Design and In vitro Validation of Multivalent Dendrimer Methotrexates as a Folate-targeting Anticancer Therapeutic

Author(s): Thommey P. Thomas, Melvin Joice, Madhuresh Sumit, Justin E. Silpe, Alina Kotlyar, Sophia Bharathi, Jolanta Kukowska-Latallo, James R. Baker, Seok Ki Choi.

Journal Name: Current Pharmaceutical Design

Volume 19 , Issue 37 , 2013

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Abstract:

Design of cancer-targeting nanotherapeutics relies on a pair of two functionally orthogonal molecules, one serving as a cancer cell-specific targeting ligand, and the other as a therapeutic cytotoxic agent. The present study investigates the validity of an alternative simplified strategy where a dual-acting molecule which bears both targeting and cytotoxic activity is conjugated to the nanoparticle as cancer-targeting nanotherapeutics. Herein, we demonstrate that methotrexate is applicable for this dual-acting strategy due to its reasonable affinity to folic acid receptor (FAR) as a tumor biomarker, and cytotoxic inhibitory activity of cytosolic dihydrofolate reductase. This article describes design of new methotrexate-conjugated poly(amidoamine) (PAMAM) dendrimers, each carrying multiple copies of methotrexate attached through a stable amide linker. We evaluated their dual biological activities by performing surface plasmon resonance spectroscopy, a cell-free enzyme assay and cell-based experiments in FAR-overexpressing cells. This study identifies the combination of an optimal linker framework and multivalency as the two key design elements that contribute to achieving potent dual activity.

Keywords: Folate receptor, methotrexate, dihydrofolate reductase, PAMAM dendrimer, multivalent binding, drug delivery.

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Article Details

VOLUME: 19
ISSUE: 37
Year: 2013
Page: [6594 - 6605]
Pages: 12
DOI: 10.2174/1381612811319370004
Price: $58

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