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Macromolecular prodrugs of ribavirin: Polymer backbone defines blood safety, drug release, and efficacy of anti-inflammatory effects.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2018-02-09 , DOI: 10.1016/j.jconrel.2018.02.012 Kaja Zuwala 1 , Camilla F Riber 2 , Kaja Borup Løvschall 2 , Anna H F Andersen 1 , Lise Sørensen 2 , Paulina Gajda 3 , Martin Tolstrup 3 , Alexander N Zelikin 4
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2018-02-09 , DOI: 10.1016/j.jconrel.2018.02.012 Kaja Zuwala 1 , Camilla F Riber 2 , Kaja Borup Løvschall 2 , Anna H F Andersen 1 , Lise Sørensen 2 , Paulina Gajda 3 , Martin Tolstrup 3 , Alexander N Zelikin 4
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Macromolecular (pro)drugs hold much promise as broad-spectrum antiviral agents as either microbicides or carriers for intracellular delivery of antiviral drugs. Intriguing opportunity exists in combining the two modes of antiviral activity in the same polymer structure such that the same polymer acts as a microbicide and also serves to deliver the conjugated drug (ribavirin) into the cells. We explore this opportunity in detail and focus on the polymer backbone as a decisive constituent of such formulations. Fourteen polyanions (polycarboxylates, polyphosphates and polyphosphonates, and polysulfonates) were analyzed for blood pro/anti coagulation effects, albumin binding and albumin aggregation, inhibitory activity on polymerases, cytotoxicity, and anti-inflammatory activity in stimulated macrophages. Ribavirin containing monomers were designed to accommodate the synthesis of macromolecular prodrugs with disulfide-exchange triggered drug release. Kinetics of drug release was fast in all cases however enhanced hydrophobicity of the polymer significantly slowed release of ribavirin. Results of this study present a comprehensive view on polyanions as backbone for macromolecular prodrugs of ribavirin as broad-spectrum antiviral agents.
中文翻译：
利巴韦林的大分子前药：聚合物主链决定了血液安全性、药物释放和抗炎作用的功效。
大分子（前）药物作为广谱抗病毒药物具有广阔的前景，可以作为杀微生物剂或细胞内递送抗病毒药物的载体。有趣的机会在于将两种抗病毒活性模式结合在同一聚合物结构中，使得同一聚合物既可充当杀微生物剂，又可将结合药物（利巴韦林）输送到细胞中。我们详细探索了这一机会，并重点关注作为此类配方的决定性组成部分的聚合物主链。分析了 14 种聚阴离子（聚羧酸盐、聚磷酸盐、聚磷酸盐和聚磺酸盐）的血液促凝/抗凝作用、白蛋白结合和白蛋白聚集、聚合酶抑制活性、细胞毒性以及受刺激巨噬细胞的抗炎活性。含有单体的利巴韦林被设计用于通过二硫键交换触发药物释放来适应大分子前药的合成。在所有情况下，药物释放动力学都很快，但聚合物疏水性的增强显着减慢了利巴韦林的释放。这项研究的结果提出了关于聚阴离子作为利巴韦林大分子前药作为广谱抗病毒药物的主干的全面观点。
更新日期：2018-02-09
中文翻译：
利巴韦林的大分子前药：聚合物主链决定了血液安全性、药物释放和抗炎作用的功效。
大分子（前）药物作为广谱抗病毒药物具有广阔的前景，可以作为杀微生物剂或细胞内递送抗病毒药物的载体。有趣的机会在于将两种抗病毒活性模式结合在同一聚合物结构中，使得同一聚合物既可充当杀微生物剂，又可将结合药物（利巴韦林）输送到细胞中。我们详细探索了这一机会，并重点关注作为此类配方的决定性组成部分的聚合物主链。分析了 14 种聚阴离子（聚羧酸盐、聚磷酸盐、聚磷酸盐和聚磺酸盐）的血液促凝/抗凝作用、白蛋白结合和白蛋白聚集、聚合酶抑制活性、细胞毒性以及受刺激巨噬细胞的抗炎活性。含有单体的利巴韦林被设计用于通过二硫键交换触发药物释放来适应大分子前药的合成。在所有情况下，药物释放动力学都很快，但聚合物疏水性的增强显着减慢了利巴韦林的释放。这项研究的结果提出了关于聚阴离子作为利巴韦林大分子前药作为广谱抗病毒药物的主干的全面观点。
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