基于α-半乳糖/乳糖衍生物的阳离子囊泡构建靶向-双响应药物/siRNA递送体系

Rational design and construction of smart carriers for effectively targeted drug/siRNA co-delivery in response to the unique features of extracellular and intracellular micro-environment of cancer cells is highly desired. Such carriers would allow for optimal clinical outcomes in cancer chemotherapy by simultaneously eliminating side effects and multidrug resistance. Galectins are overexpressed on the surface of hepatocarcinoma cells, thus we propose to fabricate cationic glycovesicles with pH-GSH dual responsiveness via self-assembly of an α-galactose/lactose residue-capped pillar[5]arene amphiphilic molecule. This will be synthesized through the formation of boric ester bonds between 1,2-diols on carbohydrate ring in ferrocene-modified α-galactose/lactose derivatives and benzene boric acid residuals in phenylboronic acid-modified pillar[5]arene molecules. The cationic vesicles are expected to be able to co-deliver drug/siRNA and display targeting ability towards HepG2 cells via galactose-galectin specific interaction. Furthermore, the release of drug/siRNA will be accelerated in cancer cells through the dual responsiveness to pH and GSH resulting from the boronic ester bonds and ferrocenium units, respectively. As a result, the cationic glycovesicles will help reduce drug side effects and overcome multidrug resistance. The conduct of this project will provide a new approach in the design towards a dual-responsive nano-carrier for efficient and targeted drug/siRNA co-delivery.

针对肿瘤细胞内外环境的特异性，设计构建高效的靶向智能纳米递送体系，对药物/siRNA进行双负载，是克服毒副作用和癌细胞的耐药性，获得肿瘤最佳临床治疗效果的重要策略。基于肝癌细胞表面半乳糖凝集素过量表达的特性，本研究提出在合成二茂铁基团修饰的半乳糖/乳糖衍生物和硼酸化的柱[5]芳烃分子的基础上，利用糖结构单元上1,2-二羟基与柱芳烃上的硼酸形成硼酯键，得到糖基修饰的柱[5]芳烃双亲性分子；该分子自组装形成的阳离子囊泡可用于对药物/siRNA的双负载。囊泡表面的糖冠与半乳糖凝集素之间的特异性识别作用赋予该体系对HepG2细胞的靶向选择性，硼酯键和二茂铁离子分别对癌细胞内部较低的pH和较高浓度GSH响应，诱发药物和siRNA在癌细胞内的快速释放，最终达到在降低药物副作用的同时，克服癌细胞的耐药性的目的。该项目的实施将为高效靶向智能纳米药物/siRNA双负载递药体系的设计提供一个新思路。

癌症是危害人类健康和生命的重大疾病之一。针对肿瘤细胞内外环境的特异性，设计构建高效的靶向智能纳米递送体系，通过化疗、光动、光热、化学动力学疗法或气体疗法等多重模式治疗，是克服毒副作用和癌细胞的耐药性，获得肿瘤最佳临床治疗效果的重要策略。本研究基于肝癌细胞表面半乳糖凝集素过量表达的特性，构建糖靶向多功能纳米负载体系应用于癌症的治疗。具体内容包括：1）通过主客体识别作用合成双亲性糖分子构建系列糖靶向刺激响应的纳米递送体系；2）通过Fe3O4纳米粒子（MNPs）或氧化铈纳米棒（CeONRs）为核，构建刺激响应的纳米载药体系用于协同和靶向药物递送；3）通过构建糖靶向多功能化纳米递送体系，以实现光动、光热、化学动力学疗法或气体疗法等的多重模式治疗。.本项目的完成，在解决癌症治疗中药物毒副作用和癌细胞的耐药性这两大难题的研究方面取得了系列创新性的研究成果。对癌症治疗具有重大意义。