Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting

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.

Graphical abstractNanotechnology platform for cancer-targeting drug delivery is designed by employing methotrexate (MTX) as a dual-acting cytotoxic molecule that targets folic acid receptor (FAR), a cancer surface biomarker.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► MTX-presenting multivalent conjugates were prepared with G5 PAMAM dendrimer. ► Their avidity to the folate receptor was enhanced by up to ∼10,000-fold over MTX. ► MTX conjugate displayed the folate receptor-targeted uptake by a KB cancer cell.