Poly(amidoamine) Dendrimer鈥揗ethotrexate Conjugates: The Mechanism of Interaction with Folate Binding Protein
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- 作者：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
- 刊名：Molecular Pharmaceutics
- 出版年：2014
- 出版时间：November 3, 2014
- 年：2014
- 卷：11
- 期：11
- 页码：4049-4058
- 全文大小：549K
- ISSN：1543-8392
文摘
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鈥損rotein 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.