π-π Stacking Induced Enhanced Molecular Solubilization, Singlet Oxygen Production, and Retention of a Photosensitizer Loaded in Thermosensitive Polymeric Micelles

Cancer photodynamic therapy (PDT) by photosensitizers (PS)-loaded polymeric micelles (PM) is hampered by the tendency of PS to aggregate in PM and/or by premature release of PS in the blood circulation. In the present study, aromatic thermosensitive PM, characterized by π-π stacking interaction, are used to encapsulate an axially solketal-substituted silicon phthalocyanine (Si(sol)₂Pc) with enhanced loading capacity, smaller size, and significantly improved retention of Si(sol)₂Pc compared with systems based on thermosensitive PM lacking aromatic groups. Interestingly, Si(sol)₂Pc is much less prone to aggregation in the aromatic PM, i.e., the amount of Si(sol)₂Pc that could be encapsulated without aggregation is 330 times higher in the aromatic PM than in the nonaromatic PM. Furthermore, Si(sol)₂Pc in the aromatic PM in a molecularly dissolved (non-aggregated) form displays three times more efficient singlet oxygen production than Si(sol)₂Pc aggregated in the non-aromatic PM. As a result, the photocytotoxicity of Si(sol)₂Pc-loaded aromatic PM to B16F10 cells is increased, compared with that of the non-aromatic PM, while no significant cytotoxicity is observed in the dark. Fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM) analysis shows cell uptake of Si(sol)₂Pc loaded in the aromatic PM, and the Si(sol)₂Pc is taken up by the cells together with the micelles. The efficient singlet oxygen production of Si(sol)₂Pc dissolved in the aromatic PM makes it an interesting formulation for cancer PDT.