Translational aspects of photodynamic therapy in drug-resistant cancer

Cancer is a physiologically and molecularly heterogeneous disease in which therapeutic contingency majorly depends on the developmental stage and intrinsic-genotypic profile. For most malignancies, standard treatment options include surgical excision, localized radiotherapy, combinatorial chemotherapy, and protein-based targeted therapies. Unfortunately, cancer cells are able to overcome most therapeutic modalities and develop resistant phenotypes largely due to pharmacologic pressure, genomic instability, and increased mutational rate. Photodynamic therapy (PDT) is a therapeutic approach introduced into the clinic in the mid-20th century that relies on the excitation of a photosensitizer (PS) with an appropriate light source in the presence of molecular oxygen to generate reactive oxygen species and kill cancer cells. In addition to spatiotemporal activation and confined cytotoxicity, PDT has been shown to re-sensitize cancer cells to chemotherapy through intrinsic regulation of intracellular redox systems, cell death mediators, as well as effective activation of immune cells. With the advent of nanomedicine and chemical synthesis, new PSs and their combination with nanocarriers have been explored in preclinical phases and recently in clinical trials. In this chapter, we review some of the fundamental and translational aspects of PDT by looking at its history and the pioneering work that led to its approval for clinical implementation, as well as novel individual and combinatorial approaches that are providing new directions in this therapeutic modality.