2. Academic Validation
  3. Endolysosomal Sequestration Effects Controlled Release of BRAF Paradox Breaker Nanoparticles

Endolysosomal Sequestration Effects Controlled Release of BRAF Paradox Breaker Nanoparticles

  • ACS Nano. 2025 Sep 30;19(38):33879-33890. doi: 10.1021/acsnano.5c09100.
Chen Chen 1 2 3,  Ana Marie Perea Del Angel 1,  Ramya Sridharan 1 2,  Daniel A Heller 1 2 3
Affiliations

Affiliations

  • 1 Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
  • 2 Weill Cornell Medicine, Cornell University, New York, New York 10065, United States.
  • 3 Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, United States.
PMID: 40954128 DOI: 10.1021/acsnano.5c09100
Abstract

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.

Keywords

drug depot; kinase inhibitor; nanomedicine; precision medicine; targeted delivery.

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