Engineering photodynamics for treatment, priming and imaging

Photodynamic therapy (PDT) is a photochemistry-based treatment approach that relies on the activation of photosensitizers by light to locally generate reactive oxygen species that induce cellular cytotoxicity, in particular for the treatment of tumours. The cytotoxic effects of PDT are depth-limited owing to light penetration limits in tissue. However, photodynamic priming (PDP), which inherently occurs during PDT, can prime the tissue microenvironment to adjuvant therapies beyond the direct PDT ablative zone. In this Review, we discuss the underlying mechanisms of PDT and PDP, and their application to the treatment of cancer, outlining how PDP can permeabilize the tumour vasculature, overcome biological barriers, modulate multidrug resistance, enhance immune responses, increase tumour permeability and enable the photochemical release of drugs. We further examine the molecular engineering of photosensitizers to improve their pharmacodynamic and pharmacokinetic properties, increase their molecular specificity and allow image guidance of PDT, and investigate engineered cellular models for the design and optimization of PDT and PDP. Finally, we discuss alternative activation sources, including ultrasound, X-rays and self-illuminating compounds, and outline key barriers to the clinical translation of PDT and PDP.