用于肿瘤光动力/光热协同治疗的低氧依赖性聚合物囊泡研究

光敏剂的胞内递送和氧依赖性是肿瘤光动力治疗中的难点。本项目拟合成pH、光氧化响应的聚乙二醇-聚己内酯-聚吡啶酮三臂聚合物，构建载双功能光敏剂Bodipy和吡啶酮内过氧化物的聚合物囊泡。通过对囊泡理化性质的调控，增强其肿瘤靶向和细胞摄取能力；囊泡进入肿瘤细胞溶酶体后，缩醛键的酸响应解离能有效促进Bodipy的持续释放；在光治疗中，囊泡中的Bodipy能同时产生单线态氧和光热效应，单线态氧在诱导光动力治疗的同时，可迅速诱导囊泡中缩硫酮的光氧化解离以及溶酶体的破裂，进一步促进Bodipy的快速释放和胞浆转运，增强其光动力治疗作用；而光热效应则在降低Bodipy耗氧量、产生光热治疗的同时，能有效诱导囊泡中吡啶酮内过氧化物快速释放单线态氧，产生非氧依赖的光动力治疗效应；最终实现低氧依赖的肿瘤光动力、光热协同治疗。本项目对探索光敏剂的高效递送及在乏氧肿瘤治疗中的应用具有重要的理论意义及实用价值。

It is difficult to achieve the intracellular delivery of photosensitizers and overcome their oxygen dependence in cancer photodynamic therapy (PDT). In this application, we propose to synthesize pH- and photo-oxidation-responsive poly (ethylene glycol)-poly(caprolactone)-poly(pyridone) terpolymer, and further construct the polymeric vesicles encapsulating both bifunctional Bodipy photosensitizer and pyridone-derived endoperoxide. The physicochemical properties of these vesicles are optimized to improve their tumor accumulation and cellular uptake. Upon their endocytosis into the lysosomes, the acetal group in the vesicles can be decomposed in response to the lysosomal acidity and thus trigger the continuously enhanced release of Bodipy from the vesicles. Meanwhile, Bodipy in the vesicles can generate both singlet oxygen and photothermal effect under light treatment. Their singlet oxygen not only generates PDT efficacy, but also induces the cleavage of thioketal group in the vesicles in response to the photo-oxidation and simultaneous lysosomal rupture, which further result in the quick release of Bodipy and subsequent cytoplasmic translocation, followed by their enhanced PDT efficacy. Moreover, their photothermal effect is also able to cause photothermal therapy of Bodipy with reduced oxygen depletion, and simultaneous singlet oxygen release from pyridone-derived endoperoxide that can produce oxygen-independent PDT efficacy. Thus, these vesicles can finally achieve the synergistically photodynamic and photothermal cancer therapies with reduced oxygen dependence. This work is very valuable to explore highly efficient intracellular delivery of photosensitizers and their uses in treating hypoxia tumors.