The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed new pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs exhibited nano-sized structure (∼100 nm) with good monodispersity, high encapsulation efficiency of both ICG and DOX, triggered DOX release in response to acid pH and reduction environment, and excellent temperature conversion with laser irradiation. In vitro cellular uptake study indicated FA Co-PMs achieved significant targeting to BEL-7404 cells via folate receptor-mediated endocytosis, and laser-induced hyperthermia further enhanced drug accumulation into cancer cells. In vivo biodistribution study indicated that FA Co-PMs prolonged drug circulation and enhanced drug accumulation into the tumor via EPR effect and FA targeting. Furthermore, the ICG-based photo-triggered hyperthermia combined with DOX-based chemotherapy synergistically induced the BEL-7404 cell death and apoptosis, and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs were promising theranostic nanocarriers for versatile antitumor drug delivery and imaging-guided cancer chemo-photothermal combination therapy.

Statement of Significance

The combination of chemotherapy and photothermal therapy in multifunctional nanovesicles has emerged as a promising strategy to improve cancer therapeutic efficacy. Herein, we designed novel pH/reduction dual-responsive and folate decorated polymeric micelles (FA Co-PMs) as theranostic nanocarrier to co-encapsulate doxorubicin (DOX) and indocyanine green (ICG) for targeted NIR imaging and chemo-photothermal combination therapy. The Co-PMs triggered DOX release in response to acid pH and reduction environment and exhibited excellent temperature conversion with laser irradiation. The results indicated FA Co-PMs achieved significant targeting to BEL-7404 cells in vitro and efficiently suppressed the BEL-7404 xenografted tumor growth while significantly reduced systemic toxicity in vivo. Therefore, the designed dual-responsive Co-PMs displayed great potential in imaging-guided cancer chemo-photothermal combination therapy as theranostic nanocarriers.

中文翻译：

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双重pH /还原反应性混合聚合物胶束，用于靶向化学-光热联合疗法

多功能纳米囊泡中化学疗法和光热疗法的结合已成为提高癌症治疗效果的一种有前途的策略。在本文中，我们设计了新的pH /还原双响应和叶酸修饰的聚合物胶束（FA Co-PMs）作为治疗诊断纳米载体，以共封装阿霉素（DOX）和吲哚菁绿（ICG），用于靶向NIR成像和化学光热联合疗法。Co-PMs表现出具有良好的单分散性的纳米级结构（〜100 nm），ICG和DOX的高封装效率，响应于酸性pH和还原环境触发了DOX的释放以及激光照射的出色温度转化。体外细胞摄取研究表明，FA Co-PMs通过叶酸受体介导的内吞作用实现了对BEL-7404细胞的显着靶向，激光诱导的高热进一步增强了药物向癌细胞的蓄积。体内生物分布研究表明，FA Co-PMs通过EPR效应和FA靶向作用延长了药物循环并增强了药物在肿瘤中的蓄积。此外，基于ICG的光触发热疗结合基于DOX的化疗可协同诱导BEL-7404细胞死亡和凋亡，并有效抑制BEL-7404异种移植肿瘤的生长，同时显着降低体内系统毒性。因此，设计的双反应性Co-PMs是有望用于多功能抗肿瘤药物递送和影像引导的癌症化学-光热联合疗法的治疗学纳米载体。

重要声明

多功能纳米囊泡中化学疗法和光热疗法的结合已成为提高癌症治疗效果的一种有前途的策略。在这里，我们设计了新型的pH /还原双响应和叶酸修饰的聚合物胶束（FA Co-PMs）作为治疗治疗纳米载体，以共封装阿霉素（DOX）和吲哚菁绿（ICG），用于靶向NIR成像和化学光热联合疗法。Co-PMs响应于酸性pH和还原环境触发了DOX的释放，并在激光辐照下表现出出色的温度转换。结果表明FA Co-PMs在体外实现了对BEL-7404细胞的显着靶向，并有效抑制了BEL-7404异种移植肿瘤的生长，同时显着降低了体内的全身毒性。所以，