Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-L-lysine nanocarrier to suppress prostate cancer growth in mice
文献类型：期刊论文
| 作者 | Guo, Jianfeng1; Cheng, Woei Ping2; Gu, Jingxia3; Ding, Caixia3; Qu, Xiaozhong3; Yang, Zhenzhong3; O'Driscoll, Caitriona1 |
| 刊名 | EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
 |
| 出版日期 | 2012-04-11 |
| 卷号 | 45期号:5页码:521-532 |
| 关键词 | Poly-l-lysine Nanocarrier Sirna Delivery Ph-induced Endolysosomal Escape Prostate Cancer |
| ISSN号 | 0928-0987 |
| DOI | 10.1016/j.ejps.2011.11.024 |
| 英文摘要 | Prostate cancer is associated with high mortality and new therapeutic strategies are necessary for improved patient outcome. The utilisation of potent, sequence-specific small interfering RNA (siRNA) to facilitate down-regulation of complementary mRNA sequences in vitro and in vivo has stimulated the development of siRNA-based cancer therapies. However, the lack of an effective siRNA delivery system significantly retards clinical application. Amphiphilic polycations with 'stealth' capacity have previously been synthesised by PEGylation of poly-L-lysine-cholic acid (PLL-CA). The benzoic imine linker between PEG and PLL-CA was designed to be stable at physiological pH but cleavable at lower pHs, consistent with the extracellular environment of tumours and the interior of endosomes/lysosomes. The selective hydrolysis of the PEG linker at these targeted sites should provide enhanced cellular uptake and endosomal escape while simultaneously ensuring prolonged blood circulation times. In this study, physicochemical profiling demonstrated nano-complex formation between the PLL derivatives and siRNA (200-280 nm in diameter). At physiological pH only a slight cationic surface charge (<20 mV) was detected, due to the masking effect of the PEG. In contrast, significantly higher positive charges (similar to 20 to 30 mV and >40 mV) were detected upon hydrolysis of the PEG linker at acidic pHs (pH = 6.8 and 5.5, respectively). The PEGylated complexes were stable in serum without significant aggregation or decomplexation of siRNA for up to 48 h. At the cellular level, PEG-PLLs were comparable with the commercial carrier INTERFRin (TM), in terms of cellular uptake, endosomal escape and in vitro reporter gene knockdown. In vivo, utilising a mouse model grafted with prostate carcinoma, significant tumour suppression was achieved using PEGylated complexes without marked toxicity or undesirable immunological response, this was accompanied by a simultaneous reduction in target mRNA levels. In summary, the advantages of these vectors include: the in vitro and in vivo silencing efficiency, and the low toxicity and immunogenicity. (C) 2011 Elsevier B.V. All rights reserved. |
| 语种 | 英语 |
| WOS记录号 | WOS:000302112800001 |
| 出版者 | ELSEVIER SCIENCE BV |
| 源URL | [http://ir.iccas.ac.cn/handle/121111/47749]  |
| 专题 | 中国科学院化学研究所 |
| 通讯作者 | O'Driscoll, Caitriona |
| 作者单位 | 1.Natl Univ Ireland Univ Coll Cork, Pharmacodelivery Grp, Cork, Ireland 2.Univ Hertfordshire, Sch Pharm, Hatfield AL10 9AB, Herts, England 3.Chinese Acad Sci, Inst Chem, State Key Lab Polymer Phys & Chem, Beijing 100080, Peoples R China |
| 推荐引用方式 GB/T 7714 | Guo, Jianfeng,Cheng, Woei Ping,Gu, Jingxia,et al. Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-L-lysine nanocarrier to suppress prostate cancer growth in mice[J]. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,2012,45(5):521-532. |
| APA | Guo, Jianfeng.,Cheng, Woei Ping.,Gu, Jingxia.,Ding, Caixia.,Qu, Xiaozhong.,...&O'Driscoll, Caitriona.(2012).Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-L-lysine nanocarrier to suppress prostate cancer growth in mice.EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,45(5),521-532. |
| MLA | Guo, Jianfeng,et al."Systemic delivery of therapeutic small interfering RNA using a pH-triggered amphiphilic poly-L-lysine nanocarrier to suppress prostate cancer growth in mice".EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 45.5(2012):521-532. |
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来源：化学研究所
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