靶向Legumain激活的槲皮素递药系统调控乳酸代谢及肿瘤微环境的研究

Large amounts of lactic acid were metabolized in tumor cells through the Warburg effect even though under oxygen-rich conditions. Lactic acid was an integral part of creating a tumor microenvironment. Lactic acid regulates tumor metastasis, invasion and promotion of tumor growth through a variety of pathways. In addition, it also promoted the exchange of signals between tumor cells and immune cells, especially the polarization of anti-inflammatory phenotypes of tumor-associated macrophages and the secretion of pro-inflammatory phenotypic cytokines. Quercetin (QU), a natural flavonoid, was a lactate inhibitor that significantly inhibited the activity of lactate dehydrogenase and monocarboxylate transporters, thus reducing lactate production and inhibiting lactate secretion. Combination of QU with doxorubicin (DOX) had a synergistic effect and significantly enhancing antitumor effects. This project combined with nanotechnology, using the acid-activated liposome modified by Legumain-specific substrate, Z-AAN-NNG-GGC and the penetrating peptide AGYLLGHINLHHLAHL(Aib)HHILC as the vectors. A combination of QU and DOX target drug delivery system was established, and a comprehensive evaluation was made for further clarifying mechanism of regulating tumor metabolic pathway of QU. The results can provide a reliable basis for the further research and development of QU, which have important theoretical significance and application value.

肿瘤细胞通过Warburg效应，在氧气充足的条件下也会代谢生成大量的乳酸。乳酸是缔造肿瘤微环境不可或缺的环节。乳酸通过多种通路调节肿瘤的转移，侵袭，促进肿瘤生长。此外，还可促进肿瘤细胞与免疫细胞的信号交流，尤其是肿瘤相关巨噬细胞向抗炎表型极化，抑制促炎表型细胞因子的分泌。槲皮素(QU)是天然的黄酮类乳酸抑制剂，能显著抑制乳酸脱氢酶和单羧酸转运体的活性，减少乳酸生成及抑制乳酸分泌。将QU与阿霉素(DOX)联用，具有协同效应，显著增强抗肿瘤作用。本项目结合纳米技术，采用Legumain特异性底物Z-AAN-NNG-GGC与穿膜肽AGYLLGHINLHHLAHL(Aib)HHIL-Cys联接修饰的酸激活脂质体作为载体材料，建立QU与DOX联合靶向给药系统，并对其进行全面的评价。进一步阐明其调节肿瘤代谢通路的作用机制。研究结果可为QU的深入研究和新药开发提供可靠依据，具有重要的理论意义和应用价值。

乳酸是肿瘤组织最主要的代谢产物之一，有利于形成并保持微酸性和免疫抑制性肿瘤微环境的，促进乳腺癌的进展。槲皮素是一种天然黄酮类化合物，具有潜在的单羧酸转运蛋白 (MCT) 抑制活性，可减少肿瘤细胞的乳酸生成。基于此，本课题开发了一种酶响应型脂质体（KC26-Lipo），共递送阿霉素和槲皮素，通过修饰legumain的发卡型多肽——KC26来促进脂质体的肿瘤内渗透。由于legumain在乳腺癌中过度表达，KC26-Lipo可以在癌组织中有效激活，随后介导有效地肿瘤内和细胞内渗透，进一步激活抗肿瘤免疫和抑制乳酸代谢。本课题为基于中药和化疗药共递送调节肿瘤代谢和免疫提供了一种有前景的乳腺癌靶向治疗策略。