活体降解与聚集的支化大分子给药系统及其协同抗乳腺癌转移研究

Breast cancer metastasis is one of the biggest problems to women health. The current breast cancer treatments are mainly surgical treatment, chemotherapy and radiotherapy. Recently, clinical studies also showed that the molecularly targeted therapy resulted in high efficacy. However, the current chemotherapy, radiotherapy and molecularly targeted therapy are limited as the therapeutic agents are largely limited by extremely low tumor-targeting, resulting in low therapy index and high side-effects to healthy tissues. Recently, nanoscale drug delivery systems have been widely studied for cancer therapeutics and diagnosis, and the therapeutic index can be improved significantly, as the small molecular agents can be delivered to cancer tissues with high accumulation. In our previous studies, stimuli-responsive polymers-based nanoscale drug delivery vehicles have showed great potential as gene/drug/imaging probe delivery for cancer therapy and diagnosis. In this project, multifunctionlized and stimuli-response dendritic systems will be designed and prepared as nanoscale vehicles for synergistic anti-breast cancer metastasis by combination of chemotherapy, molecularly targeted therapy, radiotherapy and photothermal therapy. The carriers are N-(1,3-dihydroxypropan-2-yl) methacrylamide (DHPMA) and computed tomography (CT) imaging agents-based copolymers. Those dendritic polymeric drug delivery system with chemotherapeutics, molecular targeted therapeutic drugs and radiosensitizer and photosensitizer will show in vivo biodegradation,cross-linking and aggregation features, and therefore resulted in high penetration, significantly increased accumulation and retention in tumor. Those drug delivery systems will inhabit the breast cancer and abolish the tumors as well as suppress tumor metastasis. The contents of this project included three parts: 1) the design and preparation of environmental response and nanoscale dendritic copolymers; 2) the studies on the CT and MRI-imaging guided synergistic anti-breast cancer metastasis by combination of chemotherapy, molecularly targeted therapy, radiotherapy and photothermal therapy chemotherapy, molecularly targeted therapy, radiotherapy and photothermal therapy, and the relationship between the results and compositions of drug delivery systems, and the relative molecular mechanisms, 3) the studies on biocompatibility of the drug delivery systems. The studies will overcome some bottle-neck problems to preparation of multifunctional dendritic copolymers based nanoscale drug delivery systems with significant increased therapeutic efficacy and good biosafety for breast cancer metastasis. This targeted strategy will contribute to the development of polymeric nanoscale drug delivery systems entranced into clinical application for anti-breast cancer metastasis.

本项目针对高转移性乳腺癌的精准和协同治疗难题，立足我们在大分子给药系统研究的积累，立足国际前沿，以水溶性和生物相容性良好的CT分子探针和N-(1, 3-二羟基-2-丙基)甲基丙烯酰胺聚合物为载体，通过聚合和有机合成方法构建活体内“肿瘤组织内/肿瘤细胞外降解—高渗透性—快速入胞—肿瘤细胞内交联”的支化大分子靶向给药系统，实现对高转移性乳腺肿瘤的完全抑制甚至清除以及抑制其转移的目的。建立具备血液系统中稳定的，肿瘤高靶向和长期滞留的，同时偶联化疗药物、分子靶向药物、放疗增敏剂、光敏剂和分子探针的，活体内肿瘤特异刺激响应的支化大分子给药系统的构建方法；研究给药系统在CT和MRI成像指导下的精准协同治疗高转移性乳腺癌的原理和方法；揭示给药系统抑制肿瘤转移之间构效关系以及相关分子机制；获得具有我国自主知识产权、乳腺癌转移的支化大分子给药系统，为研发高效、安全、精准和协同治疗肿瘤转移的给药系统奠定基础。