线粒体靶向的丝胶纳米药物载体同步递送吲哚菁绿/顺铂逆转肿瘤顺铂耐药性的研究

Development of resistance is a major obstacle in platinum-based chemotherapy for successful cancer treatment. Among the multifactorial mechanisms, increasing cisplatin export and inactivation, as well as the abnormal alterations in apoptotic pathways are the most important mechanisms. It is of great clinical significance to design strategies to circumvent key mechanism of cisplatin resistance for overcoming the drug resistance. Recent studies suggest that photodynamic therapy (PDT) is an effective treatment for reversing cancer drug resistance and improving the sensitivity of cancer cells to chemotherapeautic drugs, according to the capable of inhibiting drug efflux transporter proteins -mediated efflux of anticancer drugs, depletion of levels of GSH, and activating pro-apoptotic pathways. However, combined photosensitizer with chemotherapeautic drugs simply could not achieve desired treatment effects, owing to the poor efficiency of photosensitizer selective delivery to tumor site, the low efficiency of activating the photosensitizers at the target site, as well as the difference of pharmacokinetic characteristics with each drug. Base on the multifunctional sericin nanoparticles for tumor targeting and pH-responsive subcellular delivery of cancer chemotherapy drugs, as well as the sericin-coated mesoporous silica nanoparticles for reversal of cancer multidrug resistance in our previous study. We will try to build a mitochondria-targeting sericin nanoparticle system for co-delivery indocyanine green (ICG) and cisplatin (CDDP) synchronously. We expect the designed drug delivery system can specifically target to mitochondria of tumor cells to improve the efficacy of PDT, and the synergistic effect in combination with CDDP to overcome the cisplatin resistance. Moreover, we will further explore the relevant mechanisms of the combination therapy based on the co-delivery of ICG and CDDP through the mitochondria-targeted sericin nanoparticles. This project aims at developing a rationale for future clinical investigations of the therapeutic efficacy of CDDP in combination with PDT to overcome the cisplatin resistance.

肿瘤耐药是顺铂化疗失败的主要原因，肿瘤细胞内药物积累减少与失活，以及细胞凋亡水平的异常改变是顺铂耐药的关键机制。研究表明光动力治疗(PDT)能阻断上述机制用于逆转肿瘤耐药性。但光敏剂（吲哚菁绿）的肿瘤组织递送效率低，体内激活效率有限，以及不同药物体内药代动力学的差异，常规药物联用难以达到理想治疗效果。本课题组前期研究发现丝胶纳米载体可有效递送化疗药物至肿瘤并抑制肿瘤多药耐药性，在此基础上，为进一步增加药物在肿瘤的递送效率，提高治疗效果，本项目拟联合PDT治疗优势，构建肿瘤细胞线粒体靶向，同步递送吲哚菁绿与顺铂的丝胶纳米给药系统，并评价其对顺铂耐药肿瘤的治疗效果，以期实现精准的PDT效应联合顺铂化疗逆转肿瘤顺铂耐药，为临床耐药性肿瘤的治疗提供新思路。

癌症持续的高发病率与高致死率，已严重威胁人类健康。肿瘤的异质性,耐药性,以及药物的系统性毒性，使得传统的单一治疗方式，如化疗等，难以有效清除肿瘤细胞，最终导致肿瘤的复发。多模式的联合治疗已成为抗肿瘤的有效手段。如何实现肿瘤组织精准、高效的多模式治疗，是达到最佳的协同治疗效果的关键。本项目利用生物药剂学技术以及纳米材料学方法，成功设计并制备了多种新型药物递送系统，用于肿瘤的多模式联合治疗研究，并取得了一系列重要研究成果，为临床恶性肿瘤治疗提供了新思路。此外，本项目设计并制备了基于活性氧放大的纳米反应器用于耐药性细菌感染的治疗，有望为临床耐药性细菌感染治疗提供潜在药物。