Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis

Abstract

The RAS family of oncogenes (KRAS, HRAS, NRAS) are the most frequent mutations in cancers and regulate key signaling pathways that drive tumor progression. As a result, drug delivery targeting RAS-driven tumors has been a long-standing challenge in cancer therapy. Mutant RAS activates cancer cells to actively take up nutrients, including glucose, lipids, and albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate. Here, we exploit this mechanism to deliver nanoparticles in cancer cells harboring activating KRAS mutations. We have synthesized stable albumin nanoparticles that demonstrate significantly greater uptake in cancer cells with activating mutations of KRAS than monomeric albumin (i.e. dissociated form of clinically-used nab-paclitaxel). From pharmacological inhibition and semi-quantitative fluorescent microscopy studies, these nanoparticles exhibit significantly increased uptake in mutant KRAS cancer cells than wild-type KRAS cells by macropinocytosis. Importantly, we demonstrate that their uptake is driven by KRAS. This nanoparticle-based strategy targeting RAS-driven macropinocytosis is a facile approach towards improved delivery into KRAS-driven cancers.