近红外光敏剂负载抗癌药物的光声成像介导双模式肿瘤靶向治疗

Cancer, also called malignancy, is one of the most dangerous diseases to human life and health. Photodynamic therapy (PDT) is an novel approach for cancer therapy with non-intervention, minimal invasiveness and low toxicity. Compared with single therapeutic method, design and synthesis of efficient and targeted photosensitizer, packaging anticancer drugs with the resulted photosensitizer (PS) as a carrier, developing photodynamic/Chem-T dual-mode therapy can significantly improve the efficiency of tumor therapy. Therefore, we propose to synthesize a series of near-infrared absorbing Bodipy and DPP derivatives in this project. Subsequently, these molecules as absorbing antennas are covalently connected with C60 and hyaluronic acid to prepare amphiphilic photosensitizer (AC60HA). Through modification of the molecular structure, the energy transfer between Bodipy (or DPP) and C60 will be investigated to improve the NIR-absorption efficiency and the singlet oxygen generation efficiency of PS. Then, anti-cancer drugs are packaged with AC60HA as a carrier through self-assembly to obtain Drug@ AC60HA nanoparticles. We will study the relationship between the structure of photosensitizer and the loading mass, stimulating response as well as controlled release of the anticancer drug, respectively. The effect of oxygen concentration enhancement in tumor on treatment efficacy is also explored. At the same time, the targeting process of nanoparticles into tumor is monitored in real-time through photoacoustic imaging. we will study their dual-model therapeutic performance and mechanism both in vitro and in vivo, and further establish a safety evaluation system for PDT/Chem-T dual-model therapies.

癌症是对人类生命和健康威胁最大的疾病之一。光动力治疗是一种非介入、创伤小、毒性低的肿瘤治疗新方法，合成高效靶向光敏剂，以光敏剂为载体包裹抗癌药物，发展肿瘤的光动力-药物双模式治疗可显著提高肿瘤治疗效率。本项目拟合成一系列近红外BODIPY和DPP衍生物吸光天线，与富勒烯（C60）和透明质酸键接后制备两亲性光敏剂AC60HA，通过分子结构调整，研究BODIPY（或DPP）与C60之间的能量传递，增加光敏剂的近红外光利用效率和单线态氧产率；以AC60HA为载体，自组装包裹抗癌药物，制备Drug@AC60HA纳米颗粒,研究光敏剂结构与抗癌药物负载率、刺激响应及可控释放之间的构效关系，探索肿瘤内氧浓度的提高对肿瘤治疗效果的影响；通过光声成像实时监测纳米粒子进入肿瘤的靶向过程，研究纳米颗粒在小鼠模型中的光动力-药物双模式肿瘤治疗性能与机理，建立针对光动力-药物双模式肿瘤治疗的安全评价体系。

癌症是严重威胁人类生命健康的重大疾病之一，手术及放化疗等是当前临床肿瘤的常规治疗方法，但广泛存在副作用高、创伤大、选择性低等局限性。光治疗是一种光引发的低毒、高选择、低侵入的肿瘤治疗方法，具备组织选择性高、生理毒性小等优势。本项目围绕“近红外氟硼吡咯（BODIPY）光敏剂分子结构、刺激响应药物释放与肿瘤光治疗性能之间的构效关系”这一关键科学问题，开展系列研究。具体研究结果包括：.（1）针对传统BODIPY光敏剂吸收波长短、荧光量子效率差、单态氧产率低的问题，以BODIPY为给体（D）、吡咯并吡咯二酮为受体（A），设计合成出D-A-D结构BODIPY光敏剂，利用分子内给体与受体间的电子传递性质，得到吸收波长明显红移的BODIPY光敏剂，其荧光量子产率更高，系间窜跃性能更强，单线态氧产率更高，实现活体动态荧光成像引导的高效肿瘤光动力治疗。.（2）合成出两亲性席夫碱结构的PEG-DOX，用其包覆自组装aza-BODIPY光敏剂，实现肿瘤微酸响应的光动力/光热/化疗协同肿瘤治疗；此外，在光敏剂设计过程中，引入-NMe2官能团，利用光致电子转移机理，合成微酸响应型aza-BODIPY光敏剂，实现肿瘤微酸激活的光动力治疗，改善肿瘤治疗效果。.（3）针对肿瘤乏氧条件下化疗药物治疗效率低这一难题，提出“利用乏氧”策略，采用光动力治疗所造成的肿瘤乏氧来激活化疗药物，实现增强型光疗/化疗协同治疗，改善了肿瘤治疗效果；提出“克服乏氧”策略，通过负载DOX的aza-BODIPY体系中引入二氧化锰，原位催化瘤内双氧水产生氧气，有效改善肿瘤乏氧状态，增强光动力-化疗效果；提出“规避乏氧”的肿瘤治疗新策略，探索合成了I型光动力治疗aza-BODIPY纳米试剂，提高光动力治疗效率。

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