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

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.

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。

在癌症治疗中，药物对正常细胞的副作用和癌细胞不断产生的耐药性一直是化疗面临的难题，癌症化疗失败的一个重要原因就是癌细胞产生多药耐药性。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。然而，要同时解决这两种问题，需要纳米载体不仅能实现多种抗癌药物、光敏剂等制剂的协同靶向递送及肿瘤微环境选择性释放，而且还能调控肿瘤微环境，降低癌细胞的耐药性。基于此，本研究通过双亲性乳糖-药物的偶联物自组装构建纳米药物及其他制剂共运输体系来解决这两大难题。具体研究分为：1）基于双亲性乳糖-药物的偶联物自组装成功构建了3种纳米药物靶向递送体系；2）基于大环主体分子柱芳烃与客体分子的主客体相互作用制备糖基纳米载体，分别制备了3种具有肿瘤微环境刺激响应性的超分子自组装纳米药物递送体系；3）基于多糖改性MOF材料成功构建了2种多功能纳米递送体系，用于实现药物靶向递送和增强化疗效果的研究。. 运用上述制备的系列（八个）多功能纳米体系分别进行多种药物、光敏剂等制剂的负载，通过糖和蛋白相互作用，实现纳米药物选择性进入癌细胞。并进一步的利用癌细胞和正常细胞微环境的差异，通过pH、GSH和ROS调控来刺激响应促使药物在癌细胞中快速的释放，从而降低药物对正常细胞的副作用；利用姜黄素等药物降低癌细胞的耐药性，增强细胞对抗癌药物的积累；同时，通过调控肿瘤微环境，协同光疗法、化学动力学疗法等，协同增强化疗效果。. 本项目的完成，为解决癌症化疗中药物对正常细胞的副作用和癌细胞的耐药性难题，提高化疗效果的研究方面已取得系列进展，取得了创新性的研究成果。对癌症的治疗具有重大意义。