title: Design and in vitro validation of multivalent dendrimer methotrexates as a folate-targeting anticancer therapeutic.
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.
authors.affiliation: Department of Internal Medicine, Michigan Nanotechnology Institute for Medicine and Biological Sciences, USA. skchoi@umich.edu.
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: Melvin
authors.initials: M
authors.lastname: Joice
authors.forename: Madhuresh
authors.initials: M
authors.lastname: Sumit
authors.forename: Justin E
authors.initials: JE
authors.lastname: Silpe
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: Sophia
authors.initials: S
authors.lastname: Bharathi
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kukowska-Latallo
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Choi
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D015195:Drug Design; D058975:Folate Receptor 1 / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry*; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D008727:Methotrexate / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D058990:Molecular Targeted Therapy; D053758:Nanoparticles; D020349:Surface Plasmon Resonance; D054928:Validation Studies as Topic
chemical_list: D001672:Biocompatible Materials; D050091:Dendrimers; D058975:Folate Receptor 1; D005493:Folic Acid Antagonists; C104700:PAMAM Starburst; D005492:Folic Acid; D008727:Methotrexate