BACKGROUND It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal. RESULTS In this work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity. CONCLUSIONS The system developed in this work has the potential to provide new therapies for hard-to-treat cancers.

中文翻译：

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用于三阴性乳腺癌治疗的基于壳聚糖的级联响应药物递送系统。

背景技术开发针对三阴性乳腺癌（TNB）的靶向治疗极其困难，因为这些细胞不表达通常用于此目标的任何关键生物标志物。结果在这项工作中，我们开发了一种基于热敏聚（N-乙烯基己内酰胺）（PNVCL）-壳聚糖（CS）纳米颗粒（NP）的级联响应纳米平台形式的解决方案。它们进一步用细胞穿透肽 (CPP) 进行修饰，并装载化疗药物阿霉素 (DOX)。基础共聚物经过优化，可在肿瘤微环境的高温下发生相变。CS 的酸响应特性为药物释放提供了第二个触发因素，并且 CPP 的包含应确保制剂在癌组织中积累。所得的CPP-CS-co-PNVCL NPs可以在水介质中自组装成尺寸<200 nm且具有低多分散性的球形NPs。它们能够适应高 DOX 负载（14.8% w/w）。研究发现，纳米颗粒在体外和体内均被癌细胞选择性吸收，与单独使用 DOX 治疗相比，其脱靶细胞毒性较小。采用TNB异种移植小鼠模型的体内实验表明，肿瘤体积显着减小，寿命延长，且没有明显的全身毒性。结论 这项工作中开发的系统有潜力为难以治疗的癌症提供新的疗法。