Surface-modified nanoparticles for intracellular delivery of therapeutic agents and compositions for making same

Abstract

Surface-modified polymeric nanoparticles (NPs), compositions for making them, and their use in drug delivery are disclosed.

1 . A surface modified nanoparticle for delivery of therapeutic agents, said surface modified nanoparticle comprising (i) a biocompatible polymer (ii) an amphiphilic emulsifier and (iii) a charge modulator, (i), (ii) and (iii) forming a nanoparticle matrix, the weight ratio of said amphiphilic emulsifier to said charge modulator from which said nanoparticle is prepared being in the range of 4:1 to 1.5:1, said nanoparticle having a negative surface charge at neutral pH, said charge modulator being embedded in said nanoparticle matrix and extending from the nanoparticle surface, and said charge modulator being effective to reverse said surface charge from negative to positive in an acidic environment, thereby improving the efficiency of intracellular delivery of therapeutic agents carried by said nanoparticle, said surface modified nanoparticle having a greater force of adhesion to a cell membrane for enhancing cellular uptake of said nanoparticle as compared to an unmodified nanoparticle comprising said biocompatible polymer and said amphiphilic emulsifier without said charge modulator. 
     
     
         2 . The surface modified nanoparticle of  claim 1  wherein said biocompatible polymer is selected from the group consisting of polylactides, polyglycolides, poly(lactide-co-glycolide), polyanhydrides, polyorthoesters, polycyanoacrylates, polycaprolactone, poly(alkylene glycol), poly(methylmethacrylate), poly(methylacrylic acid), poly(methylmethacrylate-co-methacrylic acid), poly-allylamine and polyhydroxybutyric acid. 
     
     
         3 . The modified nanoparticle of  claim 1 , wherein said charge modulator is selected from the group consisting of synthetic cationic polymers and cationic proteins. 
     
     
         4 . The modified nanoparticle of  claim 1 , wherein said charge modulator is a synthetic cationic polymer selected from the group consisting of polylysine, polyarginine, polyornithine, DEAE-Dextran, polybrene, and polyethylenimine. 
     
     
         5 . The modified nanoparticle of  claim 1 , wherein said charge modulator is a cationic protein selected from the group consisting of histones and protamines. 
     
     
         6 . The modified nanoparticle of  claim 1 , wherein said amphiphilic emulsifier is selected from the group consisting of polyvinylalcohol, polyethyleneglycol, derivatives of polyethyleneglycol having amine, amide and carboxyl groups and poloxamers. 
     
     
         7 . The modified nanoparticle of  claim 1 , further including a therapeutic agent. 
     
     
         8 . A pharmaceutical preparation comprising a multiplicity of the nanoparticles of  claim 7 . 
     
     
         9 . The modified nanoparticle of  claim 1 , further including a diagnostic agent. 
     
     
         10 . A method for delivery of a therapeutic or diagnostic agent to a patient, said method comprising administering to said patient a multiplicity of nanoparticles as claimed in  claim 1  also including an effective amount of said therapeutic or diagnostic agent.