Redox-responsive polymer-drug conjugates based on doxorubicin and chitosan oligosaccharide-g-stearic acid for cancer therapy.
Here, a biodegradable polymer-drug conjugate of doxorubicin (DOX) conjugated with a stearic acid-grafted chitosan oligosaccharide (CSO-SA) was synthesized via disulfide linkers. The obtained polymer-drug conjugate DOX-SS-CSO-SA could self-assemble into nanosized micelles in aqueous medium with a low critical micelle concentration. The size of the micelles was 62.8 nm with a narrow size distribution. In reducing environments, the DOX-SS-CSO-SA could rapidly disassemble result from the cleavage of the disulfide linkers and release the DOX. DOX-SS-CSO-SA had high efficiency for cellular uptake and rapidly released DOX in reductive intracellular environments. In vitro antitumor activity tests showed that the DOX-SS-CSO-SA had higher cytotoxicity against DOX-resistant cells than free DOX, with reversal ability up to 34.8-fold. DOX-SS-CSO-SA altered the drug distribution in vivo, which showed selectively accumulation in tumor and reduced nonspecific accumulation in hearts. In vivo antitumor studies demonstrated that DOX-SS-CSO-SA showed efficient suppression on tumor growth and relieved the DOX-induced cardiac injury. Therefore, DOX-SS-CSO-SA is a potential drug delivery system for safe and effective cancer therapy.
†College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, People's Republic of China.
Yigang
Y
Su
†College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, People's Republic of China.
Yingwen
Y
Hu
†College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, People's Republic of China.
Yongzhong
Y
Du
‡Department of Pharmacy, School of Medicine Science, Jiaxing University, Jiaxing, Zhejiang 314001, People's Republic of China.
Xuan
X
Huang
†College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, People's Republic of China.
Jiabei
J
He
†College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, People's Republic of China.
Jian
J
You
†College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, People's Republic of China.
Hong
H
Yuan
†College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, People's Republic of China.
Fuqiang
F
Hu
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D048271:Chitosan / Q000737:chemistry*; D002853:Chromatography, Liquid; D004220:Disulfides / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000188:drug therapy*; D009844:Oligosaccharides / Q000737:chemistry*; D010084:Oxidation-Reduction; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D013229:Stearic Acids / Q000737:chemistry*
D000970:Antineoplastic Agents; D004220:Disulfides; D008823:Micelles; D009844:Oligosaccharides; D011108:Polymers; D013229:Stearic Acids; C031183:stearic acid; D004317:Doxorubicin; D048271:Chitosan
chitosan; controlled release; drug resistance; polymer−drug conjugates; redox-responsive