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Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
Xinquan Liu1, Debadyuti Ghosh1
1Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA.
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.
Insights
Researchers developed albumin nanoparticles (NPs) that are preferentially taken up by cancer cells with KRAS mutations via macropinocytosis. This targeted delivery strategy enhances drug delivery for KRAS-driven cancers.
Area of Science:
- Oncology
- Nanotechnology
- Cancer Biology
Background:
- RAS oncogenes (KRAS, HRAS, NRAS) are frequently mutated in cancers, driving tumor progression.
- Targeting RAS-driven tumors is challenging; mutant RAS promotes nutrient uptake via macropinocytosis.
- This process fuels cancer cell survival and proliferation.
Purpose of the Study:
- To exploit the macropinocytosis pathway for nanoparticle (NP) delivery into cancer cells with activating KRAS mutations.
- To develop a targeted drug delivery system for KRAS-driven cancers.
Main Methods:
- Albumin nanoparticles (NPs) were synthesized using the desolvation method.
- Physicochemical properties and stability of NPs were characterized.
- NP uptake was quantified in wild-type and mutant KRAS cells using flow cytometry and fluorescence microscopy.
- KRAS-driven macropinocytosis was confirmed via pharmacological inhibition and genetic knockdown.
Main Results:
- Stable albumin NPs were synthesized, showing significantly greater uptake in mutant KRAS cancer cells compared to monomeric albumin.
- Pharmacological inhibition and microscopy studies confirmed increased NP uptake in mutant KRAS cells via macropinocytosis.
- This demonstrates preferential uptake in KRAS-mutated cells.
Conclusions:
- Albumin nanoparticle uptake is driven by KRAS mutations.
- This NP-based strategy effectively targets RAS-driven macropinocytosis.
- It offers a facile approach for improved drug delivery into KRAS-driven cancers.
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