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

Research output: Contribution to journalArticleResearchpeer-review

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

Cite this

van Dongen, Mallory A. ; Rattan, Rahul ; Silpe, Justin ; Dougherty, Casey ; Michmerhuizen, Nicole L. ; Van Winkle, Margaret ; Huang, Baohua ; Choi, Seok Ki ; Sinniah, Kumar ; Orr, Bradford G. ; Banaszak Holl, Mark M. / Poly(amidoamine) Dendrimer-Methotrexate Conjugates : The Mechanism of Interaction with Folate Binding Protein. In: Molecular Pharmaceutics. 2014 ; Vol. 11, No. 11. pp. 4049-4058.
@article{e0dd38ab2552446dbe04229e9fba1554,
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.",
keywords = "methotrexate, multivalent binding, PAMAM dendrimer, polymer/protein interactions",
author = "{van Dongen}, {Mallory A.} and Rahul Rattan and Justin Silpe and Casey Dougherty and Michmerhuizen, {Nicole L.} and {Van Winkle}, Margaret and Baohua Huang and Choi, {Seok Ki} and Kumar Sinniah and Orr, {Bradford G.} and {Banaszak Holl}, {Mark M.}",
year = "2014",
month = "11",
day = "3",
doi = "10.1021/mp500608s",
language = "English",
volume = "11",
pages = "4049--4058",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "11",

}

van Dongen, MA, Rattan, R, Silpe, J, Dougherty, C, Michmerhuizen, NL, Van Winkle, M, Huang, B, Choi, SK, Sinniah, K, Orr, BG & Banaszak Holl, MM 2014, 'Poly(amidoamine) Dendrimer-Methotrexate Conjugates: The Mechanism of Interaction with Folate Binding Protein' Molecular Pharmaceutics, vol. 11, no. 11, pp. 4049-4058. https://doi.org/10.1021/mp500608s

Poly(amidoamine) Dendrimer-Methotrexate Conjugates : The Mechanism of Interaction with Folate Binding Protein. / van Dongen, Mallory A.; Rattan, Rahul; Silpe, Justin; Dougherty, Casey; Michmerhuizen, Nicole L.; Van Winkle, Margaret; Huang, Baohua; Choi, Seok Ki; Sinniah, Kumar; Orr, Bradford G.; Banaszak Holl, Mark M.

In: Molecular Pharmaceutics, Vol. 11, No. 11, 03.11.2014, p. 4049-4058.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Poly(amidoamine) Dendrimer-Methotrexate Conjugates

T2 - The Mechanism of Interaction with Folate Binding Protein

AU - van Dongen, Mallory A.

AU - Rattan, Rahul

AU - Silpe, Justin

AU - Dougherty, Casey

AU - Michmerhuizen, Nicole L.

AU - Van Winkle, Margaret

AU - Huang, Baohua

AU - Choi, Seok Ki

AU - Sinniah, Kumar

AU - Orr, Bradford G.

AU - Banaszak Holl, Mark M.

PY - 2014/11/3

Y1 - 2014/11/3

N2 - 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.

AB - 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.

KW - methotrexate

KW - multivalent binding

KW - PAMAM dendrimer

KW - polymer/protein interactions

UR - http://www.scopus.com/inward/record.url?scp=84921267824&partnerID=8YFLogxK

U2 - 10.1021/mp500608s

DO - 10.1021/mp500608s

M3 - Article

VL - 11

SP - 4049

EP - 4058

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

SN - 1543-8384

IS - 11

ER -

van Dongen MA, Rattan R, Silpe J, Dougherty C, Michmerhuizen NL, Van Winkle M et al. Poly(amidoamine) Dendrimer-Methotrexate Conjugates: The Mechanism of Interaction with Folate Binding Protein. Molecular Pharmaceutics. 2014 Nov 3;11(11):4049-4058. https://doi.org/10.1021/mp500608s