Nitric oxide-releasing particles for nitric oxide therapeutics and biomedical applications

Abstract

The presently disclosed subject matter relates to nitric oxide-releasing particles for delivering nitric oxide, and their use in biomedical and pharmaceutical applications.

1 . A nitric oxide-releasing particle, the nitric oxide-releasing particle comprising:
 (a) a nitric oxide donor;   (b) an interior region having a volume, the volume of the interior region being at least partially filled by a core selected from the group consisting of:
 (i) a metallic cluster; 
 (ii) a dendritic network; 
 (iii) a co-condensed silica network; and 
 (iv) a combination thereof; and 
   (c) an exterior region.   
     
     
         2 . The nitric oxide-releasing particle of  claim 1 , wherein the interior region further comprises an organic linker selected from the group consisting of:
 (a) a labile linker responsive to changes in pH;   (b) a labile linker sensitive to electromagnetic radiation;   (c) a labile linker susceptible to degradation by enzymatic action;   (d) a hydrophobic linker;   (e) an amphiphilic linker; and   (f) a combination thereof.   
     
     
         3 . The nitric oxide-releasing nanoparticle of  claim 1 , wherein the nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl nitrosamine, a nitrosothiol, a hydroxylamine, a hydroxyurea, and combinations thereof. 
     
     
         4 . The nitric oxide-releasing particle of  claim 1 , wherein the nitric oxide donor is covalently bound to one of the interior region, the exterior region, the core, and a combination thereof. 
     
     
         5 . The nitric oxide-releasing particle of  claim 1 , wherein the nitric oxide donor is encapsulated in one of the interior region, the exterior region, the core, and a combination thereof. 
     
     
         6 . The nitric oxide-releasing particle of  claim 1 , wherein the nitric oxide donor is associated with one of the interior region, the exterior region, the core, and combinations thereof via non-covalent interactions selected from the group consisting of Van der Waals interactions, electrostatic interactions, hydrogen bonding, and combinations thereof. 
     
     
         7 . The nitric oxide-releasing particle of  claim 1 , wherein the exterior region comprises one or more chemical moieties selected from the group consisting of:
 (a) a moiety that modulates nitric oxide release kinetics;   (b) a moiety that affects biocompatibility of the particle;   (c) a moiety that affects biodistribution of the particle;   (d) a moiety that provides for targeted delivery of the particle;   (e) a moiety that imparts an ability to image or track the particle;   (f) a moiety that affects solubility of the particle,   (g) a therapeutic agent; and   (h) a combination thereof.   
     
     
         8 . The nitric oxide-releasing particle of  claim 1 , wherein the core is a metallic cluster, said metallic cluster further comprising a component selected from gold, platinum, silver, magnetite, a quantum dot, and a combination thereof. 
     
     
         9 . The nitric oxide-releasing particle of  claim 8 , wherein the metallic cluster is a monolayer protected gold cluster. 
     
     
         10 . The nitric oxide-releasing particle of  claim 1 , wherein the core is a dendritic network, further wherein the dendritic network is selected from the group consisting of:
 (a) a polypropylenimine dendrimer;   (b) a polyamidoamine (PAMAM) dendrimer;   (c) a polyaryl ether dendrimer;   (d) a polypeptide dendrimer;   (e) a polyester dendrimer;   (f) a polyamide dendrimer;   (g) a dendritic polyglycerol; and   (h) a triazine dendrimer.   
     
     
         11 . The nitric oxide-releasing particle of  claim 10 , wherein the dendritic network is hyperbranched. 
     
     
         12 . The nitric oxide-releasing particle of  claim 1 , wherein the core comprises a co-condensed silica network, wherein the co-condensed silica network is synthesized from the condensation of a silane mixture comprising an alkoxysilane and an aminoalkoxysilane. 
     
     
         13 . The nitric oxide-releasing particle of  claim 12 , wherein the alkoxysilane comprises a tetraalkoxysilane of the formula Si(OR) 4 , wherein R is alkyl; and the aminoalkoxysilane is selected from the group consisting of:
 (a) an aminoalkoxysilane of the formula R″—(NH—R′) n —Si(OR) 3 , wherein R is alkyl, R′ is alkylene, branched alkylene, or aralkylene, n is 1 or 2, and R″ is selected from the group consisting of alkyl, cycloalkyl, aryl, and alkylamine;   (b) an aminoalkoxysilane of the formula NH[R′—Si(OR) 3 ] 2 , wherein R is alkyl and R′ is alkylene;   (c) an aminoalkoxysilane wherein the amine is substituted by a diazeniumdiolate, said aminoalkoxysilane having the formula R″—N(NONO − X + )—R′—Si(OR) 3 , wherein R is alkyl, R′ is alkylene or aralkylene, R″ is alkyl or alkylamine, and X +  is a cation selected from the group consisting of Na +  and K + ; and   (d) a combination thereof.   
     
     
         14 . The nitric oxide-releasing particle of  claim 13 , wherein the silane mixture comprises between about 10 mol % to about 99 mol % of the tetraalkoxysilane and about 1 mol % to about 90 mol % of the aminoalkoxysilane. 
     
     
         15 . The nitric oxide-releasing particle of  claim 14 , wherein the silane mixture further comprises about 0 mol % to about 20 mol % of a fluorinated silane; about 0 mol % to about 20 mol % of a cationic or anionic silane; and about 0 mol % to about 20 mol % of an alkylsilane. 
     
     
         16 . The nitric oxide-releasing particle of  claim 13 , wherein the tetraalkoxysilane is selected from the group consisting of tetramethyl orthosilicate and tetraethyl orthosilicate. 
     
     
         17 . The nitric oxide-releasing particle of  claim 13 , wherein the aminoalkoxysilane is selected from the group consisting of: 
       N-(6-aminohexyl)aminomethyltrimethoxysilane; 
       N-(6-aminohexyl)aminopropyltrimethoxysilane; 
       N-(6-aminoethyl)aminopropyltrimethoxysilane; 
       (3-trimethoxysilylpropyl)diethylenetriamine; 
       (aminoethylaminomethyl)phenethyltrimethoxysilane; 
       [3-(methylamino)propyl]trimethoxysilane; 
       N-butylaminopropyltrimethoxysilane; 
       N-ethylaminoisobutyltrimethoxysilane; 
       N-phenylaminopropyltrimethoxysilane; 
       N-cyclohexylaminopropyltrimethoxysilane; 
       Bis[3-(trimethoxysilyl)propyl]amine; and 
       Bis[(3-trimethoxysilyl)propyl]ethylenediamine. 
     
     
         18 . The nitric oxide-releasing particle of  claim 15 , wherein the fluorinated silane is selected from the group consisting of: 
       (heptadecafluoro-1,1,2,2-tetrahydrodecyl)triethoxysilane; 
       (3,3,3-trifluoropropyl)trimethoxysilane; and 
       (perfluoroalkyl)ethyltriethoxysilane. 
     
     
         19 . The nitric oxide-releasing particle of  claim 15 , wherein the cationic or anionic silane is selected from the group consisting of: 
       N—N-didecyl-N-methyl-N-(3-trimethoxysilyl)ammonium chloride; 
       octadecyldimethyl(3-trimethoxysilylpropyl)ammonium chloride; 
       3-trihydroxysilylpropylmethyl phosphonate, sodium salt; and 
       carboxylethylsilanetriol, sodium salt. 
     
     
         20 . The nitric oxide-releasing particle of  claim 15 , wherein the alkylsilane is selected from the group consisting of methyltrimethoxysilane, butyltrimethoxysilane, butyltriethoxysilane, propyltrimethoxysilane, and octadecyltrimethoxysilane. 
     
     
         21 . The nitric oxide-releasing particle of  claim 1 , wherein the core comprises a co-condensed silica network, wherein the co-condensed silica network is synthesized from the condensation of a silane mixture comprising an alkoxysilane and an aminoalkoxysilane, and the NO donor is formed by a method selected from:
 (a) a post-charging method, wherein the nitric oxide donor is formed after the condensation of the silane mixture; and   (b) a pre-charging method, wherein the nitric oxide donor is formed from the aminoalkoxysilane prior to the condensation of the silane mixture.   
     
     
         22 . The nitric oxide-releasing particle of  claim 2 , wherein the linker comprises a functional group capable of conferring an on/off state of nitric oxide release to the nitric oxide-releasing particle, further wherein the functional group is selected from the group consisting of an ester, a hydrazone, an acetal, a thiopropionate, a photolabile moiety, and an amino acid sequence subject to enzymatic degradation. 
     
     
         23 . The nitric oxide-releasing particle of  claim 7 , wherein the exterior comprises a moiety capable of delivering the nitric oxide-releasing particle to a target. 
     
     
         24 . The nitric oxide-releasing particle of  claim 23 , wherein the target is selected from the group consisting of a cell, a tissue, and an organ. 
     
     
         25 . The nitric oxide-releasing particle of  claim 24 , wherein the cell is a cancer cell. 
     
     
         26 . The nitric oxide-releasing particle of  claim 23 , wherein the moiety capable of delivering the nitric oxide-releasing particle to a target is selected from the group consisting of a protein responsible for antibody/antigen interaction, folic acid, guanidine, transferrin, a hormone, a carbohydrate, a peptide containing the amino acid sequence RGD, and a TAT peptide. 
     
     
         27 . The nitric oxide-releasing particle of  claim 7 , wherein the exterior comprises a moiety selected from the group consisting of a nitric oxide donor, a (poly)ethyleneoxide, a (poly)urethane, an N-(2-hydroxypropyl)methacrylamide copolymer, lactide/glycolide copolymers (e.g. PLGA), a sugar, a fluorescent moiety, an organic dye, an MRI contrast agent, a thiol, a methyl-terminated alkyl chain, an antibiotic, an anti-cancer therapeutic, a sulfonate, a carboxylate, a phosphate, a cationic amine, a quaternary amine, and combinations thereof. 
     
     
         28 . The nitric oxide-releasing particle of  claim 1 , wherein the particle has a diameter of from between about 1 nm and about 1000 nm. 
     
     
         29 . The nitric oxide-releasing particle of  claim 9 , wherein the particle has a diameter of from between about 1 nm and about 5 nm. 
     
     
         30 . The nitric oxide-releasing particle of  claim 12 , wherein the particle has a diameter of from between about 2 nm and about 10 μm. 
     
     
         31 . A method of delivering nitric oxide to a subject, the method comprising:
 (a) providing a nitric oxide-releasing particle comprising:
 (i) a nitric oxide donor; 
 (ii) an interior region having a volume, the volume of the interior region being at least partially filled by a core selected from the group consisting of:
 (1) a metallic cluster; 
 (2) a dendritic network; 
 (3) a co-condensed silica network; and 
 (4) a combination thereof; and 
 
 (iii) an exterior region; and 
   (b) administering an effective amount of the nitric oxide-releasing particle to the subject.   
     
     
         32 . The method of  claim 31 , wherein the interior further comprises an organic linker selected from the group consisting of:
 (a) a labile linker responsive to changes in pH;   (b) a labile linker sensitive to electromagnetic radiation;   (c) a labile linker susceptible to degradation by enzymatic action;   (d) a hydrophobic linker;   (e) an amphiphilic linker; and   (f) a combination thereof.   
     
     
         33 . The method of  claim 31 , wherein the nitric oxide donor is selected from the group consisting of a diazeniumdiolate, a nitrosamine, a hydroxyl nitrosamine, a nitrosothiol, a hydroxylamine, and a hydroxyurea. 
     
     
         34 . The method of  claim 31 , wherein the nitric oxide donor is covalently bound to one of the core, the interior region, the exterior region, and a combination thereof. 
     
     
         35 . The method of  claim 31 , wherein the nitric oxide donor is encapsulated in one of the core, the interior region, the exterior region, and a combination thereof. 
     
     
         36 . The method of  claim 31 , wherein the nitric oxide donor is associated with one of the core, the interior region, the exterior region, and combinations thereof via a non-covalent interaction selected from one of Van der Waals forces, an electrostatic force, hydrogen bonding, and a combination thereof. 
     
     
         37 . The method of  claim 31 , wherein the exterior region comprises one or more chemical moieties selected from:
 (a) a moiety that modulates nitric oxide release kinetics;   (b) a moiety that affects biocompatibility of the particle;   (c) a moiety that affects biodistribution of the particle;   (d) a moiety that provides for targeted delivery of the particle;   (e) a moiety that imparts an ability to image or track the particle;   (f) a moiety that affects solubility of the particle;   (g) a therapeutic agent; and   (h) a combination thereof.   
     
     
         38 . The method of  claim 31 , wherein the core comprises a metallic cluster, said metallic cluster further comprising a component selected from gold, platinum, silver, magnetite, a quantum dot, and a combination thereof. 
     
     
         39 . The method of  claim 38 , wherein the metallic cluster is a monolayer protected gold cluster. 
     
     
         40 . The method of  claim 31 , wherein the core comprises a dendritic network, further wherein the dendritic network is selected from the group of consisting of:
 (a) a polypropylenimine dendrimer;   (b) a polyamidoamine (PAMAM) dendrimer;   (c) a polyaryl ether dendrimer;   (d) a polylysine dendrimer;   (e) a polyester dendrimer;   (f) a polyamide dendrimer;   (g) a dendritic polyglycerol; and   (h) a triazine dendrimer.   
     
     
         41 . The method of  claim 40 , wherein the dendritic network is hyperbranched. 
     
     
         42 . The method of  claim 31 , wherein the core comprises a co-condensed silica network, wherein the co-condensed silica network is synthesized from the condensation of a silane mixture comprising an alkoxysilane and an aminoalkoxysilane. 
     
     
         43 . The method of  claim 42 , wherein the alkoxysilane comprises a tetraalkoxysilane of the formula Si(OR) 4 , wherein R is alkyl; and the aminoalkoxysilane is selected from the group consisting of:
 (a) an aminoalkoxysilane of the formula R″—(NH—R′) n —Si(OR) 3 , wherein R is alkyl, R′ is alkylene, branched alkylene, or aralkylene, n is 1 or 2, and R″ is selected from the group consisting of alkyl, cycloalkyl, aryl, and alkylamine;   (b) an aminoalkoxysilane of the formula: NH[R′—Si(OR) 3 ] 2 , wherein R is alkyl and R′ is alkylene;   (c) an aminoalkoxysilane wherein the amine is substituted by a diazeniumdiolate, said aminoalkoxysilane having the formula; R″—N(NONO − X + )—R′—Si(OR) 3 , wherein R is alkyl, R′ is alkylene or aralkylene, R″ is alkyl or alkylamine, and X +  is a cation selected from the group consisting of Na +  and K + ; and   (d) combinations thereof.   
     
     
         44 . The method of  claim 43 , wherein the silane mixture comprises between about 10 mol % to about 99 mol % of the tetraalkoxysilane and about 1 mol % to about 90 mol % of the aminoalkoxysilane. 
     
     
         45 . The method of  claim 44 , wherein the silane mixture further comprises about 0 mol % to about 20 mol % of a fluorinated silane; about 0 mol % to about 20 mol % of a cationic or anionic silane; and about 0 mol % to about 20 mol % of an alkylsilane. 
     
     
         46 . The method of  claim 43 , wherein the tetraalkoxysilane is selected from the group consisting of tetramethyl orthosilicate and tetraethyl orthosilicate. 
     
     
         47 . The method of  claim 43 , wherein the aminoalkoxysilane is selected from the group consisting of: 
       N-(6-aminohexyl)aminomethyltrimethoxysilane; 
       N-(6-aminohexyl)aminopropyltrimethoxysilane; 
       N-(6-aminoethyl)aminopropyltrimethoxysilane; 
       (3-trimethoxysilylpropyl)diethylenetriamine; 
       (aminoethylaminomethyl)phenethyltrimethoxysilane; 
       [3-(methylamino)propyl]trimethoxysilane; 
       n-butylaminopropyltrimethoxysilane; 
       N-ethylaminoisobutyltrimethoxysilane; 
       N-phenylaminopropyltrimethoxysilane; 
       N-cyclohexylaminopropyltrimethoxysilane; 
       Bis[3-(trimethoxysilyl)propyl]amine; and 
       Bis[(3-trimethoxysilyl)propyl]ethylenediamine. 
     
     
         48 . The method of  claim 45 , wherein the fluorinated silane is selected from the group consisting of: 
       (heptadecafluoro-1,1,2,2-tetrahydrodecyl)triethoxysilane; 
       (3,3,3-trifluoropropyl)trimethoxysilane; and 
       (perfluoroalkyl)ethyltriethoxysilane. 
     
     
         49 . The method of  claim 45 , wherein the cationic or anionic silane is selected from the group consisting of: 
       N-N-didecyl-N-methyl-N-(3-trimethoxysilyl)ammonium chloride; 
       octadecyldimethyl(3-trimethoxysilylpropyl)ammonium chloride; 
       3-trihydroxysilylpropylmethyl phosphonate, sodium salt; and 
       carboxylethylsilanetriol, sodium salt. 
     
     
         50 . The method of  claim 45 , wherein the alkylsilane is selected from the group consisting of methyltrimethoxysilane, butyltrimethoxysilane, butyltriethoxysilane, propyltrimethoxysilane, and octadecyltrimethoxysilane. 
     
     
         51 . The method of  claim 31 , wherein the core comprises a co-condensed silica network, wherein the co-condensed silica network is synthesized from the condensation of a silane mixture comprising an alkoxysilane and an aminoalkoxysilane, further wherein the NO donor is formed by a method selected from:
 (a) a post-charging method, wherein the nitric oxide donor is formed after the condensation of the silane mixture; and   (b) a pre-charging method, wherein the nitric oxide donor is formed from the aminoalkoxysilane prior to the condensation of the silane mixture.   
     
     
         52 . The method of  claim 32 , wherein the organic linker comprises a functional group capable of conferring an on/off state of nitric oxide release to the nitric oxide-releasing particle, further wherein the functional group is selected from the group consisting of an ester, a hydrazone, an acetal, a thiopropionate, a photolabile moiety, and an amino acid sequence subject to enzymatic degradation. 
     
     
         53 . The method of  claim 37 , wherein the exterior comprises a moiety capable of delivering the nitric oxide-releasing particle to a target. 
     
     
         54 . The method of  claim 53 , wherein the target is selected from the group consisting of a cell, a tissue, and an organ. 
     
     
         55 . The method of  claim 54 , wherein the cell is a cancer cell. 
     
     
         56 . The method of  claim 53 , wherein the moiety capable of delivering the nitric oxide-releasing particle to a target is selected from the group consisting of a protein responsible for antibody/antigen interaction, folic acid, guanidine, transferrin, a hormone, a carbohydrate, a peptide containing the amino acid sequence RGD, and a TAT peptide. 
     
     
         57 . The method of  claim 37 , wherein the exterior comprises a moiety selected from the group consisting of a nitric oxide donor, a (poly)ethyleneoxide, a (poly)urethane, an N-(2-hydroxypropyl)methacrylamide copolymer, a sugar, a fluorescent moiety, an organic dye, an MRI contrast agent, a thiol, a methyl-terminated alkyl chain, an antibiotic, an anti-cancer agent, a sulfonate, a carboxylate, a phosphate, a cationic amine, a quartenary amine, and combinations thereof. 
     
     
         58 . The method of  claim 38 , wherein the core comprises magnetite, and wherein the method further comprises guiding the nitric oxide-releasing particle via the magnetic properties of the magnetite core to a target, said target comprising one of the group selected from a cell, a tissue and an organ. 
     
     
         59 . A method of treating a disease state in a subject in need of treatment thereof, the method comprising:
 (a) providing a nitric oxide-releasing particle comprising:
 (i) a nitric oxide donor; 
 (ii) an interior region having a volume, the volume of the interior region being at least partially filled by a core selected from the group consisting of:
 (1) a metallic cluster; 
 (2) a dendritic network; 
 (3) a co-condensed silica network; and 
 (4) a combination thereof; and 
 
 (iii) an exterior region; and 
   (b) administering an effective amount of the nitric oxide-releasing particle to the subject.   
     
     
         60 . The method of  claim 59 , wherein the disease state is selected from the group consisting of a cancer, a cardiovascular disease, a microbial infection; platelet aggregation and platelet adhesion caused by the exposure of blood to a medical device; pathological conditions resulting from abnormal cell proliferation; transplantation rejections, autoimmune diseases, inflammation, vascular diseases; scar tissue; wound contraction, restenosis, pain, fever, gastrointestinal disorders, respiratory disorders, sexual dysfunctions, and sexually transmitted diseases. 
     
     
         61 . The method of  claim 59 , further wherein the nitric oxide-releasing particle comprises a targeting moiety capable of directing the delivery of the particle to a target in the subject, said target comprising a cell, a tissue or an organ. 
     
     
         62 . A pharmaceutical formulation comprising:
 (a) a nitric oxide-releasing particle comprising:
 (i) a nitric oxide donor; 
 (ii) an interior region having a volume, the volume of the interior region being at least partially filled by a core selected from the group consisting of:
 (1) a metallic cluster; 
 (2) a dendritic network; 
 (3) a co-condensed silica network; and 
 (4) a combination thereof; and 
 
 (iii) an exterior region; and 
   (b) a pharmaceutically acceptable carrier.   
     
     
         63 . The formulation of  claim 62 , wherein the formulation is selected from the group consisting of an oral formulation, an intravenous formulation, and a topical formulation. 
     
     
         64 . A nitric oxide-releasing polymeric film comprising an organic polymer and a nitric oxide-releasing particle, said nitric oxide-releasing particle comprising:
 (a) a nitric oxide donor;   (b) an interior region having a volume, the volume of the interior region being at least partially filled by a core selected from the group consisting of:
 (i) a metallic cluster; 
 (ii) a dendritic network; 
 (iii) a co-condensed silica network; and 
 (iv) a combination thereof; and 
   (c) an exterior region.   
     
     
         65 . The nitric oxide-releasing polymeric film of  claim 64 , wherein the organic polymer is a polyurethane. 
     
     
         66 . A medical device comprising a nitric oxide-releasing polymeric film, wherein the nitric oxide-releasing film comprises an organic polymer and a nitric oxide-releasing particle, the nitric-oxide releasing particle comprising:
 (a) a nitric oxide donor;   (b) an interior region having a volume, the volume of the interior region being at least partially filled by a core selected from the group consisting of:
 (i) a metallic cluster; 
 (ii) a dendritic network; 
 (iii) a co-condensed silica network; and 
 (iv) a combination thereof; and 
   (c) an exterior region.   
     
     
         67 . The medical device of  claim 66 , wherein one or more surface of the medical device is coated with the nitric oxide-releasing film. 
     
     
         68 . The medical device of  claim 66 , wherein the medical device is selected from the group comprising arterial stents, guide wires, catheters, trocar needles, bone anchors, bone screws, protective platings, hip and joint replacements, electrical leads, biosensors, probes, sutures, surgical drapes, wound dressings and bandages. 
     
     
         69 . A detergent comprising a nitric oxide-releasing particle, said nitric oxide-releasing particle comprising:
 (a) a nitric oxide donor;   (b) an interior region having a volume, the volume of the interior region being at least partially filled by a core selected from the group consisting of:
 (i) a metallic cluster; 
 (ii) a dendritic network; 
 (iii) a co-condensed silica network; and 
 (iv) a combination thereof; and 
   (c) an exterior region.