期刊
BIOMATERIALS
卷 46, 期 -, 页码 13-25出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2014.12.028
关键词
siRNA delivery; Hypoxia-inducible factor 1 alpha; Lipid-polymer hybrid nanoparticles; Combination therapy; Pancreatic cancer; Orthotopic tumor model
资金
- MoST 973 [2012CB934004]
- National Distinguished Young Scientists program [31325010]
- National Natural Science Foundation of China [81302082, 81272685, 31301151, 31470957, 31471340, 81472264, 81401957, 81172355]
- Key Program of Natural Science Foundation of Tianjin [11JCZDJC18400, 13YCYBYC37400]
- Major Anticancer Technologies R&D Program of Tianjin [12ZCDZSY16700]
Hypoxia-inducible factor 1 alpha (HIE1 alpha) has emerged as a promising new target for pancreatic cancer treatment over the past decade. High expression of HIF-1 alpha increases the drug resistance of the current first line chemotherapeutic drug, gemcitabine (Gem). Here we employed biocompatible lipid-polymer hybrid nanoparticles to co-deliver HIF1 alpha siRNA (si-HIF1 alpha) and Gem for pancreatic cancer treatment in subcutaneous and orthotopic tumor models. The cationic e-polylysine co-polymer (ENPs) can effectively absorb negatively charged si-HIF1 alpha on the surface and encapsulate Gem to the hydrophilic core. Further coating of ENPs with PEGylated lipid bilayer resulted formation of LENPs, with reversed surface charge. The lipid bilayer of LENPs prevented nanoparticle aggregation and si-HIF1 alpha degradation in serum, as well as Gem leakage. Those characteristics endow LENPs encapsulating drug prolonged lifetime in bloodstream and improved drug release via the enhanced tumor vasculature effect in tumor tissues. LENPs can co-deliver Gem and si-HIF1 alpha (LENP-Gem-si-HIF1 alpha) into tumor cells and effectively suppress the HIF1 alpha expression both in vitro and in vivo. LENP-Gem-siHIF1 alpha exhibited significant synergistic antitumor effects. Furthermore, LENP-Gem-si-HIF1 alpha showed excellent capability to inhibit tumor metastasis in orthotopic tumor model. (C) 2014 Elsevier Ltd. All rights reserved.
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