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Thermosensitive micellar hydrogel for enhanced anticancer therapy through redox modulation mediated combinational effects

机译：热敏胶束水凝胶通过氧化还原调节介导的联合作用增强抗癌治疗

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Cancer is increasingly viewed as an eco-system, a community in which tumor cells cooperate with other tumor cells and host cells in their microenvironment. The improved understanding of the intricate relationships in this eco-system has led to revolutionary treatments, which have evolved from relatively nonspecific cytotoxic agents to selective, mechanism-based therapeutics. Herein, from the view of dynamic equilibrium, a synergistic intracellular redox-regulation therapeutic strategy was proposed, in which combinational treatment of chemotherapeutic agents and ROS-elimination inhibitors was expected to effectively kill cancer cells and overcome redox adaptation mechanism associated drug resistance. To this end, a thermosensitive micellar hydrogel was prepared for co-delivery of nanomedicines in situ, which was capable of encapsulating and delivering multiple drugs with diverse therapeutic properties while maintaining the controlled synergistic ratio. Firstly, fluorescence resonance energy transfer (FRET) technology was adopted to track the real-time spatial pattern of drug presentation at a molecular level in this micellar hydrogel. Results suggested that the drug encapsulation in this micellar hydrogel platform proved to be a dynamic equilibrium process, during which free drug movement, drug exchange or penetration between micelles could occur. Furthermore, doxorubicin (DOX) and Zn(II) protoporphyrin IX (ZnPP) were used as the model chemotherapeutant and HO-1 inhibitor, respectively. In vitro and in vivo evaluation demonstrated that the intracellular redox-regulation mediated synergistic advantages of both two types of drugs translated into improved therapeutic outcomes. Consequently, such a thermosensitive micellar hydrogel formulation, which enabled precise control over the dosage and ratio of combination therapeutic agents to obtain the desired therapeutic effect with a single drug administration, holds great potential for spatiotemporal delivery of multiple bioactive agents for sustained combination therapy.
机译：癌症被越来越多地视为一个生态系统，在这个社区中，肿瘤细胞与它们的微环境中的其他肿瘤细胞和宿主细胞协同作用。对这个生态系统中复杂关系的更好的理解导致了革命性的治疗，其已经从相对非特异性的细胞毒性剂发展成为选择性的，基于机制的治疗剂。在此，从动态平衡的观点出发，提出了协同的细胞内氧化还原调节治疗策略，其中化学治疗剂和ROS消除抑制剂的组合治疗有望有效杀死癌细胞并克服与药物抗性相关的氧化还原适应机制。为此，制备了一种热敏胶束水凝胶以原位共递送纳米药物，该纳米药物能够封装和递送具有多种治疗特性的多种药物，同时保持受控的协同作用比。首先，采用荧光共振能量转移（FRET）技术在此胶束水凝胶中以分子水平跟踪药物呈递的实时空间模式。结果表明，该胶束水凝胶平台中的药物包封被证明是一个动态平衡过程，在此过程中，胶束之间可能发生自由的药物运动，药物交换或渗透。此外，阿霉素（DOX）和Zn（ II ）原卟啉IX（ZnPP）分别用作模型化学治疗剂和HO-1抑制剂。 体外和体内评估表明，细胞内氧化还原调节介导的两种药物的协同优势转化为改善的治疗效果。因此，这样的热敏胶束水凝胶制剂，其能够精确控制组合治疗剂的剂量和比例以通过单次药物施用获得所需的治疗效果，具有用于持续联合治疗的多种生物活性剂的时空递送的巨大潜力。

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