谷氨酰胺驱动大分子药物自传递系统触发溶酶体途径的级联反应式抗非小细胞肺癌的作用与机制研究

Much research has revealed that lysosome is a signal hub for the three major pathways of cell death (apoptosis, autophagy, and necrosis). The lysosome as a therapeutic target for macromolecules has the crucial advantages due to that the cellular uptake of macromolecules in the first step is the endosomal-lysosomal pathway. However, all of the eukaryotic cells contain lysosome organelles. So how to selectively target lysosomes of target cells is the primary problem that needs solving. In our previous study, we prepared glutamine-rich macromolecules. It was confirmed both in vitro and in vivo studies that these macromolecules effectively accumulated in non-small cell lung cancer cells by the glutamine-driven effect. This proposal is based on our previous studies to design a drug self-delivery system composed of allyl ether-glutamine macromolecules. The allyl ether and glutamine groups play the roles of lysosomal dysfunction and selective delivery, respectively. The self-drug delivery system will be optimized to successfully achieve the two-in-one system for the tumor lysosomal drug delivery and treatment of glutamine-dependent non-small cell lung cancer. That the mechanism of the drug self-delivery system triggers the "lysosomal-mitochondrial" pathway and the “autophagy-lysosomal" pathway for activation cascades in cancer cell death will be especially explored. Results of these macromolecular drug self-delivery system studies will offer a new delivery target and new treatment strategy for non-small cell lung cancer.

多量研究揭示溶酶体是细胞死亡（凋亡、自噬和坏死）三条主要通路的枢纽站。而大分子进入细胞第一步是内吞溶酶体途径，因此其以溶酶体为靶点具有天然优势。然而溶酶体是真核细胞皆有细胞器，如何选择性作用靶细胞溶酶体是需首要解决问题。我们前期研究筛选出谷氨酰胺大分子骨架，利用特定类型肿瘤谷氨酰胺成瘾的驱动作用，在体内外已证实该大分子富集于非小细胞肺癌。本申请在前期研究基础上，设计烯丙基醚-谷氨酰胺大分子药物自传递系统（drug self-delivery system），通过对干扰溶酶体功能的效应基团烯丙基醚和选择性递送基团谷氨酰胺的优化，实现以肿瘤溶酶体为靶点的药物递送与治疗二合一新型体系治疗谷氨酰胺依赖型非小细胞肺癌。探索该药物自传递系统触发溶酶体通路诱导“溶酶体-线粒体”途径和“溶酶体-自噬”途径的级联反应式肿瘤细胞死亡的作用机制，为突破抗肿瘤药物递送治疗效率不高的难题提供新的递送靶点和治疗策略。

溶酶体是细胞内信号转导和物质代谢的中心，LDL来源的胆固醇在溶酶体中的加工与转运是决定细胞整体脂质代谢状态的关键。研究发现溶酶体也是肿瘤细胞死亡（包括凋亡、自噬和坏死）多通路枢纽站。本研究依据特定肺癌谷氨酰胺成瘾的代谢特征，成功构建烯丙基醚肿瘤条件必需氨基酸大分子药物自传递系统自传递药物HAPAC。其具有一定的肿瘤选择性，对正常细胞及体内的正常组织无明显毒性作用，能够特异性的作用于肿瘤细胞溶酶体，使其发生空泡化，溶酶体功能紊乱而破坏肿瘤细胞正常生理过程，在细胞水平和原位肺癌动物模型上证实HAPAC可产生高效杀伤肿瘤的作用。进一步研究其抗肿瘤机制表明，HAPAC能够选择性抑制肿瘤细胞溶酶体酸化，干扰溶酶体中胆固醇代谢和转运相关蛋白的表达，降低溶酶体胆固醇含量，并通过胆固醇介导的通路抑制mTOR信号通路活化，诱导肿瘤细胞凋亡，达到抗肿瘤目的。HAPAC通过靶向溶酶体胆固醇代谢过程选择性杀伤肿瘤细胞，并且简化了药物的递送路径，为肿瘤治疗和药物递送提供了新思路。