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 by The American Society of Hematology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / therapeutic use
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Bridged Bicyclo Compounds, Heterocyclic / administration & dosage*
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Bridged Bicyclo Compounds, Heterocyclic / adverse effects
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Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
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Cell Line, Tumor
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Drug Carriers / chemistry
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Drug Delivery Systems
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Female
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Humans
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Lymphoma, Large B-Cell, Diffuse / drug therapy*
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Lymphoma, Large B-Cell, Diffuse / metabolism
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Mice
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism
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Nanoparticles / chemistry
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyrimidines / administration & dosage*
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Pyrimidines / adverse effects
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Pyrimidines / therapeutic use
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Sulfonamides / administration & dosage*
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Sulfonamides / adverse effects
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Sulfonamides / therapeutic use
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Therapeutic Index
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Thiophenes / administration & dosage*
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Thiophenes / adverse effects
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Thiophenes / therapeutic use
Substances
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Antineoplastic Agents
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BCL2 protein, human
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Bridged Bicyclo Compounds, Heterocyclic
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Drug Carriers
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins c-bcl-2
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Pyrimidines
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S63845
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Sulfonamides
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Thiophenes
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venetoclax