Drug Delivery System and Method of Treatment of Vascular Diseases Using Photodynamic Therapy

Abstract

This invention relates to photodynamic therapy (PDT), more specifically PDT for atherosclerotic plaque via delivering PDT-loaded nanoparticles such as liposomes, polymersomes, micelles and polymeric nanoparticles into the diseased vascular tissue. This invention provides method and formulations for delivering multiple drugs and delivering drugs to specific targeted site.

1 . A drug delivery system for regional delivery of a photodynamic therapy (PDT) drug to a vascular tissue, comprising
 a pharmaceutical formulation comprising a nanoparticles to which is adhered or within which is encapsulated at least one PDT drug;   optionally, at least one non-PDT drug adhered to or encapsulated within the nanoparticle; and,   a catheter-based drug delivery device on or in which the pharmaceutical formulation is loaded.   
     
     
         2 . The drug delivery system of  claim 1 , wherein the PDT drug is selected from the group consisting of texaphyrin, porphyrin, a porphyrin precursor, porphyrazin, porphyrazin derivatives, benzochlorin and chlorophil. 
     
     
         3 . The drug delivery system of  claim 2 , wherein the porphyrin precursor is selected from the group consisting of 5-aminoleuvinic acid (ALA) and methyl aminolevulinate (MAL). 
     
     
         4 . The drug delivery system of  claim 1 , wherein the nanoparticle comprises a liposome or polymersome. 
     
     
         5 . The drug delivery system of  claim 1 , wherein the nanoparticle comprises a micelle. 
     
     
         6 . The drug delivery system of  claim 1 , wherein the nanoparticle comprises a polymeric nanoparticle. 
     
     
         7 . The drug delivery system of  claim 1 , wherein the nanoparticle has a diameter of about 50 nm to about 800 nm. 
     
     
         8 . The drug delivery system of  claim 4 , wherein the liposome or polymersome has a diameter of about 40 nm to about 200 nm. 
     
     
         9 . The drug delivery system of  claim 1 , wherein the catheter-based delivery device comprises a coating on an outer surface of the catheter, a stent, a single diameter balloon, a multiple-diameter balloon, doubly denuded balloon and a microporous balloon. 
     
     
         10 . The drug delivery system of  claim 5 , wherein the micelle has a diameter of about 10 nm to about 100 nm. 
     
     
         11 . The drug delivery system of  claim 5 , wherein the micelle has a diameter of about 10 nm to about 20 nm and comprises biotinylated PEG(2000)-DSPE. 
     
     
         12 . The drug delivery system of  claim 11 , wherein the micelle is combined with a PDT drug loaded liposome. 
     
     
         13 . The drug delivery system of  claim 1 , wherein the nanoparticle comprises a negatively charged surface. 
     
     
         14 . The drug delivery system of  claim 13 , wherein the negatively charged surface comprises a substance selected from the group consisting of DSPG, DSPC, long chain fatty acid, and combinations thereof. 
     
     
         15 . The drug delivery system of  claim 13 , wherein the nanoparticle further comprises a ceramide. 
     
     
         16 . The drug delivery system of  claim 5 , wherein the micelle comprises PEG-PE. 
     
     
         17 . The drug delivery system of  claim 1 , wherein the PDT drug-containing nanoparticle is complexed with a substance selected from the group consisting of serum albumin, low density protein, and hemoglobin. 
     
     
         18 . The drug delivery system of  claim 7 , wherein the polymeric nanoparticle comprises a biocompatible, biodegradable polymer. 
     
     
         19 . The drug delivery system of  claim 18 , wherein the biocompatible, biodegradable polymer is selected from the group consisting of dextran, alginate, cellulose, hyaluronan, chitosan, collagen, elastin, albumin, gelatin, PVP, PEG, PLGA, L-PLGA, PLGA-PEG, PCL, polyanhydride, PEA, P(LLA-GA-CL), P(LA-GA-CL), P(LLA-CL) and poly(acrylic acid). 
     
     
         20 . The drug delivery system of  claim 18 , wherein the biodegradable polymer further comprises an amino group. 
     
     
         21 . The drug delivery system of  claim 18 , wherein the biocompatible, biodegradable polymer at an outer surface of the nanoparticle is modified with a substance selected from the group consisting of fibronectin, collagen, vitronectin, laminin, MATRIGEL™, chitosan, polylysine and polyacrylic acid. 
     
     
         22 . The drug delivery system of  claim 7 , further comprising a carrier gel, wherein the pharmaceutical formulation is mixed with the carrier gel. 
     
     
         23 . The drug delivery system of  claim 22 , wherein the carrier gel is selected from the group consisting of sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, elastin, sodium alginate, cellulosics, a low molecular weight biocompatible biodegradable polymer, polysaccharides, polyvinylpyrrolidone (PVP) and PEG. 
     
     
         24 . The drug delivery system of  claim 7 , further comprising a penetration enhancer, wherein the penetration enhancer is mixed with the pharmaceutical formulation. 
     
     
         25 . The drug delivery system of  claim 24 , wherein the penetration enhancer is selected from the group consisting of DMSO, Cremophor, NMP, EtOH, and hyaluronidase. 
     
     
         26 . The drug delivery system of  claim 7 , wherein the pharmaceutical formulation further comprises a hyperosomotic suspension. 
     
     
         27 . The drug delivery system of  claim 26 , wherein the hyperosomotic suspension comprises a substance selected from the group consisting of glucose, mannose, fructose, sucrose, trehalose, monosaccharide, disaccharide, sodium chloride, phosphate salts, glycine, Saponin, DS-1, Qh-957, EDTA, Taurochilic acid, benzalkonium chloride, capric acid, melittin, and amino acids. 
     
     
         28 . The drug delivery system of  claim 1 , wherein the pharmaceutical formulation comprises at least two different PDT drugs, each having a different excitation wavelength. 
     
     
         29 . The drug delivery system of  claim 28 , wherein the nanoparticle comprises a multi-component micelle, wherein the two different PDT drugs are incorporated in different regions of the multi-component micelle. 
     
     
         30 . The drug delivery system of  claim 1 , further comprising a monocyte to which the PDT drug is conjugated or within which the PDT drug is engulfed. 
     
     
         31 . A method of treating a vascular disease, comprising:
 providing at least two different drugs or drug formulations, wherein one drug or drug formulation comprises a PDT having a first excitation wavelength and another drug or drug formulation comprises a different PDT having a different excitation wavelength or a drug of different type; and,   administering the drug or drug formulations to a patient in need thereof.   
     
     
         32 . The method of  claim 31 , wherein the two different PDT drugs comprise a short wavelength activated PDT capable of about 200 nm to about 400 nm tissue penetration and a long wavelength activated PDT capable of deeper penetration into the tissue. 
     
     
         33 . The method of  claim 31 , wherein the second drug is selected from the group consisting of an anti-proliferative drug, an anti-inflammatory drug, an anti-thrombotic drug, a pro-healing drug, and a pro-ECM deposition drug. 
     
     
         34 . The method of  claim 31 , further comprising formulating the drugs into a formulation comprising nanoparticles selected from the group consisting of micelles, liposomes, niosomes, polymersomes, polymeric nanoparticles, nanoconjugates and any combination thereof. 
     
     
         35 . The method of  claim 34 , wherein the drugs are incorporated together in a multi-component micelle which comprises a low molecular weight tri-block copolymer having hydrophilic and hydrophobic blocks. 
     
     
         36 . The method of  claim 35 , wherein the tri-block copolymer is PEO-PEE-PMCL. 
     
     
         37 . The method of  claim 31 , further comprising
 formulating the different drugs into different formulations;   mixing the formulations together; and   administering the mixture to a patient in need thereof.   
     
     
         38 . The method of  claim 31 , further comprising
 formulating one of the different drugs into a formulation comprising nanoparticles;   dissolving or dispersing another drug in a delivery medium;   mixing the formulation with the delivery medium; and,   administering the mixture to a patient in need thereof.   
     
     
         39 . The method of  claim 31 , wherein administration is accomplished by local injection or infusion from a delivery device. 
     
     
         40 . The method of  claim 39 , wherein the delivery device is a balloon, porous balloon or double denuded balloon which is infused or coated with the drugs or the formulation(s) thereof. 
     
     
         41 . A pharmaceutical formulation for delivering a PDT drug to atherosclerotic plaque, comprising
 at least one nanoparticle, and   at least one PDT drug adhered to or incorporated within the nanoparticle;   wherein the surface of the nanoparticle is coated with Annexin V or Protein G.   
     
     
         42 . The pharmaceutical formulation of  claim 41 , wherein the nanoparticle has a diameter of from about 50 nm to about 500 nm. 
     
     
         43 . The pharmaceutical formulation of  claim 41 , wherein the nanoparticle has a diameter of from about 100 nm to about 300 nm. 
     
     
         44 . The pharmaceutical formulation of  claim 41 , wherein the nanoparticle comprises a natural, semi-synthetic or synthetic biocompatible, biodegradable polymer. 
     
     
         45 . The pharmaceutical formulation of  claim 44 , wherein the biocompatible, biodegradable polymer is selected from the group consisting of dextran and copolymers thereof, alginate, cellulose, hyaluronan, chitosan, collagen, elastin, albumin, gelatin, PVP, PEG, PLGA, L-PLGA, PLGA-PEG, PCL, polyanhydrides, PEA, P(LLA-GA-CL), P(LA-GA-CL), P(LLA-CL), and polyacrylic acid. 
     
     
         46 . The pharmaceutical formulation of  claim 41 , further comprising a drug is selected from the group consisting of fenofibrate, gluocosteroid, dexamethasone, a statin, Darapladib, an anti-inflamatory drug, a cytotoxic drug, LY 518674 and FTY 720. 
     
     
         47 . The pharmaceutical formulation of  claim 41 , further comprising a hydrophilic drug. 
     
     
         48 . The pharmaceutical formulation of  claim 47 , wherein the hydrophilic drug is selected from bisphosphonate and ApoA1. 
     
     
         49 . The pharmaceutical formulation of  claim 41 , wherein the drug is a pro-survival protein or agent selected from the group consisting of IGF-1, bFGF, PDGF, and TGF-β. 
     
     
         50 . The pharmaceutical formulation of  claim 41 , wherein the nanoparticle is selected from the group consisting of a liposome, a polymersome, a micelle, a niosome, and a low Tg polymer solid particle. 
     
     
         51 . The pharmaceutical formulation of  claim 50 , wherein the nanoparticle has a diameter of about 10 nm to about 150 nm. 
     
     
         52 . The pharmaceutical formulation of  claim 41 , wherein the surface of the nanoparticle is functionalized for attaching Annexin V or Protein G, wherein the functional group is selected from the group consisting of amine, carboxyl, and sulfhydryl. 
     
     
         53 . The pharmaceutical formulation of  claim 41 , wherein the Annexin V is labeled with technetium-99m. 
     
     
         54 . The pharmaceutical formulation of  claim 41 , wherein the surface of the nanoparticles is modified using a substance selected from sialoprotein, ICAM and VCAM specific ligands. 
     
     
         55 . The pharmaceutical formulation of  claim 41 , further comprising a viscosity modifier. 
     
     
         56 . A method for delivering drug to an atherosclerotic plaque, comprising:
 providing a PDT drug,   incorporating the PDT drug in a nanoparticle;   coating an outer surface of the nanoparticle with Annexin V or Protein G;   optionally mixing the nanoparticles with a pharmaceutically acceptable carrier; and   administering the nanoparticle or mixture to a patient in need thereof, wherein administration is performed locally or regionally.   
     
     
         57 . The method of  claim 56 , wherein the nanoparticles or mixture is delivered using an implantable device coated with the nanoparticles or mixture. 
     
     
         58 . The method of clam  56 , further comprising adding a viscosity modifier to the mixture of the nanoparticles and the carrier. 
     
     
         59 . The method of  claim 56 , further comprising coating the nanoparticle with sialoprotein, ICAM specific ligand, or VCAM specific ligand. 
     
     
         60 . An implantable medical device comprising the pharmaceutical formulation of  claim 1 .