title: Indomethacin-loaded polymeric nanocarriers based on amphiphilic polyphosphazenes with poly (N-isopropylacrylamide) and ethyl tryptophan as side groups: Preparation, in vitro and in vivo evaluation.
abstract: The effects of copolymer composition, drug structure and initial drug feed on drug loading of polymeric micelles based on amphiphilic polyphosphazenes were investigated. It was found that the drug loading capacity of micelles based on this type of amphiphilic copolymers was mainly determined by copolymer composition and the chemical structure of drug. In addition to the compatibility between drug and micellar core, hydrogen bonding interaction between drug and hydrophilic corona may significantly influence drug loading as well. In vitro drug release in 0.1 M PBS (pH 7.4) suggested that indomethacin (IND) in the micelles was released through Fickian diffusion, and no significant difference in release rate was observed for micelles based on copolymers with various EtTrp content. Compared with in vitro IND release profile, in vivo pharmacokinetic study after subcutaneous administration provides a more sustained release behavior. Additionally, in comparison with free drug solution at the same dose, IND concentration in rat plasma showed a prolonged retention when the drug was delivered through polymeric micelles. In vivo pharmacodynamic study based on both carrageenan-induced acute and complete Freund's adjuvant-induced adjuvant arthritis model indicated that sustained therapeutic efficacy could be achieved through intraarticular injection of IND-loaded micelles. Most importantly, local delivery of IND can avoid the severe gastrointestinal stimulation, which was frequently associated with oral administration.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310031, China.
authors.forename: Jian Xiang
authors.initials: JX
authors.lastname: Zhang
authors.forename: Xiao Jing
authors.initials: XJ
authors.lastname: Li
authors.forename: Li Yan
authors.initials: LY
authors.lastname: Qiu
authors.forename: Xiao Hui
authors.initials: XH
authors.lastname: Li
authors.forename: Mei Qiu
authors.initials: MQ
authors.lastname: Yan
authors.lastname: Yi Jin
authors.forename: Kang Jie
authors.initials: KJ
authors.lastname: Zhu
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D004339:Drug Compounding; D004487:Edema / Q000188:drug therapy; D007213:Indomethacin / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D053758:Nanoparticles; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000493:pharmacokinetics; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013276:Stomach Ulcer / Q000139:chemically induced; D013501:Surface-Active Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000180:Acrylic Resins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004337:Drug Carriers; D009943:Organophosphorus Compounds; D011108:Polymers; D013501:Surface-Active Agents; C108974:poly(phosphazene); C052970:poly-N-isopropylacrylamide; C025166:tryptophan ethyl ester; D014364:Tryptophan; D007213:Indomethacin