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已发表论文

使用新的 pH 响应性可激活的细胞穿透肽修饰的脂质体系统获得增强化的基于 siRNA 的癌症疗法

 

Authors Xiang B, Jia XL, Qi JL, Yang LP, Sun WH, Yan X, Yang SK, Cao DY, Du Q, Qi XR

Received 6 December 2016

Accepted for publication 28 February 2017

Published 28 March 2017 Volume 2017:12 Pages 2385—2405

DOI https://doi.org/10.2147/IJN.S129574

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Jiang Yang

Peer reviewer comments 2

Editor who approved publication: Dr Lei Yang

Abstract: As a potent therapeutic agent, small interfering RNA (siRNA) has been exploited to silence critical genes involved in tumor initiation and progression. However, development of a desirable delivery system is required to overcome the unfavorable properties of siRNA such as its high degradability, molecular size, and negative charge to help increase its accumulation in tumor tissues and promote efficient cellular uptake and endosomal/lysosomal escape of the nucleic acids. In this study, we developed a new activatable cell-penetrating peptide (ACPP) that is responsive to an acidic tumor microenvironment, which was then used to modify the surfaces of siRNA-loaded liposomes. The ACPP is composed of a cell-penetrating peptide (CPP), an acid-labile linker (hydrazone), and a polyanionic domain, including glutamic acid and histidine. In the systemic circulation (pH 7.4), the surface polycationic moieties of the CPP (polyarginine) are “shielded” by the intramolecular electrostatic interaction of the inhibitory domain. When exposed to a lower pH, a common property of solid tumors, the ACPP undergoes acid-catalyzed breakage at the hydrazone site, and the consequent protonation of histidine residues promotes detachment of the inhibitory peptide. Subsequently, the unshielded CPP would facilitate the cellular membrane penetration and efficient endosomal/lysosomal evasion of liposomal siRNA. A series of investigations demonstrated that once exposed to an acidic pH, the ACPP-modified liposomes showed elevated cellular uptake, downregulated expression of polo-like kinase 1, and augmented cell apoptosis. In addition, favorable siRNA avoidance of the endosome/lysosome was observed in both MCF-7 and A549 cells, followed by effective cytoplasmic release. In view of its acid sensitivity and therapeutic potency, this newly developed pH-responsive and ACPP-mediated liposome system represents a potential platform for siRNA-based cancer treatment.
Keywords: siRNA, ACPP, hydrazone, liposome, endosomal/lysosomal escape