Hyaluronidase-triggered anticancer drug and siRNA delivery from cascaded targeting nanoparticles for drug-resistant breast cancer therapy

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• 作者：Jie Ding ; Tingxizi Liang ; Ying Zhou ; Zhiwei He ; Qianhao Min ; Liping Jiang…
• 关键词：drug ; resistant breast cancer ; siRNA ; breast tumor cell ; penetrating peptide ; hyaluronic acid ; rattle mesoporous silica
• 刊名：Nano Research
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：10
• 期：2
• 页码：690-703
• 全文大小：
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Nanotechnology; Materials Science, general; Atomic/Molecular Structure and Spectra; Condensed Matter Physics; Biotechnology; Biomedicine, general;
• 出版者：Tsinghua University Press
• ISSN：1998-0000
• 卷排序：10

文摘

Drug resistance renders standard chemotherapy ineffective in the treatment of connective tissue growth factor (CTGF)-overexpressing breast cancer. By co-embedding the breast tumor cell-penetrating peptide (PEGA-pVEC) and hyaluronic acid (HA) as a targeting media, novel cascaded targeting nanoparticles (HACT NPs) were created on a rattle mesoporous silica (rmSiO₂) scaffold for the pinpoint delivery of siRNAs along with an anticancer drug, aiming at overcoming the drug resistance of CTGF-overexpressing breast cancer in vivo. The targeting nanoparticles selectively accumulated in the vasculature under the guidance of the PEGA-pVEC peptide, cascaded by receptor-mediated endocytosis with the aid of another targeting agent, HA, presenting a greater in vivo tumor targeting ability than single targeting ligand vectors. In addition, an HA shell prevented the leakage of therapeutic drugs during the cargo transport process, until the hyaluronidase (HAase)-triggered degradation upon lysosomes entering, guaranteeing a controllable drug release inside the target cells. When the protective shell disintegrates, the released siRNA took charge to silence the gene associated with drug resistance, CTGF, thus facilitating doxorubicin-induced apoptosis. The cascaded targeting media (PEGA-pVEC and HA) advances precision-guided therapy in vivo, while the encapsulation of siRNAs into a chemotherapy drug delivery system provides an efficient strategy for the treatment of drug resistance cancers.