ABSTRACT
The therapeutic effect of tumor photodynamic therapy is severely limited by the hypoxic tumor microenvironment. Inhibiting tumor celloxygen consumption is a more effective way than increasing its oxygen supply to overcome the tumor hypoxia and enhance photodynamic therapy. To carry out this strategy, the supramolecular nanoparticles VER-ATO-SMN loaded with photosensitizer verteporfin (VER), oxygen-consuming inhibitor atovaquone (ATO), and stabilizer polyvinylpyrrolidone (PVP)-K30 were prepared by the nanoprecipitation method, and the optimal prescription was screened and optimized by single factor experiments. The results showed that the optimal prescription for VER-ATO-SMN was ATO∶VER (w/w) = 1∶1, PVP-K30 = 100 mg, N,N-dimethylformamide∶water (v/v) = 1∶10. The morphology, particle size, particle dispersion index and encapsulation efficiency of supramolecular nanoparticles were characterized. The VER-ATO-SMN showed a spherical morphology and was well dispersed. The hydrodynamic size of VER-ATO-SMN was 101.21 ± 4.30 nm as determined by dynamic light scattering (DLS). The encapsulation efficiencies of VER and ATO in VER-ATO-SMN prepared with the optimal prescription were 70.86% and 77.52%, respectively. The VER-ATO-SMN exhibited good laser stability and also showed high stability in conditions which simulated the physiological solution. Compared with free VER and VER liposome, VER-ATO-SMN performed enhanced therapeutic effect at the cell level. The mechanism was that VER-ATO-SMN could effectively incorporate into cells and improving the intracellular oxygen concentration by reducing the oxygen consumption of tumor cells could increase the amount of reactive oxygen species generated by VER mediated photodynamic therapy. The in vivo anticancer efficacy results of tumor-bearing mice suggested that VER-ATO-SMN could effectively inhibit the tumor growth or even completely eliminate the tumor. All animal experiments were performed in line with national regulations and approved by the Animal Experiments Ethical Committee of 900 Hospital of the Joint Logistics Team.