期刊
INTERNATIONAL JOURNAL OF PHARMACEUTICS
卷 506, 期 1-2, 页码 158-173出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2016.04.035
关键词
Dual stimulus; Heat-activable; Intracellular redox environment; Cell-penetrating peptides; Small interfering RNA
资金
- National Science Foundation of China [81402874, 81202466]
- PUMC Youth Fund
- Fundamental Research Funds for the Central Universities [3332015139]
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.
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