Redox-Sensitive Micelles Based on O,N-Hydroxyethyl Chitosan-Octylamine Conjugates for Triggered Intracellular Delivery of Paclitaxel.
A redox-sensitive micellar system constructed from an O,N-hydroxyethyl chitosan-octylamine (HECS-ss-OA) conjugate with disulfide linkages between the hydrophobic alkyl chains and hydrophilic chitosan backbone was synthesized for triggered intracellular delivery of hydrophobic paclitaxel (PTX). In aqueous environments, conjugates formed micelles with high PTX loading (>30%). Mechanistically, the sensitivity of HECS-ss-OA micelles to reducing environments was investigated using the parameters of in vitro release and particle size. Intracellular release of nile red fluorescence alongside cytotoxicity studies further confirmed the potency of redox-sensitive micelles for intracellular drug delivery compared with redox-insensitive micelles. Additionally, an in vivo study confirmed the efficacy of PTX-loaded micelles in tumor-bearing mice with superior antitumor efficacy and diminished systemic toxicity when compared with the redox-insensitive micelles and a PTX solution. These results demonstrate the potential of redox-sensitive HECS-ss-OA micelles for intracellular trafficking of lipophilic anticancer drugs.
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Meirong
M
Huo
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Yao
Y
Liu
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Lei
L
Wang
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Tingjie
T
Yin
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Chen
C
Qin
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Yanyu
Y
Xiao
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Lifang
L
Yin
Department of Pharmacy, Changhai Hospital, The Second Military Medical University , Shanghai 200433, China.
Jiyong
J
Liu
State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, China.
Jianping
J
Zhou
D000588:Amines / Q000737:chemistry*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D010084:Oxidation-Reduction; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry*; D010316:Particle Size; D011108:Polymers / Q000737:chemistry
D000588:Amines; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D048271:Chitosan; D017239:Paclitaxel; C008699:octylamine
anticancer effects; paclitaxel; polymeric micelle; redox-sensitive; triggered intracellular delivery