Smart molecular designs and applications of activatable organic photosensitizers

Photodynamic therapy (PDT) - which combines light, oxygen and photosensitizers (PS) to generate reactive oxygen species - has emerged as an effective approach for targeted ablation of pathogenic cells with reduced risk of inducing resistance. Some organic PS are now being applied for PDT in the clinic or undergoing evaluation in clinical trials. A limitation of the first-generation organic PS was their potential off-target toxicity. This shortcoming prompted the design of constructs that can be activated by the presence of specific biomolecules - from small biomolecules to large enzymes - in the target cells. Here, we review advances in the design and synthesis of activatable organic PS and their contribution to PDT in the past decade. Important areas of research include novel synthetic methodologies to engineer smart PS with tuneable singlet oxygen generation, their integration into larger constructs such as bioconjugates, and finally, representative examples of their translational potential as antimicrobial and anticancer therapies.