肿瘤微环境响应逐级靶向型光控释金属有机框架纳米药物的构建及生物医学应用

Although nano-drug carrier could effectively improve the drug delivery efficiency, it still could not meet the requirement for tumor targeted precision therapy. In this project, the hierarchical targeted porphyrinic metal-organic framework nano-drug will be fabricated with tumor acidic microenvironment and photo responsiveness. By targeting delivery and accurate drug controlled release, this nano-drug would achieve the precise tumor combination therapy of photodynamic therapy and chemotherapy. To prepare this dual-responsive and hierarchical targeted nano-drug, doxorubicin (DOX) loaded porphyrinic nanoscale metal-organic framework (NMOF) will be modified with the multifunctional peptide of integrating acidic microenvironment activation, reactive oxygen species (ROS) sensitivity, cell penetration and nuclear-targeted function. Through adjusting the peptide sequence, the proportion of peptide modification, the size of NMOF and the drug loading rate, the optical nano-drug will be selected for biomedical application. In vitro experiments will be carried out to evaluate the charge reversal ability of the nano-drug in acidic microenvironment and the photo-controlled drug release ability. Additionally, the hierarchical targeted ability and combination therapy effect of the nano-drug would be evaluated both in vitro and in vivo. The research of this topic will provide more ideas for developing a novel drug delivery system for tumor precision therapy.

纳米药物载体可以有效地提高药物传递效率，但仍不能满足肿瘤靶向精准治疗的需求。本项目拟构建具有肿瘤微酸环境和光照双重响应性的肿瘤逐级靶向型卟啉类金属有机框架纳米药物，通过抗肿瘤药物的靶向传递和精确控释实现肿瘤光动力学治疗与化疗的精准联合治疗。本项目将首先构建具有可被肿瘤微酸环境激活、活性氧敏感、细胞穿膜功能和细胞核靶向功能的多肽，再以此修饰包载了化疗药物阿霉素（DOX）的卟啉类纳米金属有机框架（NMOF），制备得到该双重响应逐级靶向纳米药物。通过调控多肽序列、多肽修饰比例、NMOF尺寸及载药量等因素，筛选出性能优异的纳米药物用于生物医学研究。通过体外实验探究该纳米药物载体在微酸环境下的电荷反转能力及光响应药物控释能力，再通过细胞实验和动物实验进一步考察该纳米药物的肿瘤逐级靶向性能和联合治疗效果。本课题的实施将为开发新型的肿瘤精准治疗系统提供更多的思路。

癌症严重威胁人类生命健康，但传统抗种瘤药物普遍存在水溶性差、稳定性差、缺乏靶向性等问题，且肿瘤抑制性微环境也会降低药物的治疗效果。基于此，本项目设计并制备了一系列适应肿瘤微环境的靶向纳米药物，提高药物的靶向递送效率和生物利用率，增强药物抗肿瘤效果的同时降低其毒副作用。利用卟啉类金属有机框架包载化疗药物，并在其表面进行靶向修饰，增强药物在肿瘤部位的靶向聚集和肿瘤细胞的选择性摄取，提高药物的化疗与光动力学治疗效率。为进一步提高抗肿瘤药物在其作用位点的靶向递送效率，本项目利用双靶向嵌合肽修饰光敏剂制备靶向纳米药物，将光敏剂靶向递送至肿瘤亚细胞结构，通过原位产生活性氧（ROS）特异性破坏肿瘤细胞膜、线粒体、细胞核等，提高肿瘤光动力学治疗效果。鉴于传统载体辅助药物递送系统普遍存在载药量低、制备过程复杂、载体降解与代谢等问题，本项目利用抗肿瘤药物分子间相互作用力自组装制备了一系列自传递纳米药物，最大限度提高药物含量（接近100%），同时避免载体带来的系统毒性与免疫原性等，实现药物的自传递与靶向治疗。此外，通过筛选具有不同结构与功能的药物构建自传递体系，可改善肿瘤乏氧、破坏肿瘤ROS防御系统、逆转肿瘤免疫抑制微环境等，显著提高药物对肿瘤的生长及转移抑制效果，并大大降低其毒副作用。本项目已完成预定研究目标，为肿瘤靶向纳米平台的构建及精准个性化治疗提供了新的思路和见解。在本项目资助下，本项目研究成员以一作或通讯作者身份发表学术论文12篇，培养硕士研究生1名。