TypeⅠ型有机光敏剂在光动力治疗中的研究进展

Progress of TypeⅠOrganic Photosensitizers for Photodynamic Therapy

光动力治疗是一种临床批准的新型治疗技术,其基于光敏剂在特定光照作用下产生活性氧来实现对疾病的治疗。根据产生活性氧的类型,光敏剂可分为TypeⅠ(氧自由基)和TypeⅡ(单线态氧)型。TypeⅡ型光动力治疗严重依赖分子氧浓度,这一特性限制了其在乏氧肿瘤治疗领域的实际应用。相比之下,TypeⅠ型光动力治疗即便在低氧条件下也能有效地生成氧自由基,因而在乏氧肿瘤治疗领域展现出了巨大的应用前景。然而,当前的TypeⅠ型光敏剂种类有限,且缺乏有效的设计策略,阻碍了它的进一步发展。本文综述了当前TypeⅠ型有机光敏剂的种类、设计思路及其在光动力治疗领域的最新研究进展,旨在为未来的研究提供参考。

Significance Photodynamic therapy(PDT)is a clinically approved novel treatment modality with the advantages of non-invasive characteristics,excellent spatiotemporal precision,and negligible multidrug resistance.The cornerstone of PDT is the use of a photosensitizer that generates cytotoxic reactive oxygen species(ROS)upon activation by the appropriate light to kill tumor cells.Photosensitizers are classified based on the ROS they produce—TypeⅠphotosensitizers generate oxygen radicals,whereas TypeⅡphotosensitizers yield singlet oxygen.The efficacy of TypeⅡPDT is notably constrained by its reliance on molecular oxygen,which limits the treatment of hypoxic tumors.In contrast,TypeⅠPDT exhibits a significant advantage under hypoxic conditions because it can effectively produce oxygen radicals even in hypoxic environments,thereby holding considerable promise for the treatment of hypoxic tumors.However,the development of TypeⅠPDT has been hindered by the scarcity of TypeⅠorganic photosensitizers and the absence of reliable design strategies.Therefore,addressing these challenges is crucial for the advancement of TypeⅠPDT.The development of new TypeⅠphotosensitizers,understanding their structure‒property relationships,and overcoming the challenges in designing these molecules are pivotal steps toward realizing their potential in clinical settings.This review comprehensively summarizes the progress in existing TypeⅠorganic photosensitizers for PDT,along with an exhaustive analysis of the structure‒property relationships and discussion of the ongoing challenges in this field.We hope that the knowledge and insights presented in this review will serve as a catalyst for further innovation in the field,ultimately contributing to the advancement of TypeⅠorganic photosensitizers in clinical settings.Progress TypeⅠphotosensitizers are particularly promising due to their inherent ability to generate ROS,such as superoxide anion(O 2−•)and hydroxyl radicals(·OH),without substantial reliance on oxygen.Organic photosensitizers are preferred over their inorganic counterparts for clinical use because of their good biosafety and tunable optical properties.Therefore,recent efforts in PDT have predominantly focused on the development of TypeⅠorganic photosensitizers.The spectrum of available TypeⅠorganic photosensitizers is broad,encompassing a variety of classes,including porphyrins,phenothiazine derivatives,BODIPYs,naphthalene imine derivatives,fluorescein derivatives,aggregation-induced emission(AIE)materials,and secondary near-infrared(NIR-II)materials.Despite this diversity,the availability of effective TypeⅠorganic photosensitizers remains limited,highlighting the critical need for more focused research and development in this area.Several seminal examples that have catalyzed the development of TypeⅠorganic photosensitizers have been emphasized.For example,porphyrin-based photosensitizers,such as verteporfin and 5-aminolevulinic acid,have been approved by the US Food and Drug Administration;however,they predominantly function as TypeⅡphotosensitizers.Notably,these TypeⅡporphyrin photosensitizers can be transformed into TypeⅠphotosensitizers via biotinylation.Biotin acts as an electron-rich substrate to promote electron uptake and subsequently enhance O 2−•production efficiency.This transformation represents an innovative strategy for repurposing and augmenting the efficacy of existing photosensitizers.Further research has revealed that the incorporation of side chains containing electron-donating atoms into porphyrin structures can achieve a transition between TypeⅠ/II,exhibiting noteworthy TypeⅠPDT efficiency.Interestingly,analogous results were observed for AIE-type photosensitizers synthesized through a cationic approach and supramolecular photosensitizers constructed through a host-guest strategy.A similar feature in these systems is electron redistribution,which promotes electron dissociation,thereby enhancing ISC efficiency and fostering the TypeⅠmechanism.Additionally,rational design onα,β-linked BODIPY has been shown to prolong the lifetime of the triplet state and lower its energy level,thereby diminishing the TypeⅡprocess and enhancing O 2−•production.Similarly,NIR-II materials with inherently low triplet energy levels exhibit enormous potential for TypeⅠprocesses.As anticipated,optimizing the triplet energy levels in NIR-II materials,such as by adjusting the chalcogenide elements,fosters the preferential generation of TypeⅠROS by inhibiting TypeⅡprogress.In addition,the modification on phenothiazine derivatives creates O 2−•generators with precise targeting abilities,yielding more pronounced antitumor efficiency.Despite notable progress and innovative approaches in this field,the advancement of TypeⅠorganic photosensitizers faces significant obstacles,primarily owing to the lack of a reliable and comprehensive design strategy.Therefore,there is an urgent need to formulate a comprehensive framework that addresses the design strategy and photophysical manipulation of TypeⅠorganic photosensitizers.Conclusions and Prospects This review provides a timely summary of the progress in TypeⅠorganic photosensitizers for PDT.We aim to provide a foundational framework that can guide the development of more effective and clinically viable TypeⅠorganic photosensitizers by thoroughly examining how structural variations influence the photophysical and photochemical properties.This is crucial for both new researchers entering the field and established scientists looking to update their knowledge base or pivot their research focus.Another key component of this review is the identification and discussion of the ongoing challenges in this field.This review seeks to inform and inspire ongoing and future research efforts by understanding both current limitations and future possibilities,ultimately accelerating the translation of research findings into tangible clinical benefits.