The next frontier of photodynamic therapy: Nuclear-targeted small-molecule photosensitizers for precise tumor cell elimination

Abstract

As a new therapeutic modalities, photodynamic therapy (PDT) has become a research hotspot in recent years due to its significant advantages such as spatiotemporal accuracy, minimally invasive properties, and low damage to surrounding normal tissues. Photosensitizer (PS) which could produce reactive oxygen species (ROS) under laser irradiation is the decisive factor in the efficacy of PDT. However, the ROS generated by PS has a short lifetime (<40 ns) and a small diffusion distance (<20 nm), which limits their effectiveness in PDT. Therefore, the position of PS in cells is a key factor affecting PDT outcomes. Organelles are an indispensable part of cells in performing biological functions. It should be considered as an important choice for the optimal required distance for PDT. Among organelles, as the "brain" of cells, the nucleus is responsible for genetics and metabolism, and is also the site of action for many anticancer drugs. Therefore, nucleus-targeted PDT is lethal to cells. This review discusses the binding mode between nucleus-targeted PS and DNA, along with the way of nucleus-targeted and the applications of nucleus-targeted PS in vivo. It also emphasizes the potential applications and challenges of nucleus-targeted PS. Overall, nucleus-targeted PS could serve as a promising tool for advancing the field of PDT and improving its clinical applicability.