巨噬细胞炎症可激活的有机双光子光敏剂的设计合成及光动力治疗研究

Compared to the traditional one-photon photodynamic therapy, macrophage inflammation-activatable two-photon photodynamic therapy exhibits great perspective in treatment of atherosclerosis owing to its merits of deeper penetration depths, higher selectivity and negligible side-effects. However, the current challenge toward the treatment of atherosclerosis is serious lack of suitable activatable organic photosensitizers. This project proposed to construct organic two-photon photosensitizers with macrophage inflammation-activatable feature. Firstly, strong two-photon absorbed organic photosensitizer and quenching group are chemically linked by inflammation-responsive unit to quenching its fluorescence emission and photodynamic therapeutic capability. When as-synthesized activatable photosensitizers are internalized by the activated macrophages in atherosclerosis, the excess inflammation factor (e.g., H2O2) cleaves the linker between photosensitizer and quenching group, resulting in the recovery of fluorescence and photodynamic therapeutic capability. The fluorescence imaging can provide a multiple insightful information such as physiological and pathological details of atherosclerosis, therapy guidance, treatment assessment, and mechanistic studies. Meanwhile, the inflammation-activatable photodynamic therapy could selectively distinguished atherosclerosis from adjacent normal tissues to stabilize them, providing a precise therapy. We believe this work will greatly promote the advance of two-photon theranostic technique in diagnosis and treatment of atherosclerosis.

相较于传统单光子光动力治疗，巨噬细胞炎症可激活双光子光动力治疗具有组织穿透深度深、选择性高和副作用小等优势，在动脉粥样硬化疾病治疗方面具备极大的应用前景。但缺乏巨噬细胞炎症可激活有机双光子光敏剂是限制该类技术在动脉粥样硬化疾病诊断与治疗中的关键。本项目提出设计合成巨噬细胞炎症可激活的有机双光子光敏剂。通过巨噬细胞炎症因子（如过氧化氢）响应基团将强双光子吸收有机光敏剂和光猝灭基团联接，制备可激活有机双光子光敏剂。继而系统研究炎症因子刺激下有机双光子光敏剂荧光信号和光动力治疗能力的变化。最终通过对动脉粥样硬化疾病的可激活双光子荧光成像和光动力治疗研究，获取动脉粥样硬化疾病区域的形态结构及病变情况和光敏剂的分布及疗效评价的精准信息，实现对动脉粥样硬化疾病高选择性治疗干预，达到有效阻止动脉粥样硬化进一步恶化和相关并发症的目的，推动双光子诊疗技术在动脉粥样硬化疾病诊断与治疗中的应用。

提高光学诊疗的穿透深度和精准性是当前诊疗领域研究的热点和难点。基于传统近红外光激发的光学诊疗模式可以提高诊疗的穿透深度，但在精准性方面有一定的局限。近红外双光子激发的光动力治疗同时具有穿透深度深和三维空间选择性高的优势，但目前缺乏高效的光敏剂。本研究从有机光敏剂的构效关系出发，开发出了超高特异性激活的病理微环境智能响应双光子光敏剂，并用于疾病诊断和治疗领域的研究。本研究为未来肿瘤等重大疾病的高效特异性精准诊疗提供了重要方法及理论价值。此外，得益于本项目的资助，申请人团队是国内最早将超快光谱技术引入到光学诊疗研究的团队之一，并基于超快光学平台开展了系统、前沿的 “激发态调控与光学诊疗”研究，在国内外形成了一定的学术影响力。