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Cancer-targeting drug delivery can be based on the rational design of a therapeutic platform. This approach is typically achieved by the functionalization of a nanoparticle with two distinct types of molecules, a targeting ligand specific for a cancer cell, and a cytotoxic molecule to kill the cell. The present study aims to evaluate the validity of an alternative simplified approach in the design of cancer-targeting nanotherapeutics: conjugating a single type of molecule with dual activities to nanoparticles, instead of coupling a pair of orthogonal molecules. Herein we investigate whether this strategy can be validated by its application to methotrexate, a dual-acting small molecule that shows cytotoxicity because of its potent inhibitory activity against dihydrofolate reductase and that binds folic acid receptor, a tumor biomarker frequently upregulated on the cancer cell surface. This article describes a series of dendrimer conjugates derived from a generation 5 polyamidoamine (G5 PAMAM) presenting a multivalent array of methotrexate and also demonstrates their dual biological activities by surface plasmon resonance spectroscopy, a cell-free enzyme assay, and cell-based experiments with KB cancer cells. Copyright © 2011 Elsevier Masson SAS. All rights reserved.


Ming-Hsin Li, Seok Ki Choi, Thommey P Thomas, Ankur Desai, Kyung-Hoon Lee, Alina Kotlyar, Mark M Banaszak Holl, James R Baker. Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting. European journal of medicinal chemistry. 2012 Jan;47(1):560-72

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PMID: 22142685

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