Here, we developed Pluronic® P123/
F127 (
poloxamer) mixed
micelles for the intravenous delivery of the anticancer drug
sorafenib (SRB) or its combination with
verteporfin (VP), a
photosensitizer for
photodynamic therapy that should
complement well the cytotoxicity profile of the chemotherapeutic. SRB loading inside the core of
micelles was governed by the drug:
poloxamer weight ratio, while in the case of the SRB-VP combination, a mutual interference between the two drugs occurred and only specific ratios could ensure maximum loading efficiency. Coentrapment of SRB did not alter the photophysical properties of VP, confirming that SRB did not participate in any bimolecular process with the
photosensitizer. Fluorescence resonance energy-transfer measurement of
micelles in
serum protein-containing cell-culture medium demonstrated the excellent stability of the system in physiologically relevant conditions. These results were in line with the results of the release study showing a release rate of both drugs in the presence of
proteins slower than in
phosphate buffer. SRB release was sustained, while VP remained substantially entrapped in the
micelle core. Cytotoxicity studies in MDA-MB231 cells revealed that at 24 hours, SRB-loaded
micelles were more active than free SRB only at very low SRB concentrations, while at 24+24 hours a prolonged cytotoxic effect of SRB-loaded
micelles was observed, very likely mediated by the block in the S phase of the cell cycle. The combination of SRB with VP under light exposure was less cytotoxic than both the free combination and VP-loaded
micelles + SRB-loaded
micelles combination. This behavior was clearly explainable in terms of
micelle uptake and intracellular localization. Besides the clear advantage of delivering SRB in
poloxamer micelles, our results provide a clear example that each photochemotherapeutic combination needs detailed investigations on their particular interaction, and no generalization on enhanced cytotoxic effects should be derived a priori.