title: Synthesis and evaluation of pH-sensitive, self-assembled chitosan-based nanoparticles as efficient doxorubicin carriers.
abstract: A novel pH-responsive polymer based on amphiphilic N-acetyl histidine and arginine-grafted chitosan was synthesized using N-acetyl histidine as hydrophobic segment and arginine as hydrophilic segment by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide-mediated coupling reactions as anticancer drug delivery system for doxorubicin. The structure of the synthesized polymer was confirmed by Fourier transform infrared and1H nuclear magnetic resonance analysis. Due to self-association behavior, N-acetyl histidine and arginine-grafted chitosan structured nanoparticles with in size range of 204 nm. N-acetyl histidine and arginine-grafted chitosan with different substitution degree of N-acetyl histidine were initially prepared and characterized. The critical micelle concentration decreased with increasing substitution degree of N-acetyl histidine. Furthermore, N-acetyl histidine and arginine-grafted chitosan nanoparticles exhibited an acidic pH-triggered aggregation and disassembling nature. The doxorubicin-encapsulated nanoparticles based on synthesized conjugate ( N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles) showed a sustained drug release pattern, which could be hastened under acidic pH conditions but delayed with increasing substitution degree of N-acetyl histidine. Anticancer effects demonstrated that N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles could suppress both sensitive and resistant human breast tumor cell line (MCF-7) efficiently in a dose- and time-dependent pattern. Confocal microscopy results evidenced increased cellular uptake and enhanced retention of the synthesized nanoparticles in drug-resistant cells demonstrating better efficacy of nanoparticles over native doxorubicin. These results suggest that N-acetyl histidine and arginine-grafted chitosan/doxorubicin nanoparticles might be promising carriers for delivery of hydrophobic drug doxorubicin against drug-resistant tumors.
authors.affiliation: College of Marine Life Sciences, Ocean University of China, Qingdao, PR China.
authors.forename: Mazhar Ali
authors.initials: MA
authors.lastname: Raja
authors.affiliation: College of Marine Life Sciences, Ocean University of China, Qingdao, PR China.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Arif
authors.affiliation: College of Marine Life Sciences, Ocean University of China, Qingdao, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Feng
authors.affiliation: College of Marine Life Sciences, Ocean University of China, Qingdao, PR China.
authors.forename: Shah
authors.initials: S
authors.lastname: Zeenat
authors.affiliation: College of Marine Life Sciences, Ocean University of China, Qingdao, PR China.
authors.forename: Chen-Guang
authors.initials: CG
authors.lastname: Liu
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D003460:Crystallization / Q000379:methods; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000138:chemical synthesis; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D010316:Particle Size; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D053769:Nanocapsules; D004317:Doxorubicin; D048271:Chitosan
keywords: Doxorubicin; N-acetyl histidine; arginine; cellular uptake studies; chitosan; cytotoxicity; drug resistance; nanoparticles; pH sensitive; self-assembled