Visualizing Photodynamic Therapy in Transgenic Zebrafish Using Organic Nanoparticles with Aggregation-Induced Emission

Photodynamic therapy (PDT) is a noninvasive triggered therapeutic modality, which involves the use of photosensitizer (PS) molecules capable of generating reactive oxygen species (ROS) upon light excitation for treatment of malignant and non-malignant tumors. Over the last three decades, several PSs have been developed and some of them have been successfully used to treat different kinds of cancers [ 1 , 2 ]. PDT can also be combined with chemotherapy for synergistic therapeutic effect [ 3 ] and to achieve triggered drug release from vesicles [ 4 ]. Typically, upon light illumination, the formed PS triplet state releases energy to convert ambient oxygen molecules to reactive oxygen species (ROS) such as 1O 2 , H 2 O 2 , O 2 − · and · OH. The generated ROS can cause an increase in oxidative stress in cells. At elevated concentrations, ROS oxidize lipids, proteins and DNA, which leads to damage in various cell organelles and eventually cell death. Cancer cells operate at a sensitive oxidative threshold making them vulnerable to further increase in ROS [ 5 ]. Therefore, directly causing ROS to exceed the threshold concentration that is toxic to cells can kill cancer cells more easily as compared to that for normal cells [ 6 ]. Currently, PDT application potential is limited by low light penetration through tissue and poorly characterized tumor PS uptake. While the former can be addressed by chemiluminescence-induced ROS production [ 7 , 8 ], so far there is no straightforward tool to characterize or visualize the PS uptake. However, the success of PDT is strongly dependent on PS versus light dosage, trigger time, PS distribution and oxygen concentration in the tumor microenvironment [ 9 , 10 ]. Several clinical studies have characterized the PS dose and corresponding light dose for effective PDT in cancers of various organs [ 11 , 12 ]. The oxygen concentration variation in the process of PDT has been modeled, simulated and validated in tumor spheroid models [ 13 , 14 ]. Although the importance of quantifying PS accumulation has been realized [ 15 , 16 ], a sensitive in vivo model to do the same has not been established. Real-time quantitative visualization of PS concentration in target tissue enables concentration-dependent trigger of the PS, thereby allowing unbiased evaluation of various PS molecules.