Novel Free-Paclitaxel-Loaded Redox-Responsive Nanoparticles Based on a Disulfide-Linked Poly(ethylene glycol)鈥揇rug Conjugate for Intracellular Drug Delivery: Synthesis, Characterization, and Antitumor
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- 作者：Xingxing Chuan ; Qin Song ; Jialiang Lin ; Xianhui Chen ; Hua Zhang ; Wenbing Dai ; Bing He ; Xueqing Wang ; Qiang Zhang
- 刊名：Molecular Pharmaceutics
- 出版年：2014
- 出版时间：October 6, 2014
- 年：2014
- 卷：11
- 期：10
- 页码：3656-3670
- 全文大小：832K
- ISSN：1543-8392
文摘
To address the obstacles facing cancer chemotherapeutics, including toxicity, side effects, water insolubility, and lack of tumor selectivity, a novel stimuli-responsive drug-delivery system was developed based on paclitaxel-loaded poly(ethylene glycol)-disulfide-paclitaxel conjugate nanoparticles (PEG-SS-PTX/PTX NPs). The formulation emphasizes several benefits, including polymer鈥揹rug conjugates/prodrugs, self-assembled NPs, high drug content, redox responsiveness, and programmed drug release. The PTX-loaded, self-assembled NPs, with a uniform size of 103 nm, characterized by DLS, TEM, XRD, DSC, and 1H NMR, exhibited excellent drug-loading capacity (15.7%) and entrapment efficiency (93.3%). PEG-SS-PTX/PTX NPs were relatively stable under normal conditions but disassembled quickly under reductive conditions, as indicated by their triggered-aggregation phenomena and drug-release profile in the presence of dithiothreitol (DTT), a reducing agent. Additionally, by taking advantage of the difference in the drug-release rates between physically loaded and chemically conjugated drugs, a programmed drug-release phenomenon was observed, which was attributed to a higher concentration and longer action time of the drugs. The influence of PEG-SS-PTX/PTX NPs on in vitro cytotoxicity, cell cycle progression, and cellular apoptosis was determined in the MCF-7 cell line, and the NPs demonstrated a superior anti-proliferative activity associated with PTX-induced cell cycle arrest in G2/M phase and apoptosis compared to their nonresponsive counterparts. Moreover, the redox-responsive NPs were more efficacious than both free PTX and the non-redox-responsive formulation at equivalent doses of PTX in a breast cancer xenograft mouse model. This redox-responsive PTX drug delivery system is promising and can be explored for use in effective intracellular drug delivery.