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.
Current Pharmaceutical Design
Title:Design and In vitro Validation of Multivalent Dendrimer Methotrexates as a Folate-targeting Anticancer Therapeutic
Volume: 19 Issue: 37
Author(s): Thommey P. Thomas, Melvin Joice, Madhuresh Sumit, Justin E. Silpe, Alina Kotlyar, Sophia Bharathi, Jolanta Kukowska-Latallo, James R. Baker and Seok Ki Choi
Affiliation:
Keywords: Folate receptor, methotrexate, dihydrofolate reductase, PAMAM dendrimer, multivalent binding, drug delivery.
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.
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Cite this article as:
Thomas P. Thommey, Joice Melvin, Sumit Madhuresh, Silpe E. Justin, Kotlyar Alina, Bharathi Sophia, Kukowska-Latallo Jolanta, Baker R. James and Choi Ki Seok, Design and In vitro Validation of Multivalent Dendrimer Methotrexates as a Folate-targeting Anticancer Therapeutic, Current Pharmaceutical Design 2013; 19 (37) . https://dx.doi.org/10.2174/1381612811319370004
DOI https://dx.doi.org/10.2174/1381612811319370004 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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