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

被引：28
|
作者：
van Dongen, Mallory A. [1 ]
Rattan, Rahul [2 ,4 ]
Silpe, Justin [2 ]
Dougherty, Casey [1 ]
Michmerhuizen, Nicole L. [5 ]
Van Winkle, Margaret [5 ]
Huang, Baohua [4 ]
Choi, Seok Ki [4 ]
Sinniah, Kumar [5 ]
Orr, Bradford G. [3 ,4 ]
Holl, Mark M. Banaszak [1 ,2 ,4 ]
机构：
[1] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Phys, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Michigan Nanotechnol Inst Med & Biol Sci, Ann Arbor, MI 48109 USA
[5] Calvin Coll, Dept Chem, Grand Rapids, MI 49546 USA
来源：
MOLECULAR PHARMACEUTICS | 2014年 / 11卷 / 11期
基金：
美国国家卫生研究院;
关键词：
BIOMEDICAL APPLICATIONS; TARGETED DRUG; FOLIC-ACID; DESIGN; HYDROPHOBICITY; DISTRIBUTIONS; FLUORESCENCE; ASSOCIATION; POLYMERS; DELIVERY;
D O I：
10.1021/mp500608s
中图分类号：
R-3 [医学研究方法]; R3 [基础医学];
学科分类号：
1001 ;
摘要：
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.
引用
收藏
页码：4049 / 4058
页数：10
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