title: Poly(amidoamine) dendrimer-methotrexate conjugates: the mechanism of interaction with folate binding protein.
abstract: Generation 5 poly(amidoamine) (G5 PAMAM) methotrexate (MTX) conjugates employing two small molecular linkers, G5-(COG-MTX)n, G5-(MFCO-MTX)n were prepared along with the conjugates of the G5-G5 (D) dimer, D-(COG-MTX)n, D-(MFCO-MTX)n. The monomer G5-(COG-MTX)n conjugates exhibited only a weak, rapidly reversible binding to folate binding protein (FBP) consistent with monovalent MTX binding. The D-(COG-MTX)n conjugates exhibited a slow onset, tight-binding mechanism in which the MTX first binds to the FBP, inducing protein structural rearrangement, followed by polymer-protein van der Waals interactions leading to tight-binding. The extent of irreversible binding is dependent on total MTX concentration and no evidence of multivalent MTX binding was observed.
authors.affiliation: Departments of Chemistry, ‡Biomedical Engineering, §Physics, and ∥the Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Mallory A
authors.initials: MA
authors.lastname: van Dongen
authors.forename: Rahul
authors.initials: R
authors.lastname: Rattan
authors.forename: Justin
authors.initials: J
authors.lastname: Silpe
authors.forename: Casey
authors.initials: C
authors.lastname: Dougherty
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Michmerhuizen
authors.forename: Margaret
authors.initials: M
authors.lastname: Van Winkle
authors.forename: Baohua
authors.initials: B
authors.lastname: Huang
authors.forename: Seok Ki
authors.initials: SK
authors.lastname: Choi
authors.forename: Kumar
authors.initials: K
authors.lastname: Sinniah
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Orr
authors.forename: Mark M
authors.initials: MM
authors.lastname: Banaszak Holl
mesh_terms: D002151:Calorimetry; D004265:DNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050091:Dendrimers / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008727:Methotrexate / Q000737:chemistry* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D011073:Polyamines / Q000737:chemistry* / Q000378:metabolism; D016601:RNA-Binding Proteins; D020349:Surface Plasmon Resonance
chemical_list: D004268:DNA-Binding Proteins; D050091:Dendrimers; C492258:FUBP1 protein, human; C531249:Poly(amidoamine); D011073:Polyamines; D016601:RNA-Binding Proteins; D004265:DNA Helicases; D008727:Methotrexate
keywords: PAMAM dendrimer; methotrexate; multivalent binding; polymer/protein interactions