Next generation of porphysomes for improved photodynamic therapy applications

Porphysomes are a class of liposome-like nanoparticles that have demonstrated efficacy in photothermal therapy (PTT) and photodynamic therapy (PDT) against cancer. These nanoparticles results from the self-assembly of amphiphilic phospholipid-porphyrin (PL-Por) conjugates. Despite their potential, porphysomes exhibit a high photothermal effect and a weak photodynamic activity as long as they remain intact within the body. In this study, we present the design of a novel generation of smart porphysomes capable of undergoing active dissociation and releasing porphyrin moieties upon illumination, thereby enabling tunable photothermal properties with enhanced photodynamic efficiency. These new porphysomes are composed of smart PL-Por conjugates that exhibit one or two ROS-responsive linkers separating the polar head group from the porphyrin moiety. Among the designed molecules, we demonstrated that monosubstituted conjugates bearing either pyro-a or pheo-a porphyrinoids with one ROS-responsive bond and shorter linker showed the best performance in terms of stability, photothermal and photodynamic efficiencies in vitro. Moreover, these assemblies were found to achieve complete tumor ablation in 80 % of PC3 prostate subcutaneous tumor-bearing mice after 30 days post-PDT, compared to 0 % using conventional porphysomes. Consequently, our strategy enabled the development of a versatile platform for delivering porphyrin-based photosensitizers for enhanced photodynamic applications.