Patients with triple negative breast cancer (TNBC) often suffer relapse, and clinical improvements offered by radiotherapy and chemotherapy are modest. Although targeted therapy and immunotherapy have been a topic of significant research in recent years, scientific developments have not yet translated to significant improvements for patients with TNBC. In view of these current clinical treatment shortcomings, we designed a silica nanosystem (SNS) with Nano-Ag as the core and a complex of MnO₂ and doxorubicin (Dox) as the surrounding mesoporous silica shell. This system was coated with anti-PD-L1 to target the PD-L1 receptor, which is highly expressed on the surface of tumor cells. MnO₂ itself has been shown to act as chemodynamic therapy (CDT), and Dox is cytotoxic. Thus, the full SNS system presents a multimodal, potentially synergistic strategy for the treatment of TNBC. Given potential interest in the clinical translation of SNS, the biological safety and antitumor activity of SNS were evaluated in a series of studies that included physicochemical characterization, particle stability, blood compatibility, and cytotoxicity. We found that the particle size and zeta potential of SNS were 94.6 nm and -22.1 mV, respectively. Ultraviolet spectrum analysis showed that Nano-Ag, Dox, and MnO₂ were successfully loaded into SNS, and the drug loading ratio of Dox was about 10.2%. Stability studies found that the particle size of SNS did not change in different solutions. Hemolysis tests showed that SNS, at levels far exceeding the anticipated physiologic concentrations, did not induce red blood cell lysis. Further in vitro and in vivo experiments found that SNS did not activate platelets or cause coagulopathy and had no significant effects on the total number of blood cells or hepatorenal function. Cytotoxicity experiments suggested that SNS significantly inhibited the growth of tumor cells by damaging cell membranes, increasing intracellular ROS levels, inhibiting the release of TGF-β1 cytokines by macrophages, and inhibiting intracellular protein synthesis. In general, SNS appeared to have favorable biosafety and antitumor effects and may represent an attractive new therapeutic approach for the treatment of TNBC.

中文翻译：

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基于多模式协同处理的新型肿瘤微环境响应型可生物降解介孔二氧化硅纳米系统的制备、生物安全和细胞毒性研究

三阴性乳腺癌 (TNBC) 患者经常复发，放疗和化疗提供的临床改善不大。尽管近年来靶向治疗和免疫治疗已成为重要研究课题，但科学发展尚未转化为 TNBC 患者的显着改善。针对目前临床治疗存在的这些不足，我们设计了一种以纳米Ag为核心，以MnO ₂和阿霉素（Dox）的复合物为周围介孔二氧化硅壳的二氧化硅纳米系统（SNS）。该系统涂有抗 PD-L1，以靶向在肿瘤细胞表面高度表达的 PD-L1 受体。的MnO ₂Dox 本身已被证明可作为化学动力学疗法 (CDT)，而 Dox 具有细胞毒性。因此，完整的 SNS 系统为 TNBC 的治疗提供了一种多模式、潜在的协同策略。鉴于对 SNS 临床转化的潜在兴趣，SNS 的生物安全性和抗肿瘤活性在一系列研究中进行了评估，包括理化特性、颗粒稳定性、血液相容性和细胞毒性。我们发现 SNS 的粒径和 zeta 电位分别为 94.6 nm 和 -22.1 mV。紫外光谱分析表明 Nano-Ag、Dox 和 MnO ₂成功加载到SNS中，Dox的载药率约为10.2%。稳定性研究发现，SNS 的粒径在不同溶液中没有变化。溶血试验表明，远超过预期生理浓度的 SNS 不会诱导红细胞裂解。进一步的体外和体内实验发现，SNS不会激活血小板或引起凝血功能障碍，对血细胞总数或肝肾功能没有显着影响。细胞毒性实验表明，SNS通过破坏细胞膜、增加细胞内ROS水平、抑制TGF- β的释放来显着抑制肿瘤细胞的生长。1 巨噬细胞的细胞因子，并抑制细胞内蛋白质的合成。总的来说，SNS 似乎具有良好的生物安全性和抗肿瘤作用，可能代表了一种有吸引力的治疗 TNBC 的新治疗方法。