Thommey P. Thomas, Melvin Joice, Madhuresh Sumit, Justin E. Silpe, Alina Kotlyar, Sophia Bharathi, Jolanta Kukowska-Latallo, James R. Baker and Seok Ki Choi Pages 6594 - 6605 ( 12 )
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.
Folate receptor, methotrexate, dihydrofolate reductase, PAMAM dendrimer, multivalent binding, drug delivery.
, , , , , , , , Department of Internal Medicine, Michigan Nanotechnology Institute for Medicine and Biological Sciences, USA.