A Trimodal Closomer Drug-Delivery System Tailored with Tracing and Targeting Capabilities

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• 作者：Dr. Saurav J. Sarma ; Dr. Aslam A. Khan ; Dr. Lalit N. Goswami ; Dr. Satish S. Jalisatgi and Dr. M. Frederick Hawthorne
• 刊名：Chemistry - A European Journal
• 出版年：2016
• 出版时间：August 26, 2016
• 年：2016
• 卷：22
• 期：36
• 页码：12715-12723
• 全文大小：2566K
• ISSN：1521-3765

文摘

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.