基于肿瘤乏氧分子靶向治疗的pH响应光敏剂的设计合成及联合抗癌作用研究

Hypoxia is the characteristic feature of most solid tumors. A large number of studies have shown that hypoxia dampens the therapeutic effect of non-surgical treatment of tumors, and even lead to tumor metastasis and drug resistance, thus tumor hypoxia is a major challenge in the treatment of tumors. Based on the challenges caused by hypoxia-induced poor prognosis of PDT and PDT-induced hypoxia aggravation, the pioneering studies mainly use combination therapy utilizing nano-drug delivery system or simple mixture to solve. However the research at the molecular level is still rarely reported. This project intends to address the hypoxia challenges of PDT at the molecular level. We aim to ingeniously introduce the tumor hypoxia molecular targeted therapeutic drug RH1 into the phthalocyanine ring via a pH-responsive linker, by pH-cleavage, maximally protect the activity phthalocyanine and RH1. Thus, we intend to design and synthesize a series of novel pH-responsive photosensitizers based on tumor hypoxia molecular targeted therapy.Thus, a series of novel pH-responsive photosensitizers based on tumor hypoxia molecular targeted therapy are designed and synthesized to achieve the combination of tumor hypoxia molecular targeted therapy and photodynamic therapy at the molecular level. It will provide a new idea for clinical response to hypoxia challenge, and provide a theoretical basis for the design and development of new photosensitizers and the expansion of PDT treatment drug system.

乏氧是多数实体瘤的固有特征。大量研究结果表明乏氧导致肿瘤非手术治疗疗效明显下降，甚至导致肿瘤转移及产生耐药性，因而是肿瘤治疗中的一大难题。基于肿瘤本身乏氧导致的光动力治疗（PDT）不良预后及PDT消耗组织氧导致的乏氧加剧带来的挑战，现有的研究主要利用纳米载药体系或简单混合形式上的联合治疗来解决，而分子水平的研究尚鲜见报道。本研究拟在分子水平应对PDT面临的乏氧挑战，将肿瘤乏氧分子靶向治疗药物RH1通过pH响应连接链引入酞菁环，通过pH剪切最大限度保障酞菁和RH1的分子活性，从而制备一系列新型的基于肿瘤乏氧分子靶向治疗的pH响应光敏剂，有望在分子水平实现乏氧分子靶向治疗和光动力治疗的联合，为临床上应对肿瘤乏氧挑战提供新的思路，同时也为新型光敏剂的设计和开发、扩展PDT治疗药物体系提供理论依据。

如何提高光敏剂的靶向性及光动力治疗效果是光动力治疗领域研究的焦点。本项目将肿瘤乏氧分子靶向治疗药物（也称选择性乏氧细胞毒剂）RSU-1069、Tirapazamine、小分子靶向药物Tamoxifen及靶向多肽AAN引入酞菁环，从而制备一系列新型的分子靶向治疗光敏剂。RSU-1069、Tirapazamine、Tamoxifen及多肽AAN的引入可在提高光敏剂靶向性的同时实现分子靶向治疗和光动力治疗的联合，从而有效提高光动力治疗效果。在本项目中，课题组设计、合成系列酞菁偶合物，测定该系列偶合物的光物理、光化学、光生物活性，并分析其构效关系。主要研究结果如下：Tamoxifen的引入明显提高了酞菁锌母环的靶向性，且实现了分子靶向治疗与光动力治疗的双重作用。所得偶合物均具有很高的光动力活性，且无暗毒作用，均有望开发为抗癌光敏剂。RSU-1069、Tirapazamine偶合物的合成目前仍在进行中；AAN-酞菁偶合物已合成得到，其靶向性及光动力活性测试仍在进行中。本项目对新型光敏剂的设计和开发具有理论指导意义及实际应用价值。