A Trimodal Closomer Drug‐Delivery System Tailored with Tracing and Targeting Capabilities |
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Authors: | Dr Saurav J Sarma Dr Aslam A Khan Dr Lalit N Goswami Dr Satish S Jalisatgi Dr M Frederick Hawthorne |
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Institution: | International Institute of Nano and Molecular Medicine, School of Medicine, University of Missouri, Columbia, Missouri, USA |
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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. |
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Keywords: | cancer chlorambucil closomer drug delivery glycoconjugates |
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