» Articles » PMID: 32083466

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

Overview
Journal ACS Nano
Specialty Biotechnology
Date 2020 Feb 22
PMID 32083466
Citations 29
Authors
Affiliations
Soon will be listed here.
Abstract

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 studies that demonstrate N1-ABT-NPs can preferentially bind TNBC cells 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.

Citing Articles

The use of nanomaterials as drug delivery systems and anticancer agents in the treatment of triple-negative breast cancer: an updated review (year 2005 to date).

Ndongwe T, Zhou A, Ganga N, Matawo N, Sibanda U, Chidziwa T Discov Nano. 2024; 19(1):138.

PMID: 39225730 PMC: 11372008. DOI: 10.1186/s11671-024-04089-3.


Recent Developments in Combination Immunotherapy with Other Therapies and Nanoparticle-Based Therapy for Triple-Negative Breast Cancer (TNBC).

Battogtokh G, Obidiro O, Akala E Cancers (Basel). 2024; 16(11).

PMID: 38893132 PMC: 11171312. DOI: 10.3390/cancers16112012.


Targeting triple negative breast cancer stem cells using nanocarriers.

Dasari N, Guntuku G, Pindiprolu S Discov Nano. 2024; 19(1):41.

PMID: 38453756 PMC: 10920615. DOI: 10.1186/s11671-024-03985-y.


Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy.

Wang M, Yu F, Zhang Y, Li P Front Immunol. 2024; 15:1352484.

PMID: 38444855 PMC: 10912471. DOI: 10.3389/fimmu.2024.1352484.


Rational Formulation of targeted ABT-737 nanoparticles by self-assembled polypeptides and designed peptides.

Aibinder P, Cohen-Erez I, Rapaport H Heliyon. 2024; 10(4):e26095.

PMID: 38420433 PMC: 10900936. DOI: 10.1016/j.heliyon.2024.e26095.


References
1.
Seveno C, Loussouarn D, Brechet S, Campone M, Juin P, Barille-Nion S . γ-Secretase inhibition promotes cell death, Noxa upregulation, and sensitization to BH3 mimetic ABT-737 in human breast cancer cells. Breast Cancer Res. 2012; 14(3):R96. PMC: 3446359. DOI: 10.1186/bcr3214. View

2.
Stylianou S, Clarke R, Brennan K . Aberrant activation of notch signaling in human breast cancer. Cancer Res. 2006; 66(3):1517-25. DOI: 10.1158/0008-5472.CAN-05-3054. View

3.
Valcourt D, Dang M, Wang J, Day E . Nanoparticles for Manipulation of the Developmental Wnt, Hedgehog, and Notch Signaling Pathways in Cancer. Ann Biomed Eng. 2019; 48(7):1864-1884. PMC: 7196499. DOI: 10.1007/s10439-019-02399-7. View

4.
Speiser J, Ersahin C, Osipo C . The functional role of Notch signaling in triple-negative breast cancer. Vitam Horm. 2013; 93:277-306. DOI: 10.1016/B978-0-12-416673-8.00013-7. View

5.
Yuan X, Zhang M, Wu H, Xu H, Han N, Chu Q . Expression of Notch1 Correlates with Breast Cancer Progression and Prognosis. PLoS One. 2015; 10(6):e0131689. PMC: 4488260. DOI: 10.1371/journal.pone.0131689. View