Synapse - Tumor-targeted nanoparticles improve the therapeutic index of BCL2 and MCL1 dual inhibition

Tumor-targeted nanoparticles improve the therapeutic index of BCL2 and MCL1 dual inhibition Journal Article

Authors:	Bala Tannan, N.; Manzari, M. T.; Herviou, L.; Da Silva Ferreira, M.; Hagen, C.; Kiguchi, H.; Manova-Todorova, K.; Seshan, V.; de Stanchina, E.; Heller, D. A.; Younes, A.
Article Title:	Tumor-targeted nanoparticles improve the therapeutic index of BCL2 and MCL1 dual inhibition
Abstract:	Cancer and normal cells use multiple antiapoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing but is also associated with increased systemic toxicity. Here, we demonstrate that the dual targeting of MCL1 and BCL2 proteins using the small molecules S63845 and venetoclax induces durable remissions in mice that harbor human diffuse large B-cell lymphoma (DLBCL) tumors but is accompanied by hematologic toxicity and weight loss. To mitigate these toxicities, we encapsulated S63845 or venetoclax into nanoparticles that target P-selectin, which is enriched in tumor endothelial cells. In vivo and ex vivo imaging demonstrated preferential targeting of the nanoparticles to lymphoma tumors over vital organs. Mass spectrometry analyses after administration of nanoparticle drugs confirmed tumor enrichment of the drug while reducing plasma levels. Furthermore, nanoparticle encapsulation allowed 3.5- to 6.5-fold reduction in drug dose, induced sustained remissions, and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy. © 2021 American Society of Hematology
Journal Title:	Blood
Volume:	137
Issue:	15
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2021-04-15
Start Page:	2057
End Page:	2069
Language:	English
DOI:	10.1182/blood.2020008017
PUBMED:	33067607
PROVIDER:	scopus
PMCID:	PMC8057264
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85104091395&doi=10.1182%2fblood.2020008017&partnerID=40&md5=834717a262035a4f04d63bf4fef0a4f1
Notes:	Article -- Export Date: 3 May 2021 -- Source: Scopus