Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
| Autor: | Xinquan Liu, Debadyuti Ghosh |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Neuroblastoma RAS viral oncogene homolog
Mutant Biophysics Pharmaceutical Science Bioengineering 02 engineering and technology 010402 general chemistry medicine.disease_cause 01 natural sciences Flow cytometry Biomaterials Drug Discovery medicine HRAS medicine.diagnostic_test Chemistry Organic Chemistry General Medicine 021001 nanoscience & nanotechnology 0104 chemical sciences Tumor progression Cancer cell Drug delivery Cancer research KRAS 0210 nano-technology |
| Zdroj: | International Journal of Nanomedicine. 14:6589-6600 |
| ISSN: | 1178-2013 |
| DOI: | 10.2147/ijn.s212861 |
| Popis: | Background 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. Purpose We exploit macropinocytosis pathway to deliver nanoparticles (NPs) in cancer cells harboring activating KRAS 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 KRAS cells were quantitively determined by flow cytometry and qualitatively by fluorescent microscopy. NP uptake by KRAS-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 KRA S 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 KRAS cancer cells than wild-type KRAS cells by macropinocytosis. Conclusions The uptake of albumin nanoparticles is driven by KRAS. This NP-based strategy targeting RAS-driven macropinocytosis is a facile approach toward improved delivery into KRAS-driven cancers. |
| Databáze: | OpenAIRE |
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