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ACS Nano. 2019 Apr 23;13(4):4049-4063. doi: 10.1021/acsnano.8b08246. Epub 2019 Mar 29.

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

Author information

1
School of Pharmaceutical Sciences, Beijing Advanced Innovation Center for Structural Biology, and Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education) , Tsinghua University , Beijing 100084 , People's Republic of China.
2
Department of Pharmacology, Simmons Comprehensive Cancer Center , University of Texas Southwestern Medical Center , Dallas , Texas 75390 , United States.
3
School of Pharmaceutical Sciences , Tsinghua University , Beijing 100084 , People's Republic of China.

Abstract

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 p Ka, with dramatically increased buffer capacity in a narrow pH range (<0.3 pH). Cell studies including amino acid profiling showed that UPSM inhibited lysosomal catabolism more efficiently than conventional lysosomotropic agents ( e. g., chloroquine) and induced cell apoptosis under starved condition. Moreover, pH-triggered rapid drug release from triptolide prodrug-loaded UPSM (T-UPSM) significantly enhanced cytotoxicity over non-pH-sensitive micelles (T-NPSM). Importantly, T-UPSM demonstrated superior safety and antitumor efficacy over triptolide and T-NPSM in KRAS mutant pancreatic cancer mouse models. Our findings suggest that the ultra-pH-sensitive nanoparticles are a promising therapeutic platform to treat KRAS mutant pancreatic cancer through simultaneous lysosomal pH buffering and rapid drug release.

KEYWORDS:

drug delivery; lysosomal buffering; mutant KRAS; pancreatic cancer; ultra-pH-sensitive micelles

PMID:
30912923
DOI:
10.1021/acsnano.8b08246

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