Poly(amidoamine) Dendrimer-Methotrexate Conjugates: The Mechanism of Interaction with Folate Binding Protein

Mallory A. van Dongen, Rahul Rattan, Justin Silpe, Casey Dougherty, Nicole L. Michmerhuizen, Margaret Van Winkle, Baohua Huang, Seok Ki Choi, Kumar Sinniah, Bradford G. Orr, Mark M. Banaszak Holl

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25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4049-4058
Number of pages10
JournalMolecular Pharmaceutics
Volume11
Issue number11
DOIs
Publication statusPublished - 3 Nov 2014
Externally publishedYes

Keywords

  • methotrexate
  • multivalent binding
  • PAMAM dendrimer
  • polymer/protein interactions

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