线粒体靶向功能纳米颗粒在肿瘤细胞光动力/光热协同治疗及疗效评估中的应用研究

In the field of cancer theranostics, multifunctional nanosystems integrating targeted therapy with drug delivery and response evaluation have drawn much attention. Both photodynamic therapy (PDT) and photothermal therapy (PTT) usually involve phototherapeutic agents with little toxicity in dark, and are able to selectively kill cancer cells under light irradiation, with low side-effect to normal tissues. Thus the combination of two methods would enhance the efficacy of cancer treatment. Owing to mitochondrial vital role in the initiation of apoptosis, mitochondria-targeted drug delivery and characterization of mitochondria activity are of great importance. However, traditional mitochondria-targeted agents were intricately synthesized to achieve the combination of PDT and PTT. Furthermore, in terms of the assessment of therapeutic efficacy, diagnostic imaging functionalities of theranostic platforms are suffering from low sensitivity and other shortcomings. In this proposal, we intend to prepare a type of multifunctional theranostic nanoparticles, which possess a hybrid core composed of photosensitizer and oxygen probe, and are deposited gold nanoparticles and TPP on the surface of shell. The resulting theranostic nanoparticles could be utilized to specifically target mitochondria for an effective PDT/PTT anticancer treatment, and detect oxygen consumption rate to further study therapeutic efficacy based on the oxygen sensitivity. Compared with monolayer cells, the therapeutic outcomes of three-dimensional multicellular spheroids would be evaluated to verify the effectiveness of theranostic nanoparticles. In summary, the study is of great significance to design theranostic nanoparticles, optimize treatment parameters and understand of the mechanism of PDT/PTT-induced apoptosis.

在癌症诊疗领域，整合靶向治疗和疗效监测功能的纳米体系引起了人们广泛的兴趣。光动力治疗（PDT）和光热治疗（PTT）均为依靠激光驱动的治疗手段，且都具有精确可控和毒副作用小等优点，二者联合应用将有效地增强治疗效果。由于线粒体在细胞凋亡中起重要作用，高效地将药物输送至线粒体并表征其活性是十分关键的。传统的线粒体靶向药物需通过复杂的化学合成以获得PDT与PTT的有效结合，而且在疗效评估方面，基于诊疗纳米颗粒荧光成像的监测手段尚存在不足之处。本项目拟制备一种内部封装光敏剂和氧探针、表面复合AuNPs及靶向序列的功能纳米颗粒，通过该纳米颗粒将药物靶向输送至线粒体进行PDT/PTT协同治疗，然后基于氧气传感功能对线粒体耗氧率进行原位检测，以评估细胞损伤情况，并与三维细胞球的治疗效果进行对比，验证其效用性。该研究对于扩展诊疗纳米颗粒种类、优化治疗参数以及深化认识PDT/PTT的损伤机制方面具有重要意义。

光学治疗是利用光学手段选择性地杀死肿瘤细胞的治疗技术，主要包括光动力治疗（PDT）和光热治疗（PTT）。基于纳米材料的治疗技术为癌症的诊断与治疗提供了新的方法，通过构建稳定、高效和安全的纳米载体，整合药物治疗、靶向运输和疗效监测等功能于一体的诊疗纳米体系将具有重要的研究意义。本项目通过构建功能纳米颗粒同时整合线粒体靶向光动力治疗和基于耗氧率的疗效评估，发展了一种原位定量评估治疗效果的肿瘤诊疗一体化方法；利用功能纳米颗粒实现光敏剂和光热药剂的有效结合，拓展了光动力和光热协同治疗纳米药物的种类；通过复合光敏剂和单线态氧敏感试剂的多功能纳米颗粒，获得同时结合光动力治疗和单线态氧检测的自监测肿瘤光动力治疗平台；通过复合光热药剂与温敏探针的生物兼容双功能纳米粒子，实现肿瘤细胞的光热消融和PTT过程中的实时温度监测。基于自监测方法获得微光环境温度及单线态氧的变化，实施反馈式的肿瘤细胞光学治疗。该项目对于拓展肿瘤光学治疗纳米探针种类，优化细胞凋亡的评价体系，促进肿瘤光学疗法的标准化及临床应用具有重要意义。