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  • Title: Dual stimulus of hyperthermia and intracellular redox environment triggered release of siRNA for tumor-specific therapy.
    Author: Yang Y, Yang Y, Xie X, Xu X, Xia X, Wang H, Li L, Dong W, Ma P, Liu Y.
    Journal: Int J Pharm; 2016 Jun 15; 506(1-2):158-73. PubMed ID: 27106526.
    Abstract:
    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, non-cell 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 90nm, 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.
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