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

[Image: see text] 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 ex...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224518/
https://www.ncbi.nlm.nih.gov/pubmed/25222480
http://dx.doi.org/10.1021/mp500608s
Descripción
Sumario:[Image: see text] 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.