Journal
MOLECULAR PHARMACEUTICS
Volume 11, Issue 8, Pages 2683-2691Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp5001108
Keywords
nanodiamond; chemoresistance; mitoxantrone; ABCG2; breast cancer
Funding
- National Research Foundation Cancer Science Institute of Singapore RCE Main Grant
- National Medical Research Council (NMRC) [CBRG-NIG BNIG12nov017]
- Ministry of Education Academic Research Fund (MOE AcRF) [T1-2012 Oct-11]
- National Science Foundation [CMMI-0846323]
- Center for Scalable and Integrated Nano Manufacturing [DMI-0327077]
- V Foundation for Cancer Research Scholars Award
- Wallace H. Coulter Foundation Translational Research Award
- Society for Laboratory Automation and Screening (SLAS) Endowed Fellowship
- Beckman Coulter Life Sciences
- National Cancer Institute [U54CA151880]
- [CMMI-0856492]
- [DMR-1105060]
- Directorate For Engineering [1350197] Funding Source: National Science Foundation
- Div Of Civil, Mechanical, & Manufact Inn [1350197] Funding Source: National Science Foundation
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Chemoresistance is a prevalent issue that accounts for the vast majority of treatment failure outcomes in metastatic cancer. Among the mechanisms of resistance that markedly decrease treatment efficacy, the efflux of drug compounds by ATP-binding cassette (ABC) transporter proteins can impair adequate drug retention by cancer cells required for therapeutic cytotoxic activity. Of note, ABC transporters are capable of effluxing several classes of drugs that are clinical standards, including the anthracyclines such as doxorubicin, as well as anthracenediones such as mitoxantrone. To address this challenge, a spectrum of nanomaterials has been evaluated for improved drug retention and enhanced efficacy. Nanodiamonds (NDs) are emerging as a promising nanomaterial platform because they integrate several important properties into a single agent. These include a uniquely faceted truncated octahedral architecture that enables potent drug binding and dispersibility in water, scalably processed ND particles with uniform diameters of approximately 5 nm, and a demonstrated ability to improve drug tolerance while delaying tumor growth in multiple preclinical models, among others. This work describes a ND mitoxantrone complex that can be rapidly synthesized and mediates marked improvements in drug efficacy. Comprehensive complex characterization reveals a complex with favorable drug delivery properties that is capable of improving drug retention and efficacy in an MDA-MB-231-luc-D3H2LN (MDA-MB-231) triple negative breast cancer cell line that was lentivirally transduced for resistance against mitoxantrone. Findings from this study support the further evaluation of ND-MTX in preclinical dose escalation and safety studies toward potentially clinical validation.
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