靶点智能释放多重靶向HPMA共聚物抗癌药物的研究

Malignant tumor is one of the major causes of human death. Targeted therapy of malignant tumors has become a focus of research today due to the serious toxic to non-target of the traditional chemotherapy drugs. Molecular targeted therapy has the characteristics of high selectivity and long-term medication. Possibly, the cancer could be treated as a chronic disease due to the targeted chemotherapy. The research and development of active targeted (ligand-receptor specific recognition, such as: antibody conjugated anti-cancer drugs) and polymer passive targeted (EPR effect: Enhance Permeability and Retention, such as HPMA conjugated anti-cancer drugs) anti-cancer drugs have made encouraging progress. Unfortunately, the EPR effect is of reduced importance in smaller tumors. Active targeting of specific tumor cell antigens through antibody molecules are also being used in drug targeted delivery. But, antibody targeting of cancer cells still faces obstacles such as limited antigen accessibility, and tumor dependent antigenic heterogeneity. In this project, the active ligands (such as galactose and folic acid), anti-cancer drugs (such as 5-fluorouracil and doxorubicin) containing intelligent keys (such as hydrazone and -GFLG- tetra peptide) will be conjugated with HPMA copolymer to form the passive/active multiple targeted and intelligent release anti-cancer drugs using polymer synthesis design, improved precipitation polymerization and amino acid monomer synthesis technology. From the level of molecular recognition/binding, clarify targeting/treatment mechanism, and provide a theoretical basis for the treatment of tumors.

恶性肿瘤是导致人类死亡的主要原因之一。鉴于传统化疗的药物在非靶区毒副作用太大，恶性肿瘤的靶向治疗成为了当今研究的重点。分子靶向治疗具有高选择性，可长期用药，从而有可能使恶性肿瘤转化为"慢性病"治疗。以单克隆抗体等为主动靶向配体的主动靶向抗癌药物（配体-受体特异性识别）和高分子被动靶向抗癌药物（通过EPR效应累积）的研制开发都取得了可喜的进展。但是，对于小体积的恶性肿瘤，EPR效应有限；而单克隆抗体等又存在着抗原异质性等障碍。本项目利用高分子合成设计，拟采用改进的沉淀聚合方法和氨基酸单体化合成技术，把传统抗癌药物（比如阿霉素、5-氟尿嘧啶等）通过智能释放键（比如腙键、-GFLG-四肽键等）连接到被动靶向载体HPMA共聚物（EPR效应）上，再键接主动靶向配体（比如叶酸、半乳糖等），制成多重靶向智能化释放联合治疗的抗癌药物。从分子识别/结合的角度，阐明靶向/治疗机制，为肿瘤的治疗提供理论依据。

恶性肿瘤是导致人类死亡的主要原因之一。鉴于传统化疗的药物在非靶区毒副作用太大，恶性肿瘤的靶向治疗成为了当今研究的重点。分子靶向治疗具有高选择性，可长期用药，从而有可能使恶性肿瘤转化为“慢性病”治疗。以单克隆抗体等为主动靶向配体的主动靶向抗癌药物（配体-受体特异性识别）和高分子被动靶向抗癌药物（通过EPR效应累积）的研制开发都取得了可喜的进展。但是，对于小体积的恶性肿瘤，EPR效应有限；而单克隆抗体等又存在着抗原异质性等障碍。本项目利用高分子合成设计，拟采用改进的沉淀聚合方法和氨基酸单体化合成技术，把传统抗癌药物（比如阿霉素、5-氟尿嘧啶等）通过智能释放键（比如腙键、-GFLG-四肽键等）连接到被动靶向载体HPMA共聚物（EPR效应）上，再键接主动靶向配体（比如叶酸、半乳糖等），制成多重靶向智能化释放联合治疗的抗癌药物。从分子识别/结合的角度，阐明靶向/治疗机制，为肿瘤的治疗提供理论依据。