中文摘要
恶性肿瘤的转移以及肿瘤治疗中多次给药造成的血管刺激性等问题严重影响肿瘤的治疗效果和病人的生存质量。本项目在前期对SPDC分子设计、制备的研究基础上,寻找赋予其同时具有自组装和抑制肿瘤转移的多功能策略,发挥对肿瘤“围而攻之”的治疗目的,增强治疗效果;此外,在对SPDC自组装机制的研究基础上,寻找调控其自组装行为的策略,掌控其自组装构建不同形貌纳米结构的关键要素,实现SFPDC体外自组装构建纳米粒用于静脉给药,进入肿瘤组织后,在肿瘤pH及酶等微环境中响应性地自组装形成纤维结构驻留于肿瘤组织实现长效的目的,减少给药次数,提高病人的生存质量;在此基础上,开展由FSPDC构筑纳米药物的体内研究,阐明其在局部和全身的运转规律、瘤内分布行为、长效机制、以及代谢转运机制,初步评价其抑制肿瘤转移和杀灭肿瘤细胞的效果,探讨其抗肿瘤机制,为纳米药物的构建提供全新的材料,为肿瘤的治疗提供有益的借鉴。
英文摘要
Metastasis of malignant tumor and the vascular irritation caused by repeated administration affect the treatment of the tumor and the patient's quality of life seriously. In this project, a strategy called “besieging and attacking” will be taken to develop a cancer combination therapy. The strategy based on functional self-assembly of peptide drug conjugates (FSPDC) is designed to kill tumor cells while inhibiting the invasion and metastasis of malignant neoplasms by chelating the function of Matrix metalloproteinases 2 and 9 to enhance the anti-tumor treatment effect. Based on the previous research on self-assembly of peptide drug conjugates (SPDC) mechanism, much work will be done to regulate the self-assembly behavior of FSPDC. The strategy will modify the assembly morphology of FSPDC: firstly, multifunctional nanoparticles will be built based on the self-assemble of FSPDC for intravenous administration, and then upon tumor targeting, the nanoparticles will re-assemble to form a fibrous structure in the tumor microenvironment responsibly. Ultimately, the fibrous will stay in the tumor tissue to play a long-term role, achieving the purpose of reducing the times of injections improving the life of patients. The anti-tumor effect of FSPDC, regularity of its operation and distribution in the tumor and the whole body and the long-term mechanism will be investigated to reveal the transportation and the molecular cytology mechanism of the FSPDC at animal, tissue, cellular and molecular levels. Key factors that determine the targeting efficiency and efficacy will be identified, which will provide a new direction for the treatment of malignant tumors.
