprise administration of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or more therapeutically effective doses of a composition comprising the compounds of the subject invention as described herein. In some embodiments, doses are administered over the course of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 30 days, or more than 30 days. The frequency and duration of administration of multiple doses of the compositions is such as prevent or treat a viral infection. Moreover, treatment of a subject with a therapeutically effective amount of the compounds of the invention can include a single treatment or can include a series of treatments. It will also be appreciated that the effective dosage of a compound used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of testing for a virus. In some embodiments of the invention, the method comprises administration of the compounds at several time per day, including but not limiting to 2 times per day, 3 times per day, and 4 times per day.

As used herein, an “isolated” or “purified” compound is substantially free of other compounds. In certain embodiments, purified compounds are at least 60%by weight (dry weight) of the compound of interest. Preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight of the compound of interest. For example, a purified compound is one that is at least 90%, 91%, 92%, 93%, 94%, 95%, 98%, 99%, or 100% (w/w) of the desired compound by weight. Purity is measured by any appropriate standard method, for example, by column chromatography, thin layer chromatography, or high-performance liquid chromatography (HPLC) analysis.

By “reduces” is meant a negative alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.

By “increases” is meant as a positive alteration of at least 1%, 5%, 10%, 25%, 50%, 75%, or 100%.

As used herein, a “pharmaceutical” refers to a compound manufactured for use as a medicinal and/or therapeutic drug.

As used herein, “subject” , “host” or “organism” refers to any member of the phylum Chordata, more preferably any member of the subphylum vertebrata, or most preferably, any member of the class Mammalia, including, without limitation, humans and other primates, including non-human primates such as rhesus macaques, chimpanzees and other monkey and ape species; livestock, such as cattle, sheep, pigs, goats and horses; domestic mammals, such as dogs and cats; laboratory animals, including rabbits, mice, rats and guinea pigs; birds, including domestic, wild, and game birds, such as chickens, turkeys, ducks, and geese. The term does not denote a particular age or gender. Thus, adult, young, and new-born individuals are intended to be covered as well as male and female subjects. In some embodiments, a host cell is derived from a subject (e.g., tissue specific cells, such as hepatocytes) . In some embodiments, the subject is a non-human subject.

Colloidal Coordination Compounds and Methods of Use

Provided are compounds and compositions for treating arteriosclerosis and/or atherosclerosis. Advantageously, the compounds and compositions of the invention comprises administering to a subject an effective amount of at least one colloidal coordination compound or composition thereof. In certain embodiments, the dimensions of the colloidal coordination compound can be less than about 1000 nm, about 750 nm, about 500 nm, about 250 nm, about 100 nm, about 75 nm, about 50 nm, about 25 nm, about 10 nm, or smaller. In certain embodiments, the at least one colloidal coordination compound is selected from copper (II) oxide, copper (I) oxide, copper (II) sulfate, copper gluconate, copper (I) chloride, copper (II) chloride, copper (II) acetate, copper (I) hydroxide, copper (II) hydroxide or other naturally occurring copper minerals; coordination compounds and salts of pharmaceutical drugs, such as, for example, copper (II) aspirinate, copper (II) ibuprofenate, copper salicylate, the copper salt of 8-hydroxyquinoline, zinc pyrithione; metal-organic frameworks (MOFs) comprising any metal or combination of at least two different metals, such as, for example, copper, zinc, or a combination thereof and organic ligands, including but not limited to, for example, terephthalic acid (1, 4-benzenedicarboxylic acid) , trimesic acid (benzene-1, 3, 5-tricarboxylic acid) , 2-methylimidazole, 5, 6-dimethylbenzimidazole or other naturally occurring imidazoles.

In certain embodiments, the MOF can be a zeolitic imidzolate framework (ZIF) , including, for example, ZIF-8. In certain embodiments, the ZIF can be composed of tetrahedrally-coordinated metal ions, including, for example transition metal ions. The transition metal ions can be selected from, for example, transition metals, including, for example, Zn, Cu, Co, and Fe, gadolinium or any combination thereof. In certain embodiments, the MOF can be Cu-BTC (i.e., HKUST-1) . In certain embodiments, ZIF can comprise a vitamin B12 co-factor and zinc and/or copper. In certain embodiments, the composition can have a ratio of zinc to copper of about 1: 10000 to about 10: 1 or about 1: 20.

In certain embodiments, the colloidal coordination compound can be safe to administer to a subject. In certain embodiments, the colloidal coordination compound can Generally Regarded as Safe (GRAS) , according the regulations of the US Food and Drug Administration.

In certain embodiments, the colloidal compound can be formed by doping. In certain embodiments, the doping process can be used to introduce heteroatoms, such as, for example, copper, in a target lattice, such as, for example a ZIF. In certain embodiments, the heteroatoms can be added a percent ratio of about 1%to about 20%.

Copper (II) ions display octahedral coordination geometry in solution²⁹. In certain embodiments, a facile and straightforward photometric method (see experimental section) , which has not been used to characterize copper-doped ZIF-8 composition before, to assess the incorporation of copper (II) ions into ZIF-8. In certain embodiments, a method for characterizing the chemical stability of the colloidal coordinating compound, including copper-doped ZIF-8, in water and Fetal Bovine Serum (surrogate for human blood plasma) , can be used. In certain embodiments, the catalytic ability of the colloidal coordinating compound, including copper-doped ZIF-8, in generating nitric oxide can be validated.

Also provided are methods of using the compounds and compositions of the invention to treat arteriosclerosis including, but not limited to, atherosclerosis by administering at least one colloidal coordination compound or a composition thereof to a subject.

In specific embodiments, several applications of the compositions of the invention are administered at specific time intervals. In preferred embodiments, a first and at least one second dose of the composition of the invention are administered with a time interval of no more than 120 hours between the first and second dose. For example, the time interval between administration of a first and a second dose can be about 0.5 hour to about 120 hours; about 2 hours to about 96 hours; about 2 hours to about 72 hours; about 3 hours to about 48 hours; about 4 hours to about 44 hours; 5 hour to about 42 hours; about 6 hour to about 41 hours; about 7 hours to about 40 hours; about 8 hours to about 39 hours; about 9 hours to about 38 hours; 10 hours to about 37 hours; about 11 hours to about 36 hours; about 12 hours to about 35 hours; about 13 hours to about 34 hours; about 14 hours to about 33 hours; about 15 hours to about 32 hours; about 16 hours to about 31 hours; about 17 hours to about 30 hours; about 18 hours to about 29 hours; about 19 hours to about 28 hours; about 20 hour to about 27 hours; about 21 hour to about 26 hours; about 22 hours to about 25 hours; and about 23 hours to about 24 hours. In certain embodiments, the administration of at least a single dose of the composition of the invention is repeated for a period of at least daily, biweekly, weekly, bimonthly, monthly, yearly or at least every about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks, about 25 weeks, about 26 weeks, or longer.

In some embodiments, after administration of a first dose, at least one further dose is administered once month, once a week, bi-weekly, daily, or two to four times daily. In some embodiments, a first dose is administered at the same concentration as at least one second dose. In some embodiments a first dose is administered at a different concentration from at least one second dose. In preferred embodiments, a first dose is administered at a lower concentration than at least one second dose.

The skilled artisan will understand that the dosage of the compositions of the instant invention varies, depending upon, for example, the route of administration, the particular colloidal coordination compound to be used in the composition, other drugs being administered, and the age, condition, gender and seriousness of the disease in the subject as described above. An effective dose of a colloidal coordination compound or composition thereof of the invention generally ranges between about 1 μg/kg of body weight and 100 mg/kg of body weight. Examples of such dosage ranges include, but are not limited to, about 1.5 μg/kg to about 90 mg/kg; about 2 μg/kg to about 80 mg/kg; about 5 μg/kg to about 70 mg/kg; about 7.5 μg/kg to about 65 mg/kg; about 10 μg/kg to about 60 mg/kg; about 12.5 μg/kg to about 55 mg/kg; about 15 μg/kg to about 50 mg/kg; about 17.5 μg/kg to about 45 mg/kg; about 20 μg/kg to about 40 mg/kg; about 22.5 μg/kg to about 35 mg/kg; about 25 μg/kg to about 30 mg/kg; about 27.5 μg/kg to about 25 mg/kg; about 30 μg/kg to about 20 mg/kg; about 32.5 μg/kg to about 18 mg/kg; about 35 μg/kg to about 17 mg/kg; about 37.5 μg/kg to about 16 mg/kg; about 40 μg/kg to about 15 mg/kg; about 42.5 μg/kg to about 14 mg/kg; about 45 μg/kg to about 13 mg/kg; about 47.5 μg/kg to about 12 mg/kg; about 50 μg/kg to about 11 mg/kg; about 52.5 μg/kg to about 10 mg/kg; about 55 μg/kg to about 9 mg/kg; about 57.5 μg/kg to about 8 mg/kg; about 60 μg/kg to about 7 mg/kg; about 62.5 μg/kg to about 6 mg/kg; about 65 μg/kg to about 5 mg/kg; about 67.5 μg/kg to about 4 mg/kg; about 70 μg/kg to about 3 mg/kg; about 72.5 μg/kg to about 2 mg/kg; about 75 μg/kg to about 1 mg/kg; about 77.5 μg/kg to about 800 μg/kg; about 80 μg/kg to about 700 μg/kg; about 82.5 μg/kg to about 600 μg/kg; about 85 μg/kg to about 500 μg/kg; about 87.5 μg/kg to about 400 μg/kg; about 90 μg/kg to about 300 μg/kg; about 92.5 μg/kg to about 200 μg/kg; about 95 μg/kg to about 100 μg/kg.

In some embodiments, the therapeutically effective amount of a colloidal coordination compound composition of the invention can be administered through intravenous, oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal, intramuscular, intraperitoneal, intra-arterial, intracerebral, intraocular administration or in a form suitable for administration by inhalation or insufflation, including powders and liquid aerosol administration, or by sustained release systems such as semipermeable matrices of solid hydrophobic polymers containing the colloidal coordination compounds of the invention. Administration may be also by way of other carriers or vehicles such as patches, micelles, liposomes, vesicles, implants (e.g. microimplants) , synthetic polymers, microspheres, nanoparticles, and the like. In certain embodiments, the coordination compound compositions may be administered using a nanoparticle to passage the composition through skin for treating peripheral (close to skin) conditions.

In some embodiments, the colloidal coordination compound compositions of the instant invention may be formulated for parenteral administration e.g., by injection, for example, bolus injection, intravenous administration, or continuous infusion. In addition, the colloidal coordination compound compositions may be presented in unit dose form in ampoules, pre-filled syringes, and small volume infusion or in multi-dose containers with or without an added preservative. The colloidal coordination compound compositions may be in forms of suspensions, solutions, or emulsions in oily or aqueous vehicles. The composition may further contain formulation agents such as suspending, stabilizing and/or dispersing agents. In further embodiments, the active ingredients of the compositions according to the instant invention may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

The subject composition can further comprise one or more pharmaceutically acceptable carriers, and/or excipients, and can be formulated into preparations, for example, solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, and aerosols.

The term “pharmaceutically acceptable” as used herein means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient thereof.

Carriers and/or excipients according the subject invention can include any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline, phosphate buffered saline, or optionally Tris-HCl, acetate or phosphate buffers) , oil-in-water or water-in-oil emulsions, aqueous compositions with or without inclusion of organic co-solvents suitable for, e.g., IV use, solubilizers (e.g., Polysorbate 65, Polysorbate 80) , colloids, dispersion media, vehicles, fillers, chelating agents (e.g., EDTA or glutathione) , amino acids (e.g., glycine) , proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavorings, aromatizers, thickeners (e.g. carbomer, gelatin, or sodium alginate) , coatings, preservatives (e.g., Thimerosal, benzyl alcohol, polyquaterium) , antioxidants (e.g., ascorbic acid, sodium metabisulfite) , tonicity controlling agents, absorption delaying agents, adjuvants, bulking agents (e.g., lactose, mannitol) and the like. The use of carriers and/or excipients in the field of drugs and supplements is well known. Except for any conventional media or agent that is incompatible with the target health-promoting substance or with the composition, carrier or excipient use in the subject compositions may be contemplated.

In certain embodiments, after administration to a subject, the disintegration of the colloidal coordination compounds, including copper-doped ZIF-8, can occur slowly into blood plasma, which can cause a sustained and controlled conversion of s-nitrosothiols into nitric oxide. In certain embodiments, disintegration of the colloidal coordination compounds can occur over about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, or longer. In certain embodiments, disintegration of the colloidal coordination compounds can occur over about 1 hour to about 12 days, about 2 hours to about 11 days, about 4 hours to about 10 days, about 6 hours to about 9 days, about 12 hours to about 8 days, about 18 hours to about 7 days, about 1 day to about 6 days, or about 2 days to about 5 days. In certain embodiments, sustained and controlled conversion of s-nitrosothiols into nitric oxide can occur at a rate of about 4 μmol/hr to about 40 μmol/hr, about 8 μmol/hr to about 35 μmol/hr, about 12 μmol/hr to about 30 μmol/hr, about 16 μmol/hr to about 25 μmol/hr, or about 19.2 μmol/hr. In certain embodiments, the colloidal coordination compounds can disintegrate under acidic pH or a pH less than about 7.5, about 7.0, about 6.5, about 6.0, about 5.5, about 5.0, about 4.5, about 4.0, or a lower pH, the colloidal coordination compounds can also be used as a targeted and sustained colloidal drug carrier for acidic atherosclerotic plaques. The colloidal coordination compounds can be used for targeted delivery of metal ions, organic molecules, or a pay load of drugs or other formulations with intrinsic bioactivity resulting from structural features, such as, for example, catalytic s-nitrosothiol degradation.

MATERIALS AND METHODS

Materials

2-methylimidazole (Hmim, 99%) , copper (II) sulphate trihydrate (CuSO₄ ·3H₂O, 99%) , L-glutathione (GSH, 99%) and sodium nitrite (NaNO₂, 99%) were purchased from J&K Scientific (Beijing, China) . Zinc nitrate hexahydrate (Zn (NO₃) ₂ ·6H₂O, 98%) was purchased from Alfa Aesar (Mumbai, India) . Hydrochloric acid (HCl, GR Grade) was purchased from Duksan (Ansan, South Korea) . Sodium hydroxide (NaOH, 99.9%) was purchased from Aladdin (Shanghai, China) . Ammonium nitrate (AR) was purchased from Fisher Scientific (Loughborough, UK) . Methanol (for analysis) was purchased from Supelco (Bellefonte, PA) . Ethanol (absolute, ≥ 99.8%) was purchased from Honeywell (Charlotte, NC) . All reagents were used as received without further purification.

Synthesis of ZIF-8 particles

10 mL of 0.1 M zinc nitrate hexahydrate solution in methanol and 10 mL of 0.8 M 2-methylimidazole in methanol were mixed for 24 hours and kept on a vertical shaker at (250 rpm) . The reaction mixture was centrifuged at 7200 g for 20 minutes, then washed 2 times more with methanol. Finally, the resulting products were dried at normal pressure and at 65 ℃ for 24 hours.

Synthesis of copper-doped ZIF-8 particles

0.1 M zinc nitrate hexahydrate solution and 0.1 M copper nitrate trihydrate were mixed in methanol with different percentage ratios (1%, 5%, 10%, 20%) while the total number of moles was kept at 100 mmol. In addition, 11.3 mL of methanol and 11.3 mL of 0.708 M 2-methylimidazole were added to each mixture and stirred for 24 hours. Lastly, the 4 reaction mixtures were then centrifuged at 1800 g for 15 minutes and washed for 2 more times. Finally, it is dried at 65℃ for 24 hours.

Characterization of copper-doped ZIF-8 particles

Copper-doped ZIF-8 particles are sent PXRD analysis (SmartLab3kW) at 40 kV and 30 mA with a copper X-ray source, as well as SEM analysis (Jeol, JSM-7800F Schottky Field Emission Scanning Electron Microscope, Tokyo, Japan) . To determine the amount of copper that is incorporated during crystallization, a facile photometric method was devised. In brief, 6 set-ups containing a mixture of zinc nitrate hexahydrate (aqueous) , 2-methylimidazole (aqueous) and 6 M ammonium nitrate (aqueous) were prepared to prevent copper-doped ZIF-8 formation. Then, different concentrations of aqueous copper (II) sulfate (0.10%, 0.50%, 1%, 2.50%, 5%, 7.50%Cu: Zn mole ratio) were added to separate set-ups, and the light absorption of the corresponding solution was measured at 642 nm by a UV-Vis Spectrophotometer (Spectramax M3 Microplate, Cuvette Reader, San Jose, CA) . After the retrieval of the synthesized copper-doped ZIF-8, 0.009 g was dissolved in 0.9 mL of 6 M ammonium nitrate. The light absorbance of the resultant solution was measured at 642 nm and compared with the calibration curve. The size distribution of 1%, 5%, 10%, 20%copper-doped ZIF-8 were measured (n=200) .

Synthesis of s-nitrosoglutathione

s-nitrosoglutathione was synthesized from glutathione through acidic nitrosylation. 1 mmol of L-glutathione (reduced) was first dissolved in 1 mL of 1.2 M HCl, then mixed with 2 mL of 0.25 M sodium nitrite solution. Upon mixing, the solution turned from colorless to reddish orange. The mixture was stirred at 250 rpm under an ice bath for 15 minutes. After formation of GSNO, NaOH was added to neutralize the pH to physiological pH (pH = 7.4) to prevent the disintegration of copper-doped ZIF-8 later.

Characterization of NO generation from copper-doped ZIF-8 particles

We can measure the NO generation by measuring the drop in the concentration of s-nitrosoglutathione. A facile photometric method to observe GSNO degradation was used, which is advantageous since the analysis of NO liberation could be conducted with standard laboratory equipment. By UV-Vis Spectrophotometer, the absorption peak of GSNO was found to be 334 nm. Therefore, a drop in light absorption at 334 nm indicates GSNO degradation and NO generation. 3 setups were established using previously synthesized GSNO (0.192 M) , 20%copper-doped ZIF-8 and aqueous CuSO4 (0.0039 M) . The number of moles of Cu²⁺ are kept as 3.93 μmol in setup 2 and 3.200 μL of each setup was injected into 3 separate wells in a 96-well plate and measured change in light absorption for 3 hours at 334 nm.The absorption spectra of L-glutathione (reduced) , HCl, sodium nitrite, NaNO₂, Cu²⁺/ZIF-8 were also measured, to confirm that a change in light absorption at 334 nm is due to the change in concentration of GSNO.

Chemical stability of ZIF-8 and copper-doped ZIF-8 in water

20%copper-doped ZIF-8 and ZIF-8 were mixed with water at 1.7 wt%, under stirring of 250 rpm. At regular time intervals (1 day, 2 days, 3 days, 4 days and 5 days) , 1 mL of the mixture was drawn for further analysis. 0.5 mL ethanol was added to the mixture and the mixture was centrifuged and dried for PXRD and SEM analysis. The crystallinity of the copper-doped ZIF-8 were calculated from the XRD pattern, by dividing the area of crystalline peaks over all peaks in range of 5-15°Θ.

Chemical stability of ZIF-8 and copper-doped ZIF-8 in Fetal Bovine Serum

The chemical stability of copper-doped ZIF-8 and ZIF-8 in Fetal Bovine Serum (FBS) were also examined. The procedures are identical to those used for testing the chemical stability of ZIF-8 and copper-doped ZIF-8 in water, except that the medium is changed to FBS. The crystallinity of the copper-doped ZIF-8 were also calculated from the XRD pattern, by dividing the area of crystalline peaks over all peaks in range of 5-15° Θ.

All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

Following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

EXAMPLE 1-CHARACTERIZATION OF Cu²⁺/ZIF-8

4 copped-doped ZIF-8 were synthesized with different theoretical percentage of copper ions (1%, 5%, 10%, 20%) . As shown in FIGs. 1A-1I and FIG. 2, all 4 copper-doped ZIF-8 exhibited sodalite crystal topology and rhombic dodecahedra crystal shape, which is identical to ZIF-8. Based on the calibration graph ( [Cu²⁺] vs light absorption) set up (FIG. 3) , we calculated the actual doping percentage of Cu²⁺ into the ZIF-8 structure. From FIG. 2, the amount of copper actually incorporated during crystallization mediated solution precipitation is far below the initial ratio of [Cu²⁺] to [Zn²⁺] provided. The incorporation efficiency is just short of 2%for low concentration of [Cu²⁺] provided in solution (1 mole %) and levels off at 12%for higher concentrations provided in solution (5-20 mole %) .

EXAMPLE 2-CHARACTERIZATION OF NO GENERATION FROM Cu²⁺/ZIF-8 PARTICLES

Since no other species overlap with the peak of GSNO spectrum, change in light absorption at 334 nm is attributed to the degradation of GSNO. The catalytic characterization of copper-doped ZIF-8 is also consistent with that of a recent study²⁷, validating the usage of the facile photometric method. From the results, we could clearly see that Cu²⁺ ions from CuSO₄ demonstrated the fastest catalytic ability, which caused a large amount of NO generation in a short period of time. On the other hand, copper-doped ZIF-8 demonstrated slower catalytic activity than free Cu²⁺ ions, but still caused a greater NO release rate than freely-degrading GSNO without any catalysts. Copper-doped ZIF-8 caused a more sustained and moderate NO generation due to the slow release of Cu²⁺ from the structure, which is ideal since both NO and Cu²⁺ exhibit cytotoxicity at high dosages^30, 31.

EXAMPLE 3-CHEMICAL STABILITY OF ZIF-8 AND COPPER-DOPED ZIF-8 IN WATER

Herein, we characterized the chemical stability of copper-doped ZIF-8 in water based on its crystallinity and surface characteristics. The former is obtained by Powder X-ray Diffraction pattern while the latter is seen through Scanning Electron Microscopy, as shown in FIG. 4A. In terms of its crystallinity, copper-doped ZIF-8 retained sodalite crystal topology up to 3 days after immersion in water, but has lost its crystallinity at day 4 immersing in water. As observed by SEM, holes are found on the surface of copper-doped ZIF-8 and ZIF-8 from 1 to 5 days after immersion in water. However, most of the crystals retained a rhombic dodecahedral shape. In FIG. 4B, ZIF-8 also lost crystallinity on day 4 after immersing in water, and the same type of degradation is observed. Therefore, we conclude that the chemical stability of copper-doped ZIF-8 in water is similar to that of ZIF-8. EXAMPLE 4-CHEMICAL STABILITY OF ZIF-8 AND Cu²⁺/ZIF-8 IN FETAL BOVINE SERUM (FBS)

Next, we also characterized the chemical stability of copper-doped ZIF-8 in Fetal Bovine Serum based on its crystallinity and surface characteristics as shown in FIG. 4C. In terms of its crystallinity, copper-doped ZIF-8 retained sodalite crystal topology up to 5 days after immersion in FBS. As observed by SEM, holes are also found on the surface of copper-doped ZIF-8 and ZIF-8 from 1 to 5 days after immersion in water. In addition, more and more crystals showed absence of the rhombic dodecahedral shape as immersion time increases. In FIG. 4D, ZIF-8 also retained crystallinity after immersing in water for 5 days, and the same type of degradation is observed for 1 to 5 days after immersion in FBS. Therefore, we conclude that the chemical stability of copper-doped ZIF-8 in both water and FBS are similar to that of ZIF-8.

EXAMPLE 5-CRYSTALLINITY EVALUATION OF ZIF-8 AND COPPER-DOPED ZIF-8 IN WATER AND FBS

XRD patterns of ZIF-8 and copper-doped ZIF-8 immersed in FBS do not show any amorphous peaks throughout the 5 days, so their crystallinity remain 100%. XRD patterns of ZIF-8 and copper-doped ZIF-8 immersed in ZIF-8 showed increasing intensity of amorphous peaks throughout the 5 days, hence their crystallinity decreases. From FIG. 6, crystallinity of copper-doped ZIF-8 is higher than ZIF-8 when immersed in water, indicating that copper-doped ZIF-8 has greater chemical stability than ZIF-8 in water.

EMBODIMENTS

Embodiment 1. A composition comprising a colloidal coordination compound, wherein the colloidal coordination compound is copper (II) oxide, copper (I) oxide, copper (II) sulfate, copper gluconate, copper (I) chloride, copper (II) chloride, copper (II) acetate, copper (I) hydroxide, copper (II) hydroxide, a coordination compound or salt of a pharmaceutical drug, or a metal-organic framework (MOF) .

Embodiment 2. The composition of embodiment 1, wherein the coordination compound or salt of a pharmaceutical drug is copper (II) aspirinate, copper (II) ibuprofenate, copper salicylate, a copper salt of 8-hydroxyquinoline, or zinc pyrithione.

Embodiment 3. The composition of embodiment 1, wherein the MOF is copper-doped ZIF-8 or Cu-BTC.

Embodiment 4. The composition of embodiment 1, wherein the MOF comprises any single metal or combination of at least two different metals and organic ligands.

Embodiment 5. The composition of embodiment 4, wherein the metal is copper, zinc, or a combination thereof.

Embodiment 6. The composition of embodiment 5, wherein the ratio of zinc to copper is about 1: 10000 to about 10: 1.

Embodiment 7. The composition of embodiment 6, wherein the ratio of zinc to copper is about 1: 20.

Embodiment 8. The composition of embodiment 1, further comprising a pharmaceutically acceptable excipient and/or carrier.

Embodiment 9. A method of treating arteriosclerosis in a subject comprising administering a composition according to embodiment 1.

Embodiment 10. The method according to embodiment 9, wherein the composition is administered by intravenous, oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal, intramuscular, intraperitoneal, intra-arterial, intracerebral, or intraocular administration.

Embodiment 11. The method according to embodiment 10, wherein the composition is administered by intravenous administration.

Embodiment 12. The method of embodiment 9, wherein the arteriosclerosis is atherosclerosis.

Embodiment 13. The method of embodiment 9, wherein the coordination compound or salt of a pharmaceutical drug is copper (II) aspirinate, copper (II) ibuprofenate, copper salicylate, a copper salt of 8-hydroxyquinoline, or zinc pyrithione.

Embodiment 14. The method of embodiment 9, wherein the MOF comprises any single metal or combination of at least two different metals and organic ligands.

Embodiment 15. The method of embodiment 14, wherein the metal is copper, zinc, or a combination thereof.

Embodiment 16. The method of embodiment 15, wherein the ratio of zinc to copper is about 1: 10000 to about 10: 1.

Embodiment 17. The method of embodiment 16, wherein the ratio of zinc to copper is about 1: 20.

Embodiment 18. The method of embodiment 9, wherein the composition further comprises a pharmaceutically acceptable excipient and/or carrier.

Embodiment 19. The method of embodiment 9, wherein the colloidal coordination compound converts s-nitrosothiols in the blood of the subject into nitric oxide.

It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and/or all other elements or limitations (individually or in any combination) or any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated with the scope of the invention without limitation thereto.

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Claims

A composition comprising a colloidal coordination compound, wherein the colloidal coordination compound is copper (II) oxide, copper (I) oxide, copper (II) sulfate, copper gluconate, copper (I) chloride, copper (II) chloride, copper (II) acetate, copper (I) hydroxide, copper (II) hydroxide, a coordination compound or salt of a pharmaceutical drug, or a metal-organic framework (MOF) .
The composition of claim 1, wherein the coordination compound or salt of a pharmaceutical drug is copper (II) aspirinate, copper (II) ibuprofenate, copper salicylate, a copper salt of 8-hydroxyquinoline, or zinc pyrithione.
The composition of claim 1, wherein the MOF is copper-doped ZIF-8 or Cu-BTC.
The composition of claim 1, wherein the MOF comprises any single metal or combination of at least two different metals and organic ligands.
The composition of claim 4, wherein the metal is copper, zinc, or a combination thereof.
The composition of claim 5, wherein the ratio of zinc to copper is about 1: 10000 to about 10: 1.
The composition of claim 6, wherein the ratio of zinc to copper is about 1: 20.
The composition of claim 1, further comprising a pharmaceutically acceptable excipient and/or carrier.
A method of treating arteriosclerosis in a subject comprising administering a composition according to claim 1.
The method according to claim 9, wherein the composition is administered by intravenous, oral, rectal, bronchial, nasal, topical, buccal, sub-lingual, transdermal, vaginal, intramuscular, intraperitoneal, intra-arterial, intracerebral, or intraocular administration.
The method according to claim 10, wherein the composition is administered by intravenous administration.
The method of claim 9, wherein the arteriosclerosis is atherosclerosis.
The method of claim 9, wherein the coordination compound or salt of a pharmaceutical drug is copper (II) aspirinate, copper (II) ibuprofenate, copper salicylate, a copper salt of 8-hydroxyquinoline, or zinc pyrithione.
The method of claim 9, wherein the MOF comprises any single metal or combination of at least two different metals and organic ligands.
The method of claim 14, wherein the metal is copper, zinc, or a combination thereof.
The method of claim 15, wherein the ratio of zinc to copper is about 1: 10000 to about 10: 1.
The method of claim 16, wherein the ratio of zinc to copper is about 1: 20.
The method of claim 9, wherein the composition further comprises a pharmaceutically acceptable excipient and/or carrier.
The method of claim 9, wherein the colloidal coordination compound converts s-nitrosothiols in the blood of the subject into nitric oxide.