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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.

SUBMITTER: van Dongen MA

PROVIDER: S-EPMC4224518 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Poly(amidoamine) dendrimer-methotrexate conjugates: the mechanism of interaction with folate binding protein.

van Dongen Mallory A MA Rattan Rahul R Silpe Justin J Dougherty Casey C Michmerhuizen Nicole L NL Van Winkle Margaret M Huang Baohua B Choi Seok Ki SK Sinniah Kumar K Orr Bradford G BG Banaszak Holl Mark M MM

Molecular pharmaceutics 20141001 11

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 ...[more]

PMID: 25222480

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