title: Dendrimer-based multivalent methotrexates as dual acting nanoconjugates for cancer cell targeting.
abstract: 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.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ming-Hsin
authors.initials: MH
authors.lastname: Li
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Choi
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: Ankur
authors.initials: A
authors.lastname: Desai
authors.forename: Kyung-Hoon
authors.initials: KH
authors.lastname: Lee
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: Mark M
authors.initials: MM
authors.lastname: Banaszak Holl
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D050091:Dendrimers / Q000737:chemistry*; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007624:KB Cells; D008727:Methotrexate / Q000737:chemistry* / Q000494:pharmacology*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D058726:Nanoconjugates / Q000737:chemistry*; D020349:Surface Plasmon Resonance; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D005493:Folic Acid Antagonists; D058726:Nanoconjugates; C104700:PAMAM Starburst; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate