基于纳米氧化石墨烯构建可程序释药的双敏感联合给药系统

项目名称： 基于纳米氧化石墨烯构建可程序释药的双敏感联合给药系统

项目编号： No.21306152

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 化学工业

项目作者： 温惠云

作者单位： 西北大学

项目金额： 25万元

中文摘要： 针对肿瘤单一药物治疗易产生细胞耐药性的问题，临床上需要药物载体能同时负载多种药物并可智能调控释放。氧化石墨烯(GO)以其高药物负载率、独特的化学性质及已证实的良好生物相容性为构建此类药物载体提供了新方法。本项目以聚乙二醇功能化的GO纳米层(mPEG-GO)为基本单元，拟构建一种双敏感机制调控下，两种药物程序释放的联合给药系统。药物模型采用不呈交叉耐药性、有协同治疗作用的甲氨蝶呤(MTX)和盐酸阿霉素(DXR)。该载药纳米层静脉注射后，借助EPR效应靶向至肿瘤组织，在肿瘤酸性微环境下首先酸触释放π-π共轭负载的DXR；随后在细胞内高谷胱甘肽还原环境下，快速释放MTX。实现两种药物先后程序释放，联合作用。其中MTX以还原环境下可快速裂解的二硫键为连接化学键合在GO上。项目拟通过体外实验阐明两种药物与GO的组装机制及程序释放行为；同时在细胞水平上考察载药纳米层在肿瘤细胞内的分布及联合给药疗效。

中文关键词： 氧化石墨烯；pH敏感；GSH 敏感；药物释放；联合治疗

英文摘要： The use of single chemotherapeutic drug has shown some limitations in anti-tumor treatment, such as high toxicity and development of drug resistance. Generally, a co-delivery system with synergistic combination of two or more drugs engineered with stimulus responsive mechanism is a promising strategy to overcome these limitations. With high drug loading effiency, extraordinary chemical structural properties as well as identified biocompatibility, graphene oxide (GO) have greatly attracted the attention of researchers, providing a promising approach. In this proposal, we attempt to design a combination drug delivery system based on PEGylated nano-graphene oxide (mPEG-GO), which can program release different drugs in a controllable way triggered by different stimuli signals. Methotrexate (MTX) and Doxorubicin hydrochloride (DXR) are chosen as the two model drugs due to their excellent anti-tumor efficiency against various solid tumors. They, however, are drugs with different anticancer mechanisms, showing synergistic therapeutic effect in clinical use. MTX is conjugated on GO via a disulfide linkage which can be destroyed quickly in a reducing environment, while DXR is physically loaded on GO driven by noncovalent π-π stacking interaction. After intravenous injection, an increased circulation half-life of GO nanos

英文关键词： Graphene oxide；pH sensitive；GSH sensitive；Drug release；Combine therapy