糖靶向智能阳离子囊泡的制备及其在抗癌药物/siRNA共运输的应用研究

Drug side effects on normal cells and drug resistance of cancer cells are major obstacles of chemotherapy. Nano-drug-carriers with its characteristics of intelligent provide a promising way to overcome these obstacles. To conquer both of these two problems, nanocarriers should have not only the functions of the targeted selectivity and stimulate responsiveness, but also the function of co-delivery of drug/siRNA. Therefore, the methods we proposed are as follows: 1) Carbohydrate derivatives are linked to pillararene through host-guest assembling or covalent bond, respectively, which can be further used to fabricate the target vesicles. The carbohydrate-targeted intelligent cationic vesicles can be fabricated through the hydrophobic and hydrophilic interactions, where the carbohydrate derivatives or the responsive groups were used as hydrophilic parts and pillararenes were used as hydrophobic parts. The hydrophilicity can be controlled by the selective protection of hydroxyl groups of carbohydrate derivatives or modification of the responsive groups; 2) The carbohydrate-targeted intelligent cationic vesicles can be applied to codeliver drug/siRNA. The carbohydrate-targeted drugs enter cancer cells selectively, resulting from the interactions of carbohydrate and protein due to the higher content of galactose-type lectins in cancer cells. Moreover, the drugs release quickly in cancer cells by regulation of pH or GSH with the stimulation due to the differences of microenvironment between cancer cells and normal cells. As the results, the vesicles with the functions of the targeted selectivity and stimulate responsiveness will reduce the drug side effects on normal cells. At the same time, the vesicles with the function of co-delivery of drug/siRNA can deliver siRNA to conquer the drug resistance of cancer cells by knocking down drug resistance genes in cancer cells.

药物对正常细胞的副作用和癌细胞的耐药性是癌症化疗面临的两大难题。纳米药物载体以其可智能化等特点为解决此难题提供了一个新途径。但是，要同时解决这两大难题要求纳米载体不仅具有靶向选择性和刺激响应性，而且能够对药物和siRNA进行共运输。基于此，本申请提出：1）糖分子分别通过主客体组装和共价连接两种方式连接柱芳烃，以糖分子或响应性基团为亲水部分，柱芳烃为疏水部分，通过糖羟基的选择性保护或响应性基团的亲水性调节，构建糖靶向智能阳离子囊泡；2）运用制备的多功能囊泡进行药物/siRNA双负载，利用癌细胞表面半乳糖类凝集素含量高，通过糖和蛋白相互作用，实现糖靶向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和GSH调控来刺激响应促使药物在癌细胞中更快速的释放，从而降低药物对正常细胞的副作用；同时，运输的siRNA进入癌细胞后，通过沉默癌细胞的耐药性基因，从而克服癌细胞耐药性。

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。纳米药物载体作为一种纳米级微观范畴的亚微粒药物载体，以其微尺寸效应和可智能化，为解决这些难题提供了一个有效的新途径。但是，要同时解决这两大难题要求纳米载体不仅具有靶向选择性和刺激响应性，而且能够对药物和siRNA进行共运输。基于此，本研究通过构建糖靶向智能（阳离子）囊泡应用于抗癌药物/siRNA共运输来解决这一难题。具体研究分为：1）成功构建多功能糖纳米（阳离子）囊泡/纤维用于siRNA驱动的超分子自组装并用于小鼠体内药物/siRNA的双递送；2）基于大环主体分子柱芳烃，通过主客体识别作用合成双亲性糖分子制备糖纳米囊泡，分别构建了4种糖靶向刺激响应的纳米囊泡药物递送体系；3）基于大环主体分子柱芳烃，通过主客体识别作用制备糖基纳米载体，分别构建了两种糖靶向刺激响应的纳米(粒子)药物递送体系。. 运用上述制备的系列（七个）多功能纳米体系分别进行药物/siRNA（双）负载，利用癌细胞表面半乳糖/乳糖类凝集素含量高，通过糖和蛋白相互作用，实现糖靶向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和GSH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；同时，运输的siRNA进入癌细胞后，通过沉默癌细胞的耐药性基因，从而克服癌细胞耐药性。. 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。.