期刊
JOURNAL OF CONTROLLED RELEASE
卷 243, 期 -, 页码 54-68出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2016.09.036
关键词
Drug co-delivery; Nanoparticles; Self-assembly; Stimuli-responsive; Synergistic effect
资金
- National Natural Science Foundation of China [81102397, 81573613]
- Natural Science Foundation of Jiangsu Province [BK2012761, BK20130655]
- Qing Lan Project of Jiangsu Province [02432009]
- Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [JKPZ2013004]
- Open Fund of State Key Laboratory of Natural Medicines [SKLNMKF201612]
- Major Program for the Fundamental Research of Shanghai Committee of Science and Technology, China [14JC1491300]
Co-delivery systems capable of transporting hydrophobic chemotherapeutics and hydrophilic siRNA to the same cell population with simultaneous burst release of both drugs to maximize synergistic anticancer efficacy remains elusive. In this light, a multifunctional nanoparticle (HA-PSR) consisting of a redox-sensitive core and detachable crosslinked hyaluronic acid (HA) shell was developed. Octyl modified PEI containing disulfide linkages (PSR) were synthesized as the core materials for co-encapsulation of chemotherapeutics and siRNA, while a HAase-sensitive thiolated HA (HA-SH) was collaboratively assembled to the anionic shell for CD44-mediated active targeting along with enhanced and detachable protection for drug loaded inner cores. Resultantly, HA deprotected redox-sensitive inner cores achieved co-burst release of both cargoes when triggered by glutathione (GSH) rich environments in cytoplasm. Results of in-vivo and in-vitro testing indicated successful co-encapsulation of hydrophobic drugs and hydrophilic siRNA with adjustable ratios. Selective delivery to CD44 overexpressing tumors was achieved through passive and active targeting, followed by HAase-triggered HA de-shielding and GSH-triggered burst release of both cargos. Rapid intracellular trafficking maximized synergistic cytotoxicities of chemotherapeutics and siRNA for remarkable tumor inhibition in a xenograft animal tumor model. Consequently, the HA-PSR nanoparticle holds great potential for combined chemotherapeutics/siRNA treatment in cancer with maximized synergistic antitumor efficacy. (C) 2016 Elsevier B.V. All rights reserved.
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