Targeting the Oncogene KRAS Mutant Pancreatic Cancer by Synergistic Blocking of Lysosomal Acidification and Rapid Drug Release

Survival of KRAS mutant pancreatic cancer is critically dependent on reprogrammed metabolism including elevated macropinocytosis, autophagy, and lysosomal degradation of proteins. Lysosomal acidification is indispensable to protein catabolism, which makes it an exploitable metabolic target for KRAS mutant pancreatic cancer. Herein we investigated ultra-pH-sensitive micelles (UPSM) with pH-specific buffering of organelle pH and rapid drug release as a promising therapy against pancreatic cancer. UPSM undergo micelle-unimer phase transition at their apparent plc, with dramatically increased buffer capacity in a narrow pH range (

KRAS突变型胰腺癌的存活严重依赖于重新编程的代谢，包括增强的巨胞饮作用、自噬以及蛋白质的溶酶体降解。溶酶体酸化对于蛋白质分解代谢是必不可少的，这使其成为KRAS突变型胰腺癌的一个可利用的代谢靶点。在此，我们研究了超pH敏感胶束（UPSM），它对细胞器pH具有特定pH的缓冲作用且能快速释放药物，是一种针对胰腺癌的有前景的治疗方法。UPSM在其表观pIc处发生胶束 - 单体相变，在狭窄的pH范围内缓冲能力显著增强（