Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system

Bai Xiang,1,* Xue-Li Jia,1,* Jin-Long Qi,2 Li-Ping Yang,1 Wei-Hong Sun,1 Xiao Yan,1 Shao-Kun Yang,1 De-Ying Cao,1 Qing Du,1 Xian-Rong Qi3 1Department of Pharmaceutics, School of Pharmaceutical Sciences, 2Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, 3School of Pharmaceu...

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Autores principales:	Xiang B, Jia XL, Qi JL, Yang LP, Sun WH, Yan X, Yang SK, Cao DY, Du Q, Qi XR
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	siRNA ACPP hydrazone liposome endosomal/lysosomal escape Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/0bd741a80a614885ac3f89ae15905fd0
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spelling	oai:doaj.org-article:0bd741a80a614885ac3f89ae15905fd02021-12-02T06:33:29ZEnhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system1178-2013https://doaj.org/article/0bd741a80a614885ac3f89ae15905fd02017-03-01T00:00:00Zhttps://www.dovepress.com/enhancing-sirna-based-cancer-therapy-using-a-new-ph-responsive-activat-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Bai Xiang,1,* Xue-Li Jia,1,* Jin-Long Qi,2 Li-Ping Yang,1 Wei-Hong Sun,1 Xiao Yan,1 Shao-Kun Yang,1 De-Ying Cao,1 Qing Du,1 Xian-Rong Qi3 1Department of Pharmaceutics, School of Pharmaceutical Sciences, 2Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, 3School of Pharmaceutical Sciences, Peking University, Beijing, China *These authors contributed equally to this work 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 escapeXiang BJia XLQi JLYang LPSun WHYan XYang SKCao DYDu QQi XRDove Medical PressarticlesiRNAACPPhydrazoneliposomeendosomal/lysosomal escapeMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 2385-2405 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	siRNA ACPP hydrazone liposome endosomal/lysosomal escape Medicine (General) R5-920
spellingShingle	siRNA ACPP hydrazone liposome endosomal/lysosomal escape Medicine (General) R5-920 Xiang B Jia XL Qi JL Yang LP Sun WH Yan X Yang SK Cao DY Du Q Qi XR Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system
description	Bai Xiang,1,* Xue-Li Jia,1,* Jin-Long Qi,2 Li-Ping Yang,1 Wei-Hong Sun,1 Xiao Yan,1 Shao-Kun Yang,1 De-Ying Cao,1 Qing Du,1 Xian-Rong Qi3 1Department of Pharmaceutics, School of Pharmaceutical Sciences, 2Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, 3School of Pharmaceutical Sciences, Peking University, Beijing, China *These authors contributed equally to this work 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
format	article
author	Xiang B Jia XL Qi JL Yang LP Sun WH Yan X Yang SK Cao DY Du Q Qi XR
author_facet	Xiang B Jia XL Qi JL Yang LP Sun WH Yan X Yang SK Cao DY Du Q Qi XR
author_sort	Xiang B
title	Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system
title_short	Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system
title_full	Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system
title_fullStr	Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system
title_full_unstemmed	Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system
title_sort	enhancing sirna-based cancer therapy using a new ph-responsive activatable cell-penetrating peptide-modified liposomal system
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/0bd741a80a614885ac3f89ae15905fd0
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Enhancing siRNA-based cancer therapy using a new pH-responsive activatable cell-penetrating peptide-modified liposomal system

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