title: A Trimodal Closomer Drug-Delivery System Tailored with Tracing and Targeting Capabilities.
abstract: The construction and application of a unique monodisperse closomer drug-delivery system (CDDS) integrating three different functionalities onto an icosahedral closo-dodecaborane [B12 ](2-) scaffold is described. Eleven B-OH vertices of [closo-B12 (OH)12 ](2-) were used to attach eleven copies of the anticancer drug chlorambucil and the targeting vector glucosamine through a bifurcating lysine linker. The remaining twelfth vertex was used to attach a fluorescent imaging probe. The presence of multiple glucosamine units offered a monodisperse and highly water-soluble CDDS with a high payload of therapeutic cargo. This array enhanced the penetration of the drug into cancer cells by exploiting the overexpression of GLUT-1 receptors present on cancer cells. About 15-fold enhancement in cytotoxicity was observed for CDDS-1 against Jurkat cells, compared to CDDS-2, which lacks the GLUT-1 targeting glucosamine. A cytotoxicity comparison of CDDS-1 against colorectal RKO cells and its GLUT-1 knock-out version confirmed that GLUT-1 mediates endocytosis. Using fluorescent markers both CDDS-1 and -2 were traced to the mitochondria, a novel target for alkylating agents.
authors.affiliation: International Institute of Nano and Molecular Medicine, School of Medicine, University of Missouri, Columbia, Missouri, 65211-3450, USA.
authors.forename: Saurav J
authors.initials: SJ
authors.lastname: Sarma
authors.affiliation: International Institute of Nano and Molecular Medicine, School of Medicine, University of Missouri, Columbia, Missouri, 65211-3450, USA.
authors.forename: Aslam A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: International Institute of Nano and Molecular Medicine, School of Medicine, University of Missouri, Columbia, Missouri, 65211-3450, USA.
authors.forename: Lalit N
authors.initials: LN
authors.lastname: Goswami
authors.affiliation: International Institute of Nano and Molecular Medicine, School of Medicine, University of Missouri, Columbia, Missouri, 65211-3450, USA.
authors.forename: Satish S
authors.initials: SS
authors.lastname: Jalisatgi
authors.affiliation: International Institute of Nano and Molecular Medicine, School of Medicine, University of Missouri, Columbia, Missouri, 65211-3450, USA. hawthornem@missouri.edu.
authors.forename: M Frederick
authors.initials: MF
authors.lastname: Hawthorne
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis / Q000502:physiology*; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes
keywords: cancer; chlorambucil; closomer; drug delivery; glycoconjugates