title: Nanodiamond-mitoxantrone complexes enhance drug retention in chemoresistant breast cancer cells.
abstract: 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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore , Singapore.
authors.forename: Tan-Boon
authors.initials: TB
authors.lastname: Toh
authors.forename: Dong-Keun
authors.initials: DK
authors.lastname: Lee
authors.forename: Weixin
authors.initials: W
authors.lastname: Hou
authors.forename: Lissa Nurrul
authors.initials: LN
authors.lastname: Abdullah
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Nguyen
authors.forename: Dean
authors.initials: D
authors.lastname: Ho
authors.forename: Edward Kai-Hua
authors.initials: EK
authors.lastname: Chow
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008027:Light; D008942:Mitoxantrone / Q000008:administration & dosage / Q000737:chemistry*; D058612:Nanodiamonds / Q000737:chemistry*; D009363:Neoplasm Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012542:Scattering, Radiation; D012995:Solubility; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D058612:Nanodiamonds; D009363:Neoplasm Proteins; D008942:Mitoxantrone