基于pH响应解聚激活的抗肿瘤纳米光敏剂研究

Photodynamic therapy (PDT) is a promising modality for the treatment of a variety of premalignant and malignant tumor, and the therapeutic effects are majorly depended on photosensitizers. To improve the tumor-targeting property of photosensitizers and avoid damage to normal tissue are some urgent issues to solve for PDT. Considering the intrinsic aggregation tendency of zinc (II) phthalocyanine molecules to result in self-quenching, and the high biocompatibility and enhanced permeability and retention (EPR) effect of mesoporous silica nanoparticles (MSN), which will enhance the tumor selectivity, in this project, we will conjugate zinc (II) phthalocyanines with MSN through an endo-/lysosomal pH-responsive linker to form inactive photosensitizers as a result of aggregation through regulating the loading of photosensitizers, and construct a nanoparticle-based photosensitizer activated by pH-responsive disaggregation, which does not show photosensitizing properties during circulation in the body and can release the photosensitizers into tumor cells efficiently. A series of different nanoparticle-based photosensitizers will be prepared and characterized, and their photophysical and photochemical properties, pH-response, in vitro and in vivo activities are also going to be investigated to demonstrate the structure-activity relationships and conclude the structural characteristics of the tumor-targeted nanoparticle-based photosensitizers . This project shows a novel idea, and the study is expected to offer a new strategy for the design of tumor-targeted photosensitizers, furthermore, it also shows promising applications, and academic value for the development of multidisciplinary science.

光动力治疗是一种新兴的肿瘤治疗手段，光敏剂是决定其疗效的关键因素，如何进一步提高光敏剂的靶向性、避免对正常组织的损伤是当前该领域亟待解决的重要问题。基于锌酞菁光敏分子具有易聚集而自淬灭光敏活性的特性，并考虑到介孔二氧化硅纳米粒子生物相容性高且因EPR效应具有肿瘤组织选择性，本项目拟利用对细胞内pH敏感的连接基团，将锌酞菁负载到介孔二氧化硅纳米粒子上，并通过调整负载量，使其以无活性的聚集态存在，构建一种在体内循环过程中暂时无光敏化活性、但能够有效地在肿瘤细胞内通过pH响应解聚激活的纳米光敏剂。通过对不同组成结构特征的纳米光敏剂的制备、表征、光物理光化学性质、pH的响应情况、离体及活体生物活性的研究，揭示其构效关系，阐明具有肿瘤靶向性释药的纳米光敏剂应具备的结构特征。本项目的研究思路和研究内容新颖，其结果将为靶向抗癌光敏剂的设计提供新策略，具有重要的应用前景，并对促进学科交叉发展具有学术价值。

光动力治疗是一种新兴的肿瘤微创治疗手段，光敏剂是决定其疗效的关键因素，如何进一步提高光敏剂的靶向性、避免对正常组织的损伤是当前该领域亟待解决的重要问题。基于介孔二氧化硅纳米粒子（MSN）因EPR效应具有肿瘤组织选择性，本项目利用酞菁锌光敏分子的“聚集而自淬灭”效应，通过弱酸敏感的腙键将酞菁锌共价负载到介孔二氧化硅纳米粒子上，构建一种在体内循环过程中暂时无光敏化活性、但能够有效地在肿瘤细胞内通过pH响应解聚激活的纳米光敏剂。. 本项目首制备多种酞菁-介孔二氧化硅纳米光敏剂以研究酞菁结构和MSN的形态对纳米光敏剂的负载率和pH响应释药效率的影响。结果表明，1）体积较大的酞菁锌会降低其在MSN中的负载率；2）由于发射状的MSN与水溶液有较大的接触面积，因此较球形的MSN具有较高的pH响应释药效率；3）在一定浓度范围内增加酞菁锌的反应投料比可提高负载率；4）负载率较高的纳米光敏剂，其聚集行为和光敏能力淬灭效率更明显。基于前期的初步构效关系研究结果，我们进一步优化纳米光敏剂的组成结构，选择一个较理想的纳米光敏剂深入研究，包括pH-响应释放、离体光动力活性、亚细胞定位以及在体对肿瘤组织的选择性、pH响应激活和抑瘤效果。结果显示：1）纳米光敏剂中的酞菁锌比游离酞菁在有机溶剂和水溶液中都出现较严重的聚集，其光敏活性也明显下降；2）纳米光敏剂呈现出 pH响应释药并激活的性质；3）纳米光敏剂可在细胞内释药，且对人肝癌细胞HepG2的离体光动力活性接近对应游离的酞菁锌的光动力活性；4）纳米光敏剂可定位在呈弱酸性的溶酶体内，有助于纳米光敏剂的释药；5）纳米光敏剂能选择性在肿瘤部位被激活，并在显示对荷瘤小鼠较好的光动力抑瘤效果。. 本项目的研究思路具有新颖性，研究结果将为靶向抗癌光敏剂的设计提供新策略，具有重要的应用前景，并对促进学科交叉发展具有学术价值。