title: Development of a novel near-infrared fluorescent theranostic combretastain A-4 analogue, YK-5-252, to target triple negative breast cancer.
abstract: The treatment of triple negative breast cancer (TNBC) is a significant challenge to cancer research. The lack of hormone receptors limits the treatment options available to patients with this diagnosis, forcing them to endure prolonged radiation and chemotherapy. Anti-angiogenesis is a chemotherapeutic strategy that targets the vasculature of tumors. Combretastatin A-4 (CA-4) is a well-known vasculature-disrupting agent, which has been shown to effectively kill a variety of cancers through inhibition of tubulin polymerization. Due to its toxicity, small molecule analogues of CA-4 have been sought out. We have designed a novel dual action CA-4 prodrug, YK-5-252, which releases the drug through a disulfide bond cleavage mechanism and contains a near-infrared (NIR) fluorophore, which allows fluorescence monitoring of cleavage. This disulfide linkage causes CA-4 to become effective only when released by glutathione (GSH) reducing the toxicity of the drug while simultaneously releasing the NIR fluorophore. Therefore the prodrug, YK-5-252, represents a novel CA-4 analogue which has reduced toxicity and can be used for theranostics imaging.
authors.affiliation: Drug Discovery & Development, Inova Schar Cancer Institute; Drug Discovery Center, Inova Center for Personalized Health, 3225 Gallows Rd, Fairfax, VA 22031, United States.
authors.forename: Yali
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Natural Sciences, Bowie State University, 14000 Jericho Park Dr, Crawford 207A, Bowie, MD 20716, United States.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Smith
authors.affiliation: Fairfax High School, 3501 Rebel Run, Fairfax, VA 22030, United States.
authors.forename: Kongwen
authors.initials: K
authors.lastname: Li
authors.affiliation: Thomas Jefferson High School for Science and Technology, 6560 Braddock Road, Alexandria 22312, United States.
authors.forename: Jake
authors.initials: J
authors.lastname: Cui
authors.affiliation: James Madison High School, 2500 James Madison Drive, Vienna, VA 22181, United States.
authors.forename: John
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Oncology, Center for Drug Discovery, Georgetown University Medical Center, 3970 Reservoir Rd, Washington D.C. 20057, United States.
authors.forename: Shujie
authors.initials: S
authors.lastname: Hou
authors.affiliation: Drug Discovery & Development, Inova Schar Cancer Institute; Drug Discovery Center, Inova Center for Personalized Health, 3225 Gallows Rd, Fairfax, VA 22031, United States. Electronic address: Milton.Brown@inova.org.
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
mesh_terms: D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D013058:Mass Spectrometry; D066244:Proton Magnetic Resonance Spectroscopy; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000068936:Theranostic Nanomedicine; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D050257:Tubulin Modulators
chemical_list: D001578:Benzopyrans; D013267:Stilbenes; D050257:Tubulin Modulators; C000622718:YK-5-252