What NIR photodynamic activation offers molecular targeted nanomedicines: Perspectives into the conundrum of tumor specificity and selectivity

Near infrared (NIR) photodynamic activation is playing increasingly critical roles in cutting-edge anti-cancer nanomedicines, which include spatiotemporal control over induction of therapy, photodynamic priming, and phototriggered immunotherapy. Molecular targeted photonanomedicines (mt-PNMs) are tumor-specific nanoscale drug delivery systems, which capitalize on the unparalleled spatio-temporal precision of NIR photodynamic activation to augment the accuracy of tumor tissue treatment. mt-PNMs are emerging as a paradigm approach for the targeted treatment of solid tumors, yet remain highly complex and multifaceted. While ligand targeted nanomedicines in general suffer from interdependent challenges in biophysics, surface chemistry and nanotechnology, mt-PNMs provide distinct opportunities to synergistically potentiate the effects of ligand targeting. This review provides what we believe to be a much-need demarcation between the processes involved in tumor specificity (biomolecular recognition events) and tumor selectivity (preferential tumor accumulation) of ligand targeted nanomedicines, such as mt-PNMs, and elaborate on what NIR photodynamic activation has to offer. We discuss the interplay between both tumor specificity and tumor selectivity and the degree to which both may play central roles in cutting-edge NIR photoactivable nanotechnologies. A special emphasis is made on NIR photoactivable biomimetic nanotechnologies that capitalize on both specificity and selectivity phenomena to augment the safety and efficacy of photodynamic anti-tumor regimens.