title: Lipid nanoemulsions loaded with doxorubicin-oleic acid ionic complex: characterization, in vitro and in vivo studies.
abstract: 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.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan, P R China.
authors.forename: Xuanmiao
authors.initials: X
authors.lastname: Zhang
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
authors.forename: Jilong
authors.initials: J
authors.lastname: Li
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Zhang
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004396:Coloring Agents; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D004339:Drug Compounding; D004563:Electrochemistry; D004655:Emulsions; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles; D000442:Octanols / Q000737:chemistry; D019301:Oleic Acid / Q000737:chemistry*; D010316:Particle Size; D012995:Solubility; D013778:Tetrazolium Salts; D013844:Thiazoles; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D004396:Coloring Agents; D004337:Drug Carriers; D004655:Emulsions; D000442:Octanols; D013778:Tetrazolium Salts; D013844:Thiazoles; D014867:Water; D019301:Oleic Acid; D004317:Doxorubicin; C022616:thiazolyl blue