硫化氢响应型小分子自组装纳米药物载体的构建及应用

Endogenous stimuli-responsive carriers can controllably release loaded molecules at the right sites and are usually used for tumor-specific drug delivery to improve therapeutic efficacy. These carriers are commonly composed of high molecular weight polymers, which are modified with responsive groups. However, the interaction between the polymer chains hinders the stimuli from approaching to the responsive groups, resulting in low sensitivity and inefficient drug release. To solve this problem, here we propose to construct the nanocarriers through the self-assembly of hydrogen sulfide (H2S) responsive three-legged small molecules, which are easy to synthesize and functionalize. The nanocarriers will release drug molecules at specific tumor tissues containing high concentration of endogenous H2S. The stimuli-responsive performance of the system is supposed to be high, because the responsive groups are the main part of the building blocks. For biomedical applications, the H2S-responsive drug nanocarriers and turn-on nanoprobes will be prepared by loading anticancer drugs and FRET fluorescent molecules, respectively. The therapeutic efficacy and imaging performance will be systematically evaluated in vitro and in vivo. The success of this original research would help investigate the mechanism of constructing smart nanocarriers via self-assembly of small molecules. The study would provide an innovative new strategy for developing highly efficient stimuli-responsive drug delivery systems.

内源性物质刺激响应型载体能够对负载物进行定点可控释放，常被用于构建肿瘤特异性药物控释体系，以提高癌症治疗效果。这类载体多由高分子聚合物自组装构建而成，高分子链间的相互作用阻碍了载体中的响应基团与刺激物质的高效接触，限制了载体响应性能和药物释放效率。针对这一问题，本项目拟利用特定肿瘤中硫化氢（H2S）含量偏高的特点，结合小分子易合成、易功能化的优点，设计H2S响应性三枝状小分子组装单元。因响应基团是小分子的主要组成部分，通过其自组装形成的简单纳米载体预期具有高效的刺激响应性能。进一步，本项目通过负载抗癌药物或具有FRET效应的荧光分子对，构建H2S响应型纳米载药体系和荧光探针，研究其对肿瘤的治疗效果和成像性能，综合评价这类纳米载体在肿瘤诊疗中的应用潜力。本项目的成功实施对深入研究小分子自组装构建智能纳米材料的机制具有重要意义，有望为构建简易高效的刺激响应型纳米载体提供新思路。

硫化氢是一种气体信号分子，调节多个生理活动，包括血管生成，营养运输和代谢，细胞增殖等。目前，已发现在肝癌、前列腺癌和结直肠癌等病灶中，硫化氢大量蓄积，调控肿瘤生长进程。另外，硫化氢是化学活泼的分子，能够参与氧化/还原反应，这也为设计新型探针和智能材料提供了基础。硫化氢可被用作刺激-响应药物递送的“开关”，激活硫化氢响应材料，从而控制药物的释放，提高生物相容性和疗效。在此项目中，申请人聚焦于小分子组装技术，通过设计三枝状小分子作为结构单元，开发制备了可高效、灵敏响应硫化氢的纳米药物载体。该三枝状分子，三叠氮基苄基-三乙基氨基胺，通过其自组装可高效制备硫化氢响应型小分子纳米载体ATNPs。其中的叠氮基苄基可与硫化氢反应，并通过分子内重排解离，导致三枝状分子解体和纳米药物载体的崩解，从而释放包载的客体分子。包裹化疗药物阿霉素 (DOX) 所形成的载阿霉素纳米载体 (DOX/ATNPs)，在硫化氢触发下可以高效释放包载的DOX药物。在荷结肠瘤小鼠体内注射 DOX/ATNPs 后，肿瘤组织显示出较高的药物聚集，并有效的抑制了肿瘤生长，未见明显毒副作用。总的来说，本项目发展了一种新的硫化氢响应药物递送策略，能够将药物精确递送至富含硫化氢的病灶，可用于结肠癌等疾病的诊断和治疗。