title: Highly stable polyglutamate derivatives/siRNA polyplex efficiently down-relegate survivin expression and augment the efficacy of cisplatin.
abstract: RNA interfere (RNAi)-based technology holds great promise in cancer treatment. The use of small interfering RNA (siRNA), however, is hampered by its low delivery efficiency in vivo when they are diluted in blood biofluids and in the presence of serum and salt. In this study, we developed the polyglutamate derivative polymer brush, poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (mPEG-b-PG-g-spermine, PPGS), which could efficiently deliver survivin-siRNA under ultra-high dilution and in the presence of salt (NaCl 150mM) and serum (10% FBS), most likely due to its PEG-shelled polymer brush structure. On the contrary, aggregation occurred when PEI/siRNA polyplex dispersed in saline and serum-containing media and PEI polyplex dissociated after making a 256-fold dilution. PPGS/si-survivin polyplex exhibited high cellular uptake efficiency and efficiently down-regulated the expression of survivin mRNA in the cisplatin-resistance of non-small cell human lung adenocarcinoma (A549/DDP) cells in the presence of serum. However, either PEI polyplex or Lipofectmine 2000 complex was unstable in serum and salt-containing media and at high dilution rates, which resulted in their dramatical decrease of cellular uptake and gene-silencing efficiency in these conditions. The PPGS/si-survivin polyplex also exhibited synergistic effects of killing the cancer cells by combination treatment with cisplatin. Therefore, the PPGS gene carrier showed great potential in systemic siRNA delivery, and its combination with chemotherapeutic drug is promising in treating drug resistant cancers.
authors.affiliation: Department of Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Zhongjuan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Haijuan
authors.initials: H
authors.lastname: Zou
authors.affiliation: Department of Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Zirui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, PR China. Electronic address: xiazhsh@163.com.
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China. Electronic address: fengmin@mail.sysu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Feng
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D018014:Gene Transfer Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008055:Lipids / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D011099:Polyglutamic Acid / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D013096:Spermine / Q000737:chemistry; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008055:Lipids; C086724:Lipofectamine; D034741:RNA, Small Interfering; D000077022:Survivin; D011099:Polyglutamic Acid; D013096:Spermine; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D002945:Cisplatin
keywords: Cisplatin; Stability; Survivin; siRNA delivery