Tumor-targeted nanoparticles improve the therapeutic index of BCL2 and MCL1 dual inhibition
| Autor: | Mandana T. Manzari, Hiroto Kiguchi, Laurie Herviou, Mariana da Silva Ferreira, Daniel A. Heller, Katia Manova-Todorova, Anas Younes, Connor J Hagen, Elisa de Stanchina, Neeta Bala Tannan, Venkatraman E. Seshan |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Drug media_common.quotation_subject Immunology Antineoplastic Agents Thiophenes Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound Drug Delivery Systems 0302 clinical medicine Therapeutic index In vivo Cell Line Tumor hemic and lymphatic diseases medicine Animals Humans media_common Drug Carriers Sulfonamides Lymphoid Neoplasia Chemistry Venetoclax Cell Biology Hematology Bridged Bicyclo Compounds Heterocyclic medicine.disease Lymphoma Pyrimidines Therapeutic Index 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis Toxicity Cancer research Myeloid Cell Leukemia Sequence 1 Protein Nanoparticles Female Lymphoma Large B-Cell Diffuse Diffuse large B-cell lymphoma Ex vivo |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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