Highly effective anti-tumor nanomedicines based on HPMA copolymer conjugates with pirarubicin prepared by controlled RAFT polymerization
Highly effective anti-tumor nanomedicines based on HPMA copolymer conjugates with pirarubicin prepared by controlled RAFT polymerization
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DOI：
10.1016/j.actbio.2020.02.011
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发表时间：
2020-04-01
影响因子：
9.7
通讯作者：
Etrych, Tomas
中科院分区：
文献类型：
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作者：
Randarova, Eva;Nakamura, Hideaki;Etrych, Tomas
在这里，我们描述了基于 N-(2-羟丙基) 甲基丙烯酰胺 (HPMA) 的明确生物相容性聚合物载体及其与吡柔比星的药物缀合物的创新合成，旨在用于肿瘤组织中的受控药物输送和 pH 触发药物激活。对聚合物载体合成进行优化，以最少的合成步骤获得分散度接近 1、摩尔质量接近肾阈值的明确线性 HPMA 聚合物前体。所开发的合成方法能够制备具有高度增强的体内生物学行为的定制聚合物纳米药物，特别是生物分布、尿液消除、肿瘤积累和抗癌活性。意义声明该手稿报告了基于N-(2-羟丙基)甲基丙烯酰胺(HPMA)的明确的生物相容性亲水性共聚物的新颖合成和详细的理化表征以及体内评估，以及它们与吡柔比星的药物缀合物，能够在肿瘤组织中控制药物输送和pH触发的药物激活。聚合物载体合成经过优化，可使用受控聚合以最少的合成步骤获得明确的线性 HPMA 聚合物前体。与之前发表的基于HPMA的聚合物药物缀合物（其聚合物载体是通过自由基聚合的经典路线制备的）相比，新制备的聚合物药物缀合物表现出增强的体内生物学行为，特别是延长血液循环、尿液消除、肿瘤积累和优异的抗癌活性。我们相信，新制备的结构明确的聚合物缀合物可以显着增强人类肿瘤治疗。 (C) 2020 Acta Materialia Inc. 由 Elsevier Ltd 出版。保留所有权利。
Here, we describe innovative synthesis of well-defined biocompatible N-(2-hydroxypropyl) methacrylamide (HPMA)-based polymer carriers and their drug conjugates with pirarubicin intended for controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with dispersity close to 1 and molar mass close to renal threshold with minimal synthesis steps. The developed synthesis enables preparation of tailored polymer nanomedicines with highly enhanced biological behavior in vivo, especially the biodistribution, urine elimination, tumor accumulation and anticancer activity.Statement of SignificanceThe manuscript reports on novel synthesis and detailed physicochemical characterization and in vivo evaluation of well-defined biocompatible hydrophilic copolymers based on N-(2-hydroxypropyl) methacrylamide (HPMA) and their drug conjugates with pirarubicin enabling controlled drug delivery and pH-triggered drug activation in tumor tissue. Polymer carrier synthesis was optimized to obtain well-defined linear HPMA-based polymer precursor with minimal synthesis steps using controlled polymerization. Compared to previously published HPMA-based polymer drug conjugates whose polymer carriers were prepared by classical route via free radical polymerization, the newly prepared polymer drug conjugates exhibited enhanced biological behavior in vivo, especially the prolonged blood circulation, urine elimination, tumor accumulation and excellent anticancer activity. We believe that the newly prepared well-defined polymer conjugates could significantly enhance tumor therapy in humans. (C) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.