基于双亲性乳糖-药物的偶联物自组装构建纳米药物/siRNA双负载体系

多功能化纳米药物递送体系为解决癌症化疗面临的药物对正常细胞的毒副作用和癌细胞对药物产生的耐药性提供了高效的新途径。基于此，本申请提出基于糖-药物偶联构建糖靶向刺激响应性阳离子纳米载体实现对药物和siRNA双负载：1）将乳糖分子和抗癌药物通过对GSH响应的二硫键、二茂铁或pH响应的硼酯键等共价键连接，合成糖-药物偶联的双亲性前体药物分子，通过自组装制备新型糖靶向和双刺激响应的阳离子纳米载体；2）运用阳离子纳米载体负载siRNA，实现抗癌药物和siRNA的共同运输。利用糖靶向使抗癌药物能够选择性的进入癌细胞；利用癌细胞和正常细胞的微环境的差异，通过pH或GSH调控促使药物在癌细胞中快速释放；同时通过共运输的siRNA沉默癌细胞的耐药性基因。通过体外细胞实验和活体动物实验，验证双亲性糖-药物的偶联物自组装构建纳米药物/siRNA双负载体系减小药物对正常细胞的毒副作用和克服癌细胞多药耐药性的效果。

To solve problems of drug side effects on normal cells and drug resistance of cancer cells which are main obstacles of cancer chemotherapy, multifunctional nano-drug delivery system provides a new promising way to overcome these issues. Therefore, the methods we proposed are as follows: the targeted cationic nano-carriers based on carbohydrate-drug conjugates can not only target to cancer cells but also be released in cancer cells. What’s more, the carriers can co-delivery drug and siRNA. 1) Lactose is linked with anti-cancer drug through redox-sensitive disulfide bond, ferrocene or acid-sensitive boron-ester bond to construct amphiphilic prodrug, respectively, which can self-assemble into dual responsive cationic target nano-carriers. 2) This multifunctional drug delivery system is a cationic carrier which can be used to co-deliver drug and siRNA. This targeted drug nano-carrier can enter cancer cells selectively. Moreover, the drugs can be released in cancer cells quickly by pH or GSH which is based on the differences of microenvironment between cancer cells and normal cells. Meanwhile, the co-delivery nano-carriers can knock down drug resistance genes in cancer cells. We will verify that these nano-prodrug carriers can reduce drug side effects on normal cells and overcome multi-drug resistance of cancer cells through cell and animal experiments.