Unsatisfactory drug loading capability, potential toxicity of the inert carrier and the limited therapeutic effect of a single chemotherapy drug are all vital inhibitory factors of carrier-assisted drug delivery systems for chemotherapy. To address the above obstacles, a series of carrier-free nanoplatforms self-assembled by dual-drug conjugates was constructed to reinforce chemotherapy against tumors by simultaneously disrupting intratumoral DNA activity and inhibiting mitochondria function. In this nanoplatform, the mitochondria-targeting small-molecular drug, α-tocopheryl succinate (TOS), firstly self-assembled into nanoparticles, which then were used as the carrier to conjugate cisplatin (CDDP). Systematic characterization results showed that this nanoplatform exhibited suitable particle size and a negative surface charge with good stability in physicochemical environments, as well as pH-sensitive drug release and efficient cellular uptake. Due to the combined effects of reactive oxygen species (ROS) generation by TOS and DNA damage by CDDP, the developed nanoplatform could induce mitochondrial dysfunction and elevated cell apoptosis, resulting in highly efficient anti-tumor outcomes in vitro. Collectively, the combined design principles adopted for carrier-free nanodrugs construction in this study aimed at targeting different intracellular organelles for facilitating ROS production and DNA disruption can be extended to other carrier-free nanodrugs-dependent therapeutic systems.

中文翻译：

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α-生育酚琥珀酸酯自组装的线粒体作用无载体纳米平台携带顺铂用于肿瘤联合治疗


载药能力不理想、惰性载体的潜在毒性以及单一化疗药物的治疗效果有限都是载体辅助化疗药物递送系统的重要抑制因素。为了解决上述障碍，构建了一系列由双药缀合物自组装的无载体纳米平台，通过同时破坏肿瘤内DNA活性和抑制线粒体功能来增强对肿瘤的化疗。在该纳米平台中，靶向线粒体的小分子药物α-生育酚琥珀酸酯（TOS）首先自组装成纳米颗粒，然后将纳米颗粒用作缀合顺铂（CDDP）的载体。系统表征结果表明，该纳米平台具有合适的粒径和负表面电荷，在理化环境中具有良好的稳定性，以及pH敏感的药物释放和高效的细胞摄取。由于TOS产生的活性氧（ROS）和CDDP损伤DNA的综合作用，所开发的纳米平台可以诱导线粒体功能障碍并增加细胞凋亡，从而在体外产生高效的抗肿瘤结果。总的来说，本研究中无载体纳米药物构建所采用的组合设计原则旨在针对不同的细胞内细胞器以促进 ROS 产生和 DNA 破坏，可以扩展到其他无载体纳米药物依赖性治疗系统。