PEG-PDMAEMA嵌段共聚物结构对肝素与聚电解质复合物形成的影响,Biomacromolecules

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PEG-PDMAEMA嵌段共聚物结构对肝素与聚电解质复合物形成的影响
Biomacromolecules ( IF 5.5 ) Pub Date : 2016-08-08 00:00:00 , DOI: 10.1021/acs.biomac.6b00699
Salla Välimäki ₁ , Alexey Khakalo ₂ , Ari Ora ₁ , Leena-Sisko Johansson ₂ , Orlando J. Rojas ₂ , Mauri A. Kostiainen ₁

Affiliation

肝素是由硫酸化多糖主链组成的天然存在的聚电解质。在大型外科手术中，它被广泛用作抗凝剂。但是，相关的出血风险需要在手术后迅速中和。肝素的唯一临床批准的解毒剂是硫酸鱼精蛋白，但是，它对低分子量肝素无效，并可能导致严重的不良反应。在这项研究中，提出了阳离子中性二嵌段共聚物的简便合成及其与肝素的有效结合。聚（乙二醇）-聚（甲基丙烯酸2-（二甲基氨基）乙酯）（PEG-PDMAEMA）嵌段共聚物是使用PEG作为大分子引发剂，通过原子转移自由基聚合（ATRP）分两步合成的。通过动态光散射和亚甲基蓝置换试验研究了肝素与一系列PEG-PDMAEMA嵌段共聚物和一种均聚物之间的溶液状态结合。还利用发色肝素抗Xa分析研究了血浆中的体外结合。此外，石英晶体微天平和多参数表面等离子体共振用于研究肝素层上聚合物的表面吸附动力学。结果表明，嵌段共聚物和肝素形成具有不同胶体性质的静电结合复合物，其中嵌段长度在控制肝素结合亲和力，聚电解质复合物的大小和表面电荷中起关键作用。使用优化的聚合物（PEG ₁₁₄ PDMAEMA ₅₂和PEG ₁₁₄ PDMAEMA ₁₀₀），肝素可以剂量依赖的方式被中和，并有效地结合成小的中性复合物，其流体力学半径小于100 nm。这些复合物对细胞生存力只有有限的影响。基于这些研究，我们的方法为开发新型聚合物肝素结合剂铺平了道路。

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Effect of PEG–PDMAEMA Block Copolymer Architecture on Polyelectrolyte Complex Formation with Heparin

Heparin is a naturally occurring polyelectrolyte consisting of a sulfated polysaccharide backbone. It is widely used as an anticoagulant during major surgical operations. However, the associated bleeding risks require rapid neutralization after the operation. The only clinically approved antidote for heparin is protamine sulfate, which is, however, ineffective against low molecular weight heparin and can cause severe adverse reactions in patients. In this study, the facile synthesis of cationic-neutral diblock copolymers and their effective heparin binding is presented. Poly(ethylene glycol)–poly(2-(dimethylamino)ethyl methacrylate) (PEG–PDMAEMA) block copolymers were synthesized in two steps via atom-transfer radical polymerization (ATRP) using PEG as a macroinitiator. Solution state binding between heparin and a range of PEG–PDMAEMA block copolymers and one homopolymer was studied with dynamic light scattering and methylene blue displacement assay. Also in vitro binding in plasma was studied by utilizing a chromogenic heparin anti-Xa assay. Additionally, quartz crystal microbalance and multiparametric surface plasmon resonance were used to study the surface adsorption kinetics of the polymers on a heparin layer. It was shown that the block copolymers and heparin form electrostatically bound complexes with varying colloidal properties, where the block lengths play a key role in controlling the heparin binding affinity, polyelectrolyte complex size and surface charge. With the optimized polymers (PEG₁₁₄PDMAEMA₅₂ and PEG₁₁₄PDMAEMA₁₀₀), heparin could be neutralized in a dose-dependent manner, and bound efficiently into small neutral complexes, with a hydrodynamic radius less than 100 nm. These complexes had only a limited effect on cell viability. Based on these studies, our approach paves the way for the development of new polymeric heparin binding agents.

更新日期：2016-08-08

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