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

页码：4049 / 4058

页数：10

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