Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis

Xinquan Liu, Debadyuti GhoshDivision of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USACorrespondence: Debadyuti GhoshCollege of Pharmacy, The University of Texas at Austin, 2409 University Avenue,Austin, TX 78712, USATel +1 51...

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Autores principales:	Liu X, Ghosh D
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	Albumin nanoparticles KRAS mutation macropinocytosis Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/164c1d56e17a48ea99eb826e1bea10fe
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spelling	oai:doaj.org-article:164c1d56e17a48ea99eb826e1bea10fe2021-12-02T09:05:04ZIntracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis1178-2013https://doaj.org/article/164c1d56e17a48ea99eb826e1bea10fe2019-08-01T00:00:00Zhttps://www.dovepress.com/intracellular-nanoparticle-delivery-by-oncogenic-kras-mediated-macropi-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Xinquan Liu, Debadyuti GhoshDivision of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USACorrespondence: Debadyuti GhoshCollege of Pharmacy, The University of Texas at Austin, 2409 University Avenue,Austin, TX 78712, USATel +1 512 471 7390Fax +1 512 471 7474Email dghosh@austin.utexas.eduBackground: 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.&#x00A0Results: We have synthesized stable albumin NPs that demonstrate significantly greater uptake in cancer cells with activating mutations of KRAS 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.Keywords: albumin nanoparticles, KRAS mutation, macropinocytosisLiu XGhosh DDove Medical PressarticleAlbumin nanoparticlesKRAS mutationmacropinocytosisMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 6589-6600 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Albumin nanoparticles KRAS mutation macropinocytosis Medicine (General) R5-920
spellingShingle	Albumin nanoparticles KRAS mutation macropinocytosis Medicine (General) R5-920 Liu X Ghosh D Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
description	Xinquan Liu, Debadyuti GhoshDivision of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USACorrespondence: Debadyuti GhoshCollege of Pharmacy, The University of Texas at Austin, 2409 University Avenue,Austin, TX 78712, USATel +1 512 471 7390Fax +1 512 471 7474Email dghosh@austin.utexas.eduBackground: 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.&#x00A0Results: We have synthesized stable albumin NPs that demonstrate significantly greater uptake in cancer cells with activating mutations of KRAS 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.Keywords: albumin nanoparticles, KRAS mutation, macropinocytosis
format	article
author	Liu X Ghosh D
author_facet	Liu X Ghosh D
author_sort	Liu X
title	Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
title_short	Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
title_full	Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
title_fullStr	Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
title_full_unstemmed	Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis
title_sort	intracellular nanoparticle delivery by oncogenic kras-mediated macropinocytosis
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/164c1d56e17a48ea99eb826e1bea10fe
work_keys_str_mv	AT liux intracellularnanoparticledeliverybyoncogenickrasmediatedmacropinocytosis AT ghoshd intracellularnanoparticledeliverybyoncogenickrasmediatedmacropinocytosis
_version_	1718398226646695936

Intracellular nanoparticle delivery by oncogenic KRAS-mediated macropinocytosis

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