Sequential delivery of therapeutic agents using a rationally designed disulfide-linked glycolipid-like nanocarrier.
Usage of combination therapies to deliver multiple therapeutics to increase treatment efficacy has shown promising results in the clinic. In an effort to maximize the synergistic effect of co-delivery of a drug and siRNA, we have developed a time-dependent sequential drug delivery system (DDS) based on a disulfide-linked chitosan-based nanocarrier (CS-ss-SA) for the co-delivery of paclitaxel (PTX) and Bcl-2 specific siRNA (siBcl-2). This CS-ss-SA nanocarrier is able to transport both drug and siRNA by entrapment of PTX and adsorption of siRNA on the shell by electrostatic attraction. We show that this nanocarrier transports siRNA into tumor cells via its glycolipid-like spatial structure and releases a hydrophobic model drug, Nile Red 8-11 h later. Next, when siRNA and the hydrophobic drug PTX were co-delivered to tumor cells, a synergistic effect was observed in both cell cycle arrest and cell viability. Ultimately, the co-delivery of PTX and siBcl-2 by CS-ss-SA may prove to be more efficacious and may even help overcome drug resistance.
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.|Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States of America.
Yingwen
Y
Hu
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
Na
N
Liu
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
Bolin
B
Cheng
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
Yanan
Y
Tan
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
Lijuan
L
Wen
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
Hong
H
Yuan
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
Fuqiang
F
Hu
D000327:Adsorption; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000031:analogs & derivatives / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D004339:Drug Compounding; D065546:Drug Liberation; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061986:MCF-7 Cells; D058726:Nanoconjugates; D050997:Nanomedicine; D010078:Oxazines / Q000737:chemistry; D017239:Paclitaxel / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000067492:RNAi Therapeutics / Q000379:methods*; D055672:Static Electricity; D013229:Stearic Acids / Q000737:chemistry*; D013499:Surface Properties; D013997:Time Factors; D014162:Transfection
D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D004220:Disulfides; D058726:Nanoconjugates; D010078:Oxazines; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013229:Stearic Acids; C031183:stearic acid; D048271:Chitosan; C044808:nile red; D017239:Paclitaxel
co-delivery; combined therapy; drug resistance; redox-responsive; sequential