Progress of Type Ⅰ Organic Photosensitizers for Photodynamic Therapy
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-Type Ⅰ photosensitizers generate oxygen radicals,whereas Type Ⅱphotosensitizers yield singlet oxygen.The efficacy of Type Ⅱ PDT is notably constrained by its reliance on molecular oxygen,which limits the treatment of hypoxic tumors.In contrast,Type Ⅰ PDT 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 Type Ⅰ PDT has been hindered by the scarcity of Type Ⅰ organic photosensitizers and the absence of reliable design strategies.Therefore,addressing these challenges is crucial for the advancement of Type Ⅰ PDT.The development of new Type Ⅰ photosensitizers,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 Type Ⅰ organic 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 Type Ⅰ organic photosensitizers in clinical settings.Progress Type Ⅰ photosensitizers are particularly promising due to their inherent ability to generate ROS,such as superoxide anion(O2-·)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 Type Ⅰ organic photosensitizers.The spectrum of available Type Ⅰ organic 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 Type Ⅰ organic 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 Type Ⅰ organic 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 Type Ⅱ photosensitizers.Notably,these Type Ⅱ porphyrin photosensitizers can be transformed into Type Ⅰphotosensitizers via biotinylation.Biotin acts as an electron-rich substrate to promote electron uptake and subsequently enhance O2-·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 Type Ⅰ/Ⅱ,exhibiting noteworthy Type Ⅰ PDT 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 Type Ⅰ mechanism.Additionally,rational design on a,β-linked BODIPY has been shown to prolong the lifetime of the triplet state and lower its energy level,thereby diminishing the Type Ⅱ process and enhancing O2-·production.Similarly,NIR-Ⅱ materials with inherently low triplet energy levels exhibit enormous potential for Type Ⅰprocesses.As anticipated,optimizing the triplet energy levels in NIR-Ⅱ materials,such as by adjusting the chalcogenide elements,fosters the preferential generation of Type Ⅰ ROS by inhibiting Type Ⅱ progress.In addition,the modification on phenothiazine derivatives creates O2-·generators with precise targeting abilities,yielding more pronounced antitumor efficiency.Despite notable progress and innovative approaches in this field,the advancement of Type Ⅰ organic 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 Type Ⅰ organic photosensitizers.Conclusions and Prospects This review provides a timely summary of the progress in Type Ⅰ organic photosensitizers for PDT.We aim to provide a foundational framework that can guide the development of more effective and clinically viable Type Ⅰ organic 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.
medical opticsbiophotonicsorganic photosensitizersphotodynamic therapyreactive oxygen speciessinglet oxygen
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