构建放大肿瘤活性氧信号的光激活型纳米载体用于精准药物递送和增强抗肿瘤效果

“Smart” bioresponsive drug delivery systems (DDSs) are appealing therapeutic platforms for the development of next-generation precision medications. There are still key issues in response efficacy of the DDSs in tumor treatment due to the heterogeneity of physiological signals among and within individuals. Therefore, this project develops a new light-activated nanocarrier, leveraging light to modulate the physiological signals of the tumor microenvironment, which can amplify the reactive oxygen species (ROS) signal in tumors for achieving precision drug delivery and enhancing anticancer efficacy. Furthermore, we innovatively explore a strategy to amplify the tumor ROS signal by synergistically weakening the antioxidant defense and reducing the oxygen consumption rate (OCR) of cancer cells, which would further improve the response efficiency and combined anticancer efficacy of the DDS. Specifically, a light-activated ROS-response DDS is designed to accomplish the combination chemotherapy and photodynamic therapy for effective cancer treatment. This system can amplify the level of the ROS signal through three approaches. Firstly, the ROS level is increased due to the generation of numerous singlet oxygen (1O2) by light activation of photosensitizer Chlorin e6 (Ce6), resulting in the dissociation of nanocarriers. Meanwhile, the release of drug Quinone methide (QM) is expected to weaken the antioxidant defense systems by glutathione (GSH) depletion. Subsequently, the delivery of Metformin (MET) or Atovaquone (ATO) is used to rapidly decrease the OCR for alleviating tumor hypoxia. In summary, this project will provide a novel strategy for the design of the smart light-responsive DDSs by generating or amplifying physiological signals, and would lay the foundation for the clinical development of precision-controlled drug delivery.

“智能”生物响应性递药系统将会成为引人注目的新一代精准药物治疗平台。针对药物载体因肿瘤个体性差异而对本征信号不能响应的问题，本课题提出发展新型光激活纳米递药系统，用光调控肿瘤微环境的生理因素，放大肿瘤活性氧（ROS）信号，实现精准控制药物递送和增强抗肿瘤效果。同时创新性提出通过降低肿瘤抗氧化能力和降低癌细胞耗氧率的方法协同放大肿瘤ROS信号，进一步提高递药系统的控释效率和联合治疗效果。本课题拟用光激活光敏剂Ce6产生大量单线态氧提高细胞内ROS水平以促进载体释放；释放药物苯醌甲基化物（QM）消耗细胞内抗氧化剂谷胱甘肽（GSH），以削弱肿瘤抗氧化防御系统；同时运载药物二甲双胍（MET）或阿托伐醌（ATO）降低癌细胞耗氧率以减缓肿瘤乏氧等三种途径放大ROS信号，共同构筑光激活ROS响应递药系统，实现对肿瘤化疗和光动力治疗等联合治疗。本课题为发展智能光控递药系统用于临床新药的精准递送奠定基础。

“智能”生物响应性递药系统将会成为引人注目的新一代精准药物治疗平台。本研究关注发展新型光激活型纳米递药系统用于肿瘤联合治疗。意在针对临床肿瘤新疗法的需求，研究新型纳米药物，增强或提高癌症新疗法的疗效，同时减轻治疗造成的不良反应。我们提出根据“光-肿瘤微环境-药”三位一体原则构建纳米药物。首先，构建治疗乏氧肿瘤的纳米药物。本研究提出新思路，通过加速肿瘤原位氧气生成效率、下调肿瘤细胞抗氧化能力、以及降低癌细胞耗氧率等途径，协同放大乏氧肿瘤的ROS信号水平，提高了乏氧肿瘤对光动力治疗响应性，显著提高了乏氧肿瘤的联合治疗效果。解决药物载体因肿瘤个体性差异而对本征信号不能响应的问题。其次，构建诊疗一体化纳米药物。基于光热效应构建多种新型的纳米药物，通过有效促进药物被肿瘤细胞摄取、实现肿瘤的深层渗透、实现光热或核磁共振成像引导治疗，有效解决肿瘤耐药和跟踪药物时空分布和控制释放，显著提高了肿瘤的联合治疗效果。有助于实现精确控制的癌症治疗。最后，基于放大肿瘤ROS信号构建新型肿瘤免疫联合治疗纳米药物。分别构建放大ROS信号和下调肿瘤内GSH的免疫纳米药物，实现让冷肿瘤变成热肿瘤，显著增强免疫细胞的肿瘤浸润能力，提高了肿瘤响应率及治疗效果，为肿瘤免疫治疗提供了新的思路。综上所述，我们发展光激活型纳米药物，用光调控肿瘤微环境的生理因素，产生或放大肿瘤ROS信号、光热效应以及免疫信号，实现临床抗癌药物的有效递送；实现化疗和光动力疗法、光热疗法以及免疫疗法等多种临床新疗法的联合治疗，增强肿瘤疗效；此外，实现肿瘤诊疗一体化，解决肿瘤耐药性、转移以及治疗带来的组织系统毒性等问题。本研究制备和评价多种新型光激活型纳米药物的生化性能和抗肿瘤活性，为构建有效的抗乏氧肿瘤、肿瘤转移及耐受的纳米药物提供理论和应用基础，为癌症精准给药提供新的思路和手段，也为发展智能光控递药系统用于临床新药的精准递送奠定基础。

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