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Poly(2-ethyl-2-oxazoline) conjugates with doxorubicin for cancer therapy: In vitro and in vivo evaluation and direct comparison to poly[N-(2-hydroxypropyl)methacrylamide] analogues
Biomaterials ( IF 14.0 ) Pub Date : 2017-09-06 , DOI: 10.1016/j.biomaterials.2017.09.003
Ondrej Sedlacek , Bryn D. Monnery , Jana Mattova , Jan Kucka , Jiri Panek , Olga Janouskova , Anita Hocherl , Bart Verbraeken , Maarten Vergaelen , Marie Zadinova , Richard Hoogenboom , Martin Hruby

We designed and synthesized a new delivery system for the anticancer drug doxorubicin based on a biocompatible hydrophilic poly(2-ethyl-2-oxazoline) (PEtOx) carrier with linear architecture and narrow molar mass distribution. The drug is connected to the polymer backbone via an acid-sensitive hydrazone linker, which allows its triggered release in the tumor. The in vitro studies demonstrate successful cellular uptake of conjugates followed by release of the cytostatic cargo. In vivo experiments in EL4 lymphoma bearing mice revealed prolonged blood circulation, increased tumor accumulation and enhanced antitumor efficacy of the PEtOx conjugate having higher molecular weight (40 kDa) compared to the lower molecular weight (20 kDa) polymer. Finally, the in vitro and in vivo anti-cancer properties of the prepared PEtOx conjugates were critically compared with those of the analogous system based on the well-established PHPMA carrier. Despite the relatively slower intracellular uptake of PEtOx conjugates, resulting also in their lower cytotoxicity, there are no substantial differences in in vivo biodistribution and anti-cancer efficacy of both classes of polymer-Dox conjugates. Considering the synthetic advantages of poly(2-alkyl-2-oxazoline)s, the presented study demonstrates their potential as a versatile alternative to well-known PEO- or PHPMA-based materials for construction of drug delivery systems.

中文翻译:

聚(2-乙基-2-恶唑啉)与阿霉素的共轭物用于癌症治疗:体内体外评估以及与聚[ N-(2-羟丙基)甲基丙烯酰胺]类似物的直接比较

我们基于具有线性结构和较窄摩尔质量分布的生物相容性亲水性聚(2-乙基-2-恶唑啉)(PEtOx)载体,设计并合成了一种新的抗癌药物阿霉素递送系统。该药物通过酸敏感的link连接子连接到聚合物主链,从而允许其在肿瘤中触发释放。在体外研究表明共轭其次是抑制细胞生长的货物释放的成功细胞吸收。与具有较低分子量(20 kDa)的聚合物相比,具有较高分子量(40 kDa)的PEtOx缀合物在携带EL4淋巴瘤的小鼠中进行的体内实验显示血液循环延长,肿瘤积累增加和抗肿瘤功效增强。最后,将制备的PEtOx缀合物的体外体内抗癌特性与基于完善的PHPMA载体的类似系统的抗癌特性进行了严格的比较。尽管PEtOx缀合物的细胞内吸收相对较慢,也导致它们的细胞毒性较低,但两类聚合物-Dox缀合物的体内生物分布和抗癌功效均无实质性差异。考虑到聚(2-烷基-2-恶唑啉)的合成优势,本研究证明了其作为众所周知的基于PEO或PHPMA的材料的通用替代品在构建药物输送系统方面的潜力。
更新日期:2017-09-06
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