Dual stimulus of hyperthermia and intracellular redox environment triggered release of siRNA for tumor-specific therapy

被引：22

作者：

Yang, Yanfang ^{[1
,2
,3
]}

Yang, Yang ^{[4
]}

Xie, Xiangyang ^{[5
]}

Xu, Xueqing ^{[1
,2
,3
]}

Xia, Xuejun ^{[1
,2
,3
]}

Wang, Hongliang ^{[1
,2
,3
]}

Li, Lin ^{[1
,2
,3
]}

Dong, Wujun ^{[1
,2
,3
]}

Ma, Panpan ^{[1
,2
,3
]}

Liu, Yuling ^{[1
,2
,3
]}

机构：

[1] Chinese Acad Med Sci, Inst Mat Med, State Key Lab Bioact Subst & Funct Nat Med, Beijing 100050, Peoples R China

[2] Peking Union Med Coll, Beijing 100050, Peoples R China

[3] Chinese Acad Med Sci, Inst Mat Med, Beijing Key Lab Drug Delivery Technol & Novel For, Beijing 100050, Peoples R China

[4] Beijing Inst Pharmacol & Toxicol, Beijing 100850, Peoples R China

[5] Guangzhou Mil Command, Wuhan Gen Hosp, Wuhan 430070, Peoples R China

来源：

INTERNATIONAL JOURNAL OF PHARMACEUTICS | 2016年 / 506卷 / 1-2期

基金：

美国国家科学基金会;

关键词：

Dual stimulus; Heat-activable; Intracellular redox environment; Cell-penetrating peptides; Small interfering RNA; TEMPERATURE-SENSITIVE LIPOSOMES; DRUG-DELIVERY; THERMOSENSITIVE LIPOSOMES; SOLID TUMORS; DOXORUBICIN; NANOPARTICLES; ULTRASOUND; CONJUGATE; PEPTIDES; PROTEINS;

D O I：

10.1016/j.ijpharm.2016.04.035

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Small interfering RNA (siRNA) offers a new and potential therapeutic strategy for tackling many diseases at the molecular level. Recently, cell-penetrating peptides (CPPs) conjugated with siRNA via disulfide-bonds (designated as siRNA-CPPs) were reported to form glutathione-sensitive carriers. However, noncell specificity, CPPs degradation and the unwanted reduction of siRNA-CPPs before reaching the targeted tissue in vivo hampered the development of siRNA-CPPs. Herein, utilizing the dual stimulus of hyperthermia and the intracellular redox environment, we devised a thermosensitive liposome (TSL) containing an Asparagine-Glycine-Arginine (NGR) peptide and reducible siRNA-CPPs for tumor-specific siRNA transfection (siRNA-CPPs/NGR-TSL), in which siRNA-CPPs were "caged" in NGR-TSL to overcome their limitations in vivo. The functional nanocarrier possessed a small particle size of approximately 90 nm, a high drug encapsulation efficiency of approximately 86% and good serum stability. Both free siRNA-CPPs and siRNA-CPPs/NGR-TSL (preheated) silenced c-myc in human fibrosarcoma (HT-1080) cells in vitro. However, in an HT-1080 xenograft murine model, siRNA-CPPs/NGR-TSL with hyperthermia displayed superior in vivo antitumor efficacy (about 3-fold) and gene silencing efficiency (about 2-fold) compared with free siRNA-CPPs under hyperthermia. This study demonstrates that the constructed vesicle in combination with hyperthermia could greatly improve the in vivo stability of siRNA-CPPs and synergistically enhance its cancer therapy efficiency. (c) 2016 Elsevier B.V. All rights reserved.

引用

页码：158 / 173

页数：16

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