Endolysosomal Sequestration Effects Controlled Release of BRAF Paradox Breaker Nanoparticles.

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.