Lipid nanoemulsions loaded with doxorubicin-oleic acid ionic complex: characterization, in vitro and in vivo studies

This study aimed at developing a novel lipid nanoemulsion formulation of doxorubicin (DOX) which is feasible for scale-up production, exhibits good parenteral acceptability, and further improves the therapeutic index of the drug. Oleic acid was used to form ionic complex with DOX in order to enhance its lipophilicity. The lipid nanoemulsions loaded with doxorubicin-oleic acid complex (DOX-OA-LNs) were prepared using a simple high-pressure homogenization method and fully characterized from physicochemical and in vitro release standpoint. Afterwards, the DOX-OA-LNs and free DOX were compared with respect to their in vitro cellular uptake and cytotoxicity, and their in vivo pharmacokinetics and biodistribution behavior in mice were also investigated. The obtained DOX-OA-LNs could achieve high encapsulation efficiency of 93.7 +/- 1.2% under optimal conditions. The in vitro release behavior displayed biphasic drug release pattern with rapid release at the initial stage and prolonged release afterwards. The DOX-OA-LNs exhibited higher growth inhibitory effect than free DOX by MTT assay. Flow cytometry and confocal microscopy studies showed that the cellular uptake of free DOX and DOX-OA-LNs were comparable. Pharmacokinetics and in vivo distribution studies in mice showed that DOX-OA-LNs demonstrated significantly higher DOX level in blood and longer circulation time than free DOX. Moreover, DOX-OA-LNs significantly decreased DOX concentration in heart, lung and kidney. These results suggested that DOX-OA-LNs could be a promising formulation for the delivery of DOX in tumor chemotherapy.