可用近红外光控制药物释放的纳米递送系统及其抗肿瘤治疗研究

The insufficient intracellular drug release is one of most leading reason for the reduced efficacy of nanocarriers-assisted chemotherapy. It has been demonstrated that the responsive vectors based on intracellular acidic or redox environment can improve the release rate of the drug through regulating their physical or chemical properties, leading to more pronounced anti-cancer effect. As exogenous stimuli, near-infrared light is believed as more stable and easily to control. The design of nanocarriers in response to near-infrared light to accelerate drug release will further enhance the therapeutic efficacy. The project intends to design a type of delivery system containing the photosensitizer and a singlet oxygen-labile bond. After entering the tumor cells, the photosensitizer molecules would produce singlet oxygen under irradiation of near-infrared light on the tumor tissues. Then, photosensitizer molecules would dissociate from polymer backbone and the hydrophobic block would transit to the hydrophilic block, accelerating degradation of the nanoparticle and drug release. This project will focus on synthesis and preparation of the delivery system, establishing the characterization method for polymer degradation and exploring the relationship between material composition/light irradation and delivery efficacy. The strategy would provide valuable information for the generation of novel light-stimulated nanocarriers in cancer therapy.

胞内药物释放不足是纳米载体疗效降低的重要原因之一。已有研究显示，基于胞内酸性或氧化还原环境的响应性载体可以通过调控颗粒性质提高药物释放速度，有效增强药物抗肿瘤疗效。作为外界刺激源，近红外激光具有较好的穿透性、可控性和选择性，依据近红外光构建响应性药物释放载体有助于提升药物输送效果，推动响应性载体研究发展。本项目拟设计一种由690 nm激光控制药物释放的载体系统，在进入肿瘤细胞后，精准照射肿瘤组织的激光将刺激光敏剂分子产生单线态氧，使光敏剂从聚合物侧基脱落，将疏水嵌段转变为亲水嵌段，解离纳米颗粒进而加速药物释放，实现对肿瘤细胞可控的高强度、特异性杀伤。在合成制备预期载体体系基础上，项目将建立对聚合物降解的表征分析手段，重点研究不同近红外光条件对疗效的影响，揭示可用近红外光控制药物释放的载体在肿瘤治疗中的优势和重要意义，为载体设计提供新的思路。

近年来，基于肿瘤微环境响应的纳米药物载体在提高抗癌药物疗效方面取得了很好的进展。与内源性刺激源（如pH、过表达酶或氧化还原条件）相比，近红外激光作为外部刺激源，其具有穿透性强、稳定性好、可控性高和可重复性等特点，基于激光调控纳米药物载体的性能具备较好应用潜力。在本项目中，我们基于活性氧响应的硫缩酮醇键，构建了多种高分子材料，这些材料的共性是可被近红外光激活的光动力学反应过程生成的活性氧降解，从而改变纳米药物载体的物理结构，促使包载的药物快速释放。我们在优化高分子材料的合成方法基础上，建立分析方法，重点探讨高分子材料及相应药物载体在近红外光刺激后的化学组分和物理结构变化，对随之产生的药物“爆释”行为做定性定量分析。进而，在细胞和动物水平，我们采取多种方法，对这些药物输送系统的疗效进行验证。研究结果表明，近红外光触发的光动力学反应及细胞内释放的化疗药物，可对肿瘤细胞进行光动力-化疗联合治疗，综合改善药物疗效，增强肿瘤生长抑制效果。由于近红外激光属于外加刺激源，其可精准照射于肿瘤部位，使纳米药物载体的效果更加可控，具有高度可重复性。相关研究成果发表SCI论文5篇，包括Chemistry of Materials、Biomaterials等本领域重要期刊。本项目的研究成果揭示了近红外光控制药物释放的纳米载体在肿瘤治疗中的优势和重要意义，为高分子纳米药物载体设计提供了新的思路。