From the clinical perspective of photodynamic therapy and photothermal Therapy: Structure-Activity-Practice

There is no doubt that phototherapy has become one of the most popular frontiers for both research and treatment. In practice, the selection of photosensitizers (Ps) or photothermal agents (PTAs) is significant to the efficacy of phototherapy. With the increased demand for precision medicine, the development of new generations of reagents is more and more urgent, especially for the clinical applications. Therefore, we review a series of Ps and PTAs that are used successfully in the clinic. At the molecular level, we have outlined the designing mechanism, structure-activity relationships, and working strategies for clinical applications, involving: (1) Rational molecular modification to improve precision: introducing long alkyl chains and aromatic groups into the molecular structure to regulate lipophilicity and to enhance targeting; introducing different types and positions of substituents, utilizing the heavy atom, altering the conjugation structure, and improving purity to modulate both the light absorption of Ps and the penetration depth of light; (2) Adjusting the drug-light interval in PDT to improve the delivery: a sufficient drug-light interval ensures the effective transportation of Ps into tumor cells, enabling the exertion of phototoxicity; (3) Reasonable laser dose to improve molecular efficiency: using a fractionated and low-dose laser irradiation can control the appropriate rate of oxygen consumption, so as to persistently generate reactive oxygen species (ROS); (4) Synergistic effect of phototherapy with other treatment modalities to overcome limitations: the combination of phototherapy with other treatment modalities can compensate for the shortcomings of phototherapy and enable its wider application in clinics. Efforts have always been made in phototherapy to enhance tumor targeting and reduce the side effects. We expect these strategies can provide valuable insights for the development of novel, highly selective, and rapidly metabolized Ps or PTAs, thereby promoting the development of the next generation of phototherapy for clinical applications.