可逆激活型光热/光动力试剂功能化长余辉纳米粒子用于肿瘤成像及治疗

Cancer poses a serious threat to human health. The development of precision diagnosis and therapy of cancer is of great significance. Theranostics, which integrates both diagnostic and photodynamic therapy (PDT) into a single platform, offers promising opportunities for precision therapy of cancer. However, the available PDT has the intrinsic disadvantage of phototoxicity and tissue damage due to the continuous irradiation with an external laser for a long time. Besides, most of the available photosensitizers are lack of tumor target and specificity, leading to side-effect to normal tissue. The project aims to develop tumor specifically activated photothermal/photodynamic therapy (PTT/PDT) system without any need for continuous external light irradiation for tumor-targeting imaging and efficient therapy. For this purpose, tumor acidic microenvironment activated asymmetric cyanine with photothermal/photodynamic effect will be synthesized and serve as PTT/PDT agent. Further introduction of hydrophobic cations (such as triphenylphosphine) endows the PTT/PDT agent with active tumor mitochondrial-targeting ability. Besides, near infrared-emitting long-persistent luminescence nanoparticles (PLNPs) will be prepared and act as both tumor-specific imaging unit and the internal light source. And then, the activated PTT/PDT system irradiated with PLNPs will be fabricated from the as-prepared PTT/PDT agent and PLNPs. Further functionalization with polyethylene glycol and cell penetrating peptide endows the nanoprobe with good biocompatibility and enhances the cell penetrability. The project will play an important role in promoting the development of tumor precision diagnosis and therapy.

癌症严重危害人类生命健康，开发癌症精准诊断及治疗技术具有重要意义。集诊断与光动力治疗于一体的诊疗一体化模式为癌症精准治疗提供了希望。现有光动力治疗体系受制于外光源连续照射引发的光毒性及组织损伤，且所用光敏剂大多缺乏肿瘤特异性，对正常组织存在非特异性损伤。本项目旨在构建免外光源连续激发的肿瘤特异性光热/光动力联合诊疗体系，实现肿瘤靶向成像及高效特异性治疗。拟合成集光热与光动力功能于一体的、肿瘤弱酸性微环境特异性激活型不对称菁类分子作为光热/光动力试剂，并修饰三苯基膦等阳离子赋予其肿瘤线粒体靶向性；制备近红外长余辉纳米粒子作为成像单元及内置激发光源；将两者偶联，进一步修饰聚乙二醇和细胞穿膜肽以增加复合材料的生物相容性及细胞摄入量，制得基于长余辉发光激发的肿瘤线粒体靶向可激活型光热/光动力诊疗系统，实现免外光源连续激发的肿瘤靶向成像及高效治疗。本项目的实施对肿瘤精准诊断及治疗的发展具有推动作用。

集诊断与高效治疗于一体的诊疗一体化模式为癌症精准治疗提供了希望。本项目围绕多功能智能诊疗探针的构建及其精准成像指引高效治疗开展工作，制备了肿瘤弱酸性特异性激活型光热/光动力一体化试剂，克服了现有治疗剂特异性差，副作用严重等问题；建立了高性能小粒径长余辉纳米粒子的可控制备方法，解决了制约长余辉材料用于生物应用的瓶颈问题；进一步发展了长余辉基光热/光动力诊疗一体化平台，实现了免外光源连续激发的精准成像指引光热/光动力治疗。本项目为高灵敏、高特异性诊疗一体化探针的构建提供了新材料和新策略。项目研究成果在本领域主流期刊上发表相关论文18篇（包含1篇Angew. Chem. Int. Ed.、1篇Chem. Sci.、1篇Adv. Funct. Mater.、2篇Anal. Chem.、3篇ACS Appl. Mater. Interfaces）。申请发明专利3项，已授权2项。