Star-shaped immunoglobulin-containing HPMA-based conjugates with doxorubicin for cancer therapy
Star-shaped immunoglobulin-containing HPMA-based conjugates with doxorubicin for cancer therapy
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DOI：
10.1016/j.jconrel.2007.06.007
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发表时间：
2007-09-11
影响因子：
10.8
通讯作者：
Ulbrich, Karel
中科院分区：
文献类型：
--
作者：
Etrych, Tomas;Mrkvan, Tomas;Ulbrich, Karel
合成了一种新型星形免疫球蛋白-多柔比星（DOX）偶联物，并对其抗癌活性进行了初步研究。用于合成免疫球蛋白-聚合物-药物缀合物的聚合物前体基于N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物，抗癌药物DOX通过pH敏感性腙键连接到免疫球蛋白修饰的聚合物。这样的聚合物-DOX缀合物在pH 7.4（血浆的pH）的水溶液中是稳定的，并且药物在pH 5-5.5（靶细胞的内体或溶酶体中的pH）的弱酸性环境中释放。半遥爪共聚物链通过单点连接与免疫球蛋白连接，以避免在我们早期研究的系统中观察到的缀合物的支化。在几种癌细胞系上测试的缀合物的细胞抑制活性与游离DOX-HCl的细胞抑制活性相似，并且与特定细胞系对DOX的敏感性相关。当在携带EL 4 T细胞淋巴瘤的小鼠中测试时，含有免疫球蛋白的星形缀合物显示出比不含免疫球蛋白的非靶向聚合物缀合物显著更高的体内抗肿瘤活性。(c)2007 Elsevier B. V.保留所有权利。
Synthesis and preliminary anticancer activity of new star-shaped immunoglobulin-containing polymer-doxorubicin (DOX) conjugates were investigated. The polymer precursors used for the synthesis of immunoglobulin-polymer-drug conjugates are based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers, the anticancer drug DOX is attached to the immunoglobulin-modified polymer via a pH-sensitive hydrazone linkage. Such polymer-DOX conjugates are stable in aqueous solution at pH 7.4 (pH of blood plasma) and the drug is released in mildly acid environment at pH 5-5.5 (pH in endosomes or lysosomes of target cells). Semitelechelic copolymer chains are linked to the immunoglobulin via one-point attachment to avoid branching of the conjugate observed in our earlier studied systems. The cytostatic activity of the conjugates tested on several cancer cell lines was similar to that of free DOX-HCl and correlated with the sensitivity of a particular cell line to DOX. The star-shaped conjugates containing immunoglobulin showed a significantly higher antitumor activity in vivo than immunoglobulin-free non-targeted polymer conjugates when tested in mice bearing EL4 T-cell lymphoma. (c) 2007 Elsevier B.V. All rights reserved.