Nanoparticle-Mediated Co-Delivery of Notch-1 Antibodies and ABT-737 as a Potent Treatment Strategy for Triple-Negative Breast Cancer

摘要

Triple-negative breast cancer (TNBC) accounts for nearly one-quarter of all breast cancer cases, but effective targeted therapies for this disease remain elusive because TNBC cells lack expression of the three most common receptors seen on other subtypes of breast cancer. Here, we exploit TNBC cells' overexpression of Notch-1 receptors and Bcl-2 anti-apoptotic proteins to provide an effective targeted therapy. Prior studies have shown that the small molecule drug ABT-737, which inhibits Bcl-2 to reinstate apoptotic signaling, is a promising candidate for TNBC therapy. However, ABT-737 is poorly soluble in aqueous conditions, and its orally bioavailable derivative causes severe thrombocytopenia. To enable targeted delivery of ABT-737 to TNBC and enhance its therapeutic efficacy, we encapsulated the drug in poly(lactic-co-glycolic acid) nanoparticles (NPs) that were functionalized with Notch-1 antibodies to produce N1-ABT-NPs. The antibodies in this NP platform enable both TNBC cell-specific binding and suppression of Notch signaling within TNBC cells by locking the Notch-1 receptors in a ligand unresponsive state. This Notch inhibition potentiates the effect of ABT-737 by up-regulating Noxa, resulting in effective killing of TNBC cells. We present the results of in vitro studies that demonstrate N1-ABT-NPs can preferentially bind TNBC cells versus noncancerous breast epithelial cells to effectively regulate Bcl-2 and Notch signaling to induce cell death. Further, we show that N1-ABT-NPs can accumulate in subcutaneous TNBC xenograft tumors in mice following systemic administration to reduce tumor burden and extend animal survival. Together, these findings demonstrate that NP-mediated co-delivery of Notch-1 antibodies and ABT-737 is a potent treatment strategy for TNBC that may improve patient outcomes with further development and implementation.