Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis.

BACKGROUND

The family of oncogenes () are the most frequent mutations in cancers and regulate key signaling pathways that drive tumor progression. As a result, drug delivery targeting -driven tumors has been a long-standing challenge in cancer therapy. Mutant activates cancer cells to actively take up nutrients, including glucose, lipids, and albumin, via macropinocytosis to fulfill their energetic requirements to survive and proliferate.

PURPOSE

We exploit macropinocytosis pathway to deliver nanoparticles (NPs) in cancer cells harboring activating mutations.

METHODS

NPs were synthesized by the desolvation method. The physicochemical properties and stability of NPs were characterized by dynamic light scattering and transmission electron microscopy. Uptake of fluorescently labelled NPs in wild-type and mutant cells were quantitively determined by flow cytometry and qualitatively by fluorescent microscopy. NP uptake by -driven macropinocytosis was confirmed by pharmacological inhibition and genetic knockdown.

RESULTS

We have synthesized stable albumin NPs that demonstrate significantly greater uptake in cancer cells with activating mutations of than monomeric albumin (ie, dissociated form of clinically used nab-paclitaxel). From pharmacological inhibition and semi-quantitative fluorescent microscopy studies, these NPs exhibit significantly increased uptake in mutant cancer cells than wild-type S cells by macropinocytosis.

CONCLUSIONS

The uptake of albumin nanoparticles is driven by . This NP-based strategy targeting -driven macropinocytosis is a facile approach toward improved delivery into -driven cancers.