基于环糊精主客体识别载药量精准可控的多重刺激响应性纳米载体的研究

Tumor microenvironments-responsive smart materials attract a lot of attentions in cancer therapy, due to their impressive capability of releasing the drug on demand in response to specific biological stimuli in tumor microenvironments (such as pH, redox and enzyme, etc.). Motivated by this rationale, we proposed a novel microenvironments-responsive supramolecular nanocarrier that could respond to pH, intracellular GSH and ROS to release the carried drug. Firstly, a well-defined triblock copolymers mPEG-PDns-PCD was synthetized. Then, ferrocene (Fc) modified camptothecin (CPT) was anchored onto the triblock copolymers via the host-guest interactions between Fc and β-cyclodextrin (β-CD) to obtain a supramolecular nanocarrier system (mPEG-PDns-PCD/Fc-CPT), which could further self-assemble into stable micelles in aqueous solution. Due to the use of pH-responsive and inherent fluorescence characteristics of Dns groups, hydrogen peroxide-cleavable CD/Fc connection and GSH-responsive disulfide bond, these multi stimuli-responsive feature enables the fine-tuning of the release behaviors of encapsulated molecules.. Various studies such as the structural characterization, fluorescence properties, encapsulation studies, drug releasing behaviors, cell viability studies, cellular entry mechanism and measurement of cytotoxicity in vitro and in vivo will be performed on these polymeric micelles. It is anticipated that this supramolecular drug delivery system may serve as a promising alternative to the drug delivery system.

肿瘤微环境刺激响应性智能材料可以在肿瘤部位的特殊生物环境刺激下实现药物的按需释放，引起了研究者的广泛兴趣。本项目构筑一类pH、GSH以及ROS三重肿瘤微环境开关响应的超分子药物载体，实现化疗药的肿瘤靶向释放。项目从聚乙二醇-b-聚丹磺酰-b-聚环糊精（mPEG-PDns-PCD）三嵌段共聚物的合成出发，利用β-环糊精与二茂铁的主客体包合作用，将内含双硫键的二茂铁修饰的喜树碱（Fc-CPT）分子构筑到共聚物上，最终得到可在水中自组装形成纳米胶束的超分子药物载体mPEG-PDns-PCD/Fc-CPT。结合丹磺酰的pH响应性及荧光特性，二茂铁与环糊精的主-客体包合过氧化氢响应性，以及双硫键的GSH响应性，实现纳米药物载体的多重刺激响应性可调控释放。通过对载体结构、荧光效应、药物的包载与释放、细胞毒性评价、细胞内吞过程以及体内外活性的研究，验证并优化完成一种具有应用前景的超分子载药系统的开发。

肿瘤微环境刺激响应性智能材料可以在肿瘤部位的特殊生物环境刺激下实现药物的按需释放，引起了研究者的广泛兴趣。在国家自然基金的支持下，我们主要针对肿瘤细胞内存在的高浓度谷胱甘肽（GSH），高浓度的活性氧（ROS）及酸性等微环境特性，利用环糊精修饰的主体聚合物分子和金刚烷修饰的抗癌药物喜树碱（ADA-CPT），通过环糊精与金刚烷的特异性主客体识别作用，简单高效地构筑了一类多重肿瘤微环境刺激响应性的纳米递药体系。当纳米药物载体通过肿瘤组织的 EPR 作用富集在肿瘤组织中，并进一步被肿瘤细胞内吞后，肿瘤细胞内的特异性微环境将使得主客体作用瓦解，并进一步释放出抗癌药物，实现对肿瘤细胞的杀灭作用。通过利用肿瘤细胞内的酸性环境及高浓度 氧化还原环境，这类微环境刺激响应性的纳米递药体系还可以实现抗癌药物的分步按需释放，提供更为灵巧的控制释放性能。在这三年的资助期间，我们围绕肿瘤微环境的特性，同时开发了一系列的刺激响应性纳米递药体系，包括刺激响应性多糖递药体系，刺激响应性天然药物纳米递药体系，取得了一系列不错的成果，为肿瘤的精准治疗提供了新的可能。