title: Co-delivery of siRNA and paclitaxel into cancer cells by biodegradable cationic micelles based on PDMAEMA-PCL-PDMAEMA triblock copolymers.
abstract: Biodegradable cationic micelles were prepared from PDMAEMA-PCL-PDMAEMA triblock copolymers and applied for the delivery of siRNA and paclitaxel into cancer cells. PDMAEMA-PCL-PDMAEMA copolymers were readily obtained by reversible addition-fragmentation chain transfer (RAFT) polymerization of dimethylaminoethyl methacrylate (DMAEMA) using CPADN-PCL-CPADN (CPADN: 4-cyanopentanoic acid dithionaphthalenoate; PCL: 3600 Da) as a macro-RAFT agent. The molecular weights of PDMAEMA blocks, controlled by monomer/CPADN-PCL-CPADN mole ratios, varied from 2700, 4800 to 9100 (denoted as polymer 1, 2 and 3, respectively). These triblock copolymers formed nano-sized micelles in water with positive surface charges ranging from +29.3 to +35.5 mV. Both micelles 1 and 2 revealed a low cytotoxicity. Gel retardation assay showed that micelles 1 and 2 could effectively complex with siRNA at and above N/P ratios of 4/1 and 2/1, respectively. Notably, GFP siRNA complexed with micelle 1 exhibited significantly enhanced gene silencing efficiency as compared to that formulated with 20 kDa PDMAEMA or 25kDa branched PEI in GFP-expressed MDA-MB-435-GFP cells. Moreover, micelle 1 loaded with paclitaxel displayed higher drug efficacy than free paclitaxel in PC3 cells, due to most likely improved cellular uptake. The combinatorial delivery of VEGF siRNA and paclitaxel showed an efficient knockdown of VEGF expression. Confocal laser scanning microscope studies on GFP siRNA complexed with nile red-loaded micelle revealed that nile red was delivered into GFP-expressed MDA-MB-435-GFP cells and that GFP expression was significantly inhibited. These results demonstrated that cationic biodegradable micelles are highly promising for the combinatorial delivery of siRNA and lipophilic anti-cancer drugs.
authors: Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, PR China.
authors: Caihong
authors: C
authors: Zhu
authors: Sooyeon
authors: S
authors: Jung
authors: Sibin
authors: S
authors: Luo
authors: Fenghua
authors: F
authors: Meng
authors: Xiulin
authors: X
authors: Zhu
authors: Tae Gwan
authors: TG
authors: Park
authors: Zhiyuan
authors: Z
authors: Zhong
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000494:pharmacology; D002412:Cations / Q000737:chemistry*; D045744:Cell Line, Tumor / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008422:Materials Testing; D008689:Methacrylates / Q000737:chemistry*; D008823:Micelles; D015394:Molecular Structure; D008970:Molecular Weight; D009757:Nylons / Q000737:chemistry*; D017239:Paclitaxel / Q000378:metabolism* / Q000494:pharmacology; D010316:Particle Size; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002412:Cations; D004337:Drug Carriers; D008689:Methacrylates; D008823:Micelles; D009757:Nylons; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C407037:poly(2-(dimethylamino)ethyl methacrylate); D049452:Green Fluorescent Proteins; D017239:Paclitaxel