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Tumor microenvironment-targeted poly-L-glutamic acid-based combination conjugate for enhanced triple negative breast cancer treatment
Biomaterials ( IF 14.0 ) Pub Date : 2018-09-18 , DOI: 10.1016/j.biomaterials.2018.09.023
Juan J. Arroyo-Crespo , Ana Armiñán , David Charbonnier , Leandro Balzano-Nogueira , Francisco Huertas-López , Cristina Martí , Sonia Tarazona , Jerónimo Forteza , Ana Conesa , María J. Vicent

The intrinsic characteristics of the tumor microenvironment (TME), including acidic pH and overexpression of hydrolytic enzymes, offer an exciting opportunity for the rational design of TME-drug delivery systems (DDS). We developed and characterized a pH-responsive biodegradable poly-L-glutamic acid (PGA)-based combination conjugate family with the aim of optimizing anticancer effects. We obtained combination conjugates bearing Doxorubicin (Dox) and aminoglutethimide (AGM) with two Dox loadings and two different hydrazone pH-sensitive linkers that promote the specific release of Dox from the polymeric backbone within the TME. Low Dox loading coupled with a short hydrazone linker yielded optimal effects on primary tumor growth, lung metastasis (∼90% reduction), and toxicological profile in a preclinical metastatic triple-negative breast cancer (TNBC) murine model. The use of transcriptomic analysis helped us to identify the molecular mechanisms responsible for such results including a differential immunomodulation and cell death pathways among the conjugates. This data highlights the advantages of targeting the TME, the therapeutic value of polymer-based combination approaches, and the utility of –omics-based analysis to accelerate anticancer DDS.



中文翻译:

以肿瘤微环境为靶点的基于聚L-谷氨酸的联合缀合物,用于增强三阴性乳腺癌的治疗

肿瘤微环境(TME)的固有特征,包括酸性pH和水解酶的过表达,为合理设计TME药物输送系统(DDS)提供了令人兴奋的机会。我们开发并表征了一种基于pH响应的可生物降解的聚L-谷氨酸(PGA)组合结合物家族,旨在优化抗癌效果。我们获得了带有两个阿霉素负载量和两个不同的pH pH敏感连接子的阿霉素(Dox)和氨基谷氨酰胺(AGM)的结合共轭物,它们促进了TME从TME内的聚合物主链上特异性释放Dox。低Dox负荷加上短的link连接子对原发性肿瘤生长,肺转移(减少约90%)产生了最佳效果,临床前转移性三阴性乳腺癌(TNBC)鼠模型中的毒理学和毒理学概况。转录组学分析的使用帮助我们确定了导致这种结果的分子机制,包括缀合物之间的差异免疫调节和细胞死亡途径。该数据突出了靶向TME的优势,基于聚合物的联合方法的治疗价值以及基于–组学的分析可加快抗癌DDS的实用性。

更新日期:2018-09-19
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