肿瘤乏氧检测与光动力治疗一体化的新型多功能荧光分子探针研究

Hypoxia is an important microenvironment character of solid tumors. It has become an important research field to develop theranostic molecular probes aiming at tumor hypoxia determination and photodynamic therapy (PDT). Currently, reagents used in hypoxia determination and PDT are often compounds containing heavy atoms or rare-earth metals. It is difficult to develop molecular probes which have low dark cytotoxicity and high photo cytotoxicity. In this proposal, a series of pure organic fluorescence hypoxia-responsive molecular probes will be developed with low toxicity and multi-functions. They are designed and will be synthesized based on a class of fluorescein derivatives with a delayed-fluorescence which is a new research achievement in my research group. The designed multi-functional molecular probes will be used in tumor hypoxia determination and PDT at the same small molecule. These molecular probes provide many good advantages including capability of activation by bio-reductase, target on carbonic anhydrase IX, hypoxia determination and overcoming the limits of hypoxia in PDT.

乏氧是实体瘤的一个重要微环境特征，针对乏氧开展肿瘤诊疗一体化研究，是一个非常重要的研究方向。当前乏氧监测和光动力治疗试剂普遍使用含重原子或稀土金属，开发兼具低的暗毒性和高的光毒性的分子探针是一个科学难题。本项目基于前期一类延迟荧光性质的荧光素衍生染料的研究成果，拟设计合成一系列纯有机的新型低毒多功能荧光分子探针，用于肿瘤乏氧检测和光动力治疗中。这类多功能型诊疗一体化小分子探针，兼具可被生物还原酶激活、靶向羧酸酐酶、乏氧检测和克服光动力治疗的乏氧限制等优势。

肿瘤乏氧是肿瘤微环境的典型特征，严重削弱了光动力诊疗的治疗效果。针对这一难题，本项目开展了多功能荧光分子探针和光敏剂的研究。多功能光敏剂的研究包含以下三个方面的内容。一、激活型光敏剂，利用硝基还原酶的在微乏氧条件下的激活能力，开发了微乏氧激活策略的光敏剂；同时开发了肿瘤酸性微环境激活的光敏剂。二、靶向型光敏剂。开发了生物素靶向和整合素靶向的光敏剂。三、活性氧开源节流型纳米光敏剂。开发了有机无机复合的纳米光敏剂， 实现消耗谷胱甘肽和活性氧的自供应，达到协同增强光动力治疗效果。项目最重要的研究成果是提出了一种意料之外的生物素靶向光敏剂的策略，获得了缓解肿瘤乏氧限制提升光动力治疗效率的有效方法。基于这种生物素化策略同时兼具肿瘤靶向和耐低氧能力。这个研究成果具有普适性，可以将传统的II型光动力光敏剂转为不受乏氧限制的I型光敏剂。研究结果发表在Nature Communications, 2022, 13, 2225。这些成果，为解决肿瘤光动力治疗存在的乏氧限制，提供了多种有效解决方案。项目执行期发表相关 SCI 论文 34 篇，获得授权专利4项。