Self-Assembled pH-Sensitive Polymeric Nanoparticles for the Inflammation-Targeted Delivery of Cu/Zn-Superoxide Dismutase
Xiangshi Sun, Kongtong Yu, Yulin Zhou, Shiyan Dong, Wenji Hu, Yating Sun, Yuhuan Li, Yuhuan Li, Jing Xie, Robert J. Lee, Fengying Sun, Yifan Ma, Shengnian Wang, Betty Y.S. Kim, Yifan Wang, Zhaogang Yang, Wen Jiang, Youxin Li, Youxin Li, Lesheng Teng
Abstract
The use of superoxide dismutase (SOD) is currently limited by its short half-life, rapid plasma clearance rate, and instability. We synthesized a small library of biofriendly amphiphilic polymers that comprise methoxy poly(ethylene glycol)-poly(cyclohexane-1,4-diyl acetone dimethyleneketal) (mPEG-PCADK) and mPEG-poly((cyclohexane86.7%, 1,5-pentanediol13.3%)-1,4-diyl acetone dimethylene ketal) (PK3) for the targeted delivery of SOD. The novel polymers could self-assemble into micellar nanoparticles with favorable hydrolysis kinetics, biocompatibility, long circulation time, and inflammation-targeting effects. These materials generated a better pH-response curve and exhibited better hydrolytic kinetic behavior than PCADK and PK3. The polymers showed good biocompatibility with protein drugs and did not induce an acidic microenvironment during degradation in contrast to materials such as PEG-block-poly(lactic-co-glycolic acid) (PLGA) and PLGA. The SOD that contained reverse micelles based on mPEG2000-PCADK exhibited good circulation and inflammation-targeting properties. Pharmacodynamic results indicated exceptional antioxidant and anti-inflammatory activities in a rat adjuvant-induced arthritis model and a rat peritonitis model. These results suggest that these copolymers are ideal protein carriers for targeting inflammation treatment.