Endolysosomal sequestration effects controlled release of BRAF paradox breaker nanoparticles Journal Article

  

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Authors:	Chen, C.; Perea Del Angel, A. M.; Sridharan, R.; Heller, D. A.
Article Title:	Endolysosomal sequestration effects controlled release of BRAF paradox breaker nanoparticles
Abstract:	<p>BRAF remains one of the most important therapeutic targets in cancer, but BRAF inhibitors can cause "paradoxical" pathway activation and drug resistance through RAF dimerization. A clinical "paradox breaker" inhibitor of BRAF monomers and dimers can potentially evade drug resistance. However, patients are required to receive a high oral daily drug dose to achieve the target therapeutic window. Co-administration of a cytochrome P450 blocker can improve drug exposure, but the combination can lead to drug-drug interactions. We investigated delivery via fucoidan-based nanocarriers to improve pharmacologic properties. We found that the nanoparticles extended BRAF inhibition in cancer cells due to sequestration into endolysosomes, followed by controlled release from a lysosomal depot. Following intraperitoneal administration, nanoparticles improved drug pharmacokinetics in vivo without inhibiting cytochrome P450 and also resulted in substantial improvements in antitumor efficacy. This work describes a general nanotherapeutic strategy to improve the pharmacologic properties of drugs via intracellular depot formation.</p>
Keywords:	prediction; nanomedicine; dimerization; resistance; efficacy; kinase inhibitor; mechanisms; advanced melanoma; targeted delivery; indocyanine green; raf inhibitors; precision medicine; drug depot
Journal Title:	ACS Nano
Volume:	19
Issue:	38
ISSN:	1936-0851
Publisher:	American Chemical Society
Publication status:	Published
Date Published:	2025-09-30
Online Publication Date:	2025-09-15
Start Page:	33879
End Page:	33890
Language:	English
ACCESSION:	WOS:001572335900001
DOI:	10.1021/acsnano.5c09100
PROVIDER:	wos
PUBMED:	40954128
Notes:	Article; Early Access -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Daniel Heller -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/229118