title: Pluronic®P123/F127 mixed micelles delivering sorafenib and its combination with verteporfin in cancer cells.
abstract: 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.
authors.affiliation: Research Nucleus of Photodynamic Therapy, Chemistry Department, State University of Maringá, Maringá, Brazil; Drug Delivery Laboratory, Department of Pharmacy, University of Naples Federico II, Naples.
authors.forename: Diogo Silva
authors.initials: DS
authors.lastname: Pellosi
authors.affiliation: Cell Biology Unit, Department of Biology, University of Padova, Padua.
authors.forename: Francesca
authors.initials: F
authors.lastname: Moret
authors.affiliation: Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Aurore
authors.initials: A
authors.lastname: Fraix
authors.affiliation: Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Nino
authors.initials: N
authors.lastname: Marino
authors.affiliation: Drug Delivery Laboratory, Department of Pharmacy, University of Naples Federico II, Naples.
authors.forename: Sara
authors.initials: S
authors.lastname: Maiolino
authors.affiliation: Cell Biology Unit, Department of Biology, University of Padova, Padua.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gaio
authors.affiliation: Research Nucleus of Photodynamic Therapy, Chemistry Department, State University of Maringá, Maringá, Brazil.
authors.forename: Noboru
authors.initials: N
authors.lastname: Hioka
authors.affiliation: Cell Biology Unit, Department of Biology, University of Padova, Padua.
authors.forename: Elena
authors.initials: E
authors.lastname: Reddi
authors.affiliation: Laboratory of Photochemistry, Department of Drug Sciences, University of Catania, Catania, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Sortino
authors.affiliation: Drug Delivery Laboratory, Department of Pharmacy, University of Naples Federico II, Naples.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Quaglia
keywords: Pluronic® micelles; chemotherapy; photodynamic therapy; sorafenib; verteporfin