具有肿瘤微环境选择性调控能力的纳米药物的制备与机理研究

Tumorigenesis and metastasis are closely related to the tumor microenvironment (TME) of cancer cells which plays important roles in the enhancement of drug resistance of tumor cells and the maintenance of cancer stem cell niche. Under the circumstances of drug stimulation, a variety of cell types in the TME have been proved to assist the maintenance or re-modeling of the TME and to promote the progress, invasiveness and metastasis of the tumor cells through autocrine and paracrine secretion. Therefore, the regulation of TME is essential for the efficient treatment of cancer. The key of TME regulation lies in the selective inhibition of target cells in order to avoid the damage of non-target cells and the emergence of drug resistance and metastasis of tumor cells. To this end, based on the different types and contents of endogenous hydrolase in different cells in the TME, we proposed to design nanomedicines with preferential tumor accumulation and penetration, to overcome multidrug resistance and to selectively act on the target cells in the complex TME. With the in-depth understanding of the mechanism of the selectivity and the influence on the intracellular communication in complex TME, it is expected that the selective regulation of the TME and the effective inhibition of tumor growth and metastasis could be achieved by the co-administration of nanomedicines with different selectivity. Through the successful implementation of this project, we hope to provide some effective drugs and new thoughts for the anticancer therapeutic strategies based on TME regulation.

肿瘤细胞所处微环境与肿瘤的发生和转移有着密切联系，对肿瘤细胞耐药性提升和肿瘤干细胞巢的维持也具有重要作用。在药物刺激下，肿瘤微环境中多种细胞可以通过自分泌和旁分泌维持或重塑肿瘤微环境并促进肿瘤的发展、侵袭和转移。因此肿瘤微环境调控对于肿瘤的治疗而言具有重要意义。调控的关键在于选择性抑制目标细胞以防止非目标细胞的损伤诱导肿瘤细胞的耐药性和转移的产生。为此，基于肿瘤微环境中不同细胞间内源性水解酶种类和含量差异,本项目提出制备具有优良的肿瘤富集与穿透能力、抗多药耐药能力以及复杂微环境中的细胞选择能力的纳米药物，系统地研究上述纳米药物在复杂的肿瘤微环境中对目标细胞选择性作用的机理及其对细胞间通讯的影响。在此基础上利用具有不同选择性的纳米药物的协同给药实现对肿瘤微环境的选择性调控以及对肿瘤的生长和转移的有效抑制，为基于肿瘤微环境调控的肿瘤治疗提供有效药物及新的思路。

肿瘤细胞所处微环境与肿瘤的发生和转移有着密切联系，对肿瘤细胞耐药性提升和肿瘤干细胞巢的维持也具有重要作用。在药物刺激下，肿瘤微环境中多种细胞可以通过自分泌和旁分泌维持或重塑肿瘤微环境并促进肿瘤的发展、侵袭和转移。因此肿瘤微环境调控对于肿瘤的治疗而言具有重要意义。调控的关键在于选择性抑制目标细胞以防止非目标细胞的损伤诱导肿瘤细胞的耐药性和转移的产生。为此，基于肿瘤微环境中不同细胞间内源性水解酶种类和含量差异,本项目设计并合成了基于多种化疗药物的化疗前药分子，根据不同前药分子的化学键敏感性，可实现对肿瘤组织中不同细胞内环境的选择性识别和杀伤。基于前药分子本身高载药量的优势，进一步结合具有增强的肿瘤富集和穿透能力的聚合物载体，成功实现对肿瘤组织中目标细胞的选择性清除、肿瘤细胞多药耐药性克服、肿瘤干细胞靶向以及耐药肿瘤的个性化精准组合治疗等新型功能。在此基础上实现对多种耐药肿瘤模型生长的高效抑制，针对肿瘤微环境调控的机理研究为临床肿瘤化疗的用药选择提供了一定的指导和参考。