title: Photochemical release of methotrexate from folate receptor-targeting PAMAM dendrimer nanoconjugate.
abstract: Nanoparticle (NP)-based targeted drug delivery involves cell-specific targeting followed by a subsequent therapeutic action from the therapeutic carried by the NP system. NPs conjugated with methotrexate (MTX), a potent inhibitor of dihydrofolate reductase (DHFR) localized in cytosol, have been under investigation as a delivery system to target cancer cells to enhance the therapeutic index of methotrexate, which is otherwise non-selectively cytotoxic. Despite improved therapeutic activity from MTX-conjugated NPs in vitro and in vivo, the therapeutic action of these conjugates following cellular entry is poorly understood; in particular it is unclear whether the therapeutic activity requires release of the MTX. This study investigates whether MTX must be released from a nanoparticle in order to achieve the therapeutic activity. We report herein light-controlled release of methotrexate from a dendrimer-based conjugate and provide evidence suggesting that MTX still attached to the nanoconjugate system is fully able to inhibit the activity of its enzyme target and the growth of cancer cells.
authors.affiliation: Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan, Ann Arbor, MI 48109, USA. skchoi@umich.edu
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Choi
authors.forename: Thommey P
authors.initials: TP
authors.lastname: Thomas
authors.forename: Ming-Hsin
authors.initials: MH
authors.lastname: Li
authors.forename: Ankur
authors.initials: A
authors.lastname: Desai
authors.forename: Alina
authors.initials: A
authors.lastname: Kotlyar
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D006801:Humans; D008727:Methotrexate / Q000633:toxicity*; D058726:Nanoconjugates / Q000737:chemistry* / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy; D010782:Photolysis; D013056:Spectrophotometry, Ultraviolet; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D050091:Dendrimers; D005493:Folic Acid Antagonists; D058726:Nanoconjugates; C104700:PAMAM Starburst; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate