RESUMO
BACKGROUND/AIM: Glioma is a deadly form of brain cancer. Doxorubicin is cytotoxic against glioma cells. However, the blood-brain barrier (BBB) limits its ability to be delivered to the brain. MATERIALS AND METHODS: Liposomes (R8PLP) formed from, 1,2-dioleoyl-3-trimethylammonium-propane chloride (DOTAP), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000] (PEG-DSPE), cholesterol and egg phosphatidylcholine (ePC) were modified by cell-penetrating peptide R8 conjugated with oleic acid as a novel method for delivering doxorubicin. The antitumor effect of R8PLP was evaluated by uptake, cytotoxicity and brain accumulation. RESULTS: The size of R8PLP was 95 nm. Doxorubicin was loaded into R8PLP by active loading with more than 95% encapsulation efficiency. Cellular uptake of R8PLP by U87-MG cells was 8.6-fold higher than that of unmodified liposomes. R8PLP reduced cell viability by 16.18% and 18.11% compared to cholesterol-ePC-liposomes and free doxorubicin, respectively, at 3.6 µM after 24 h treatment. The biodistribution of doxorubicin in the brain was significantly improved by R8PLP. The area under the concentration-time curve (AUC0.5-12 h) of R8PLP was 2.4-times higher than that of cholesterol-ePC-PEG-DSPE-liposomes. CONCLUSION: These results suggest that R8-conjugated oleic acid-modified liposomes are effective delivery vehicles for glioma.
Assuntos
Peptídeos Penetradores de Células/administração & dosagem , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Nanopartículas/administração & dosagem , Barreira Hematoencefálica/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Colesterol/química , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Ácidos Graxos Monoinsaturados/química , Glioma/patologia , Humanos , Lipossomos/administração & dosagem , Lipossomos/química , Nanopartículas/química , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Compostos de Amônio Quaternário/química , Distribuição Tecidual/efeitos dos fármacosRESUMO
PURPOSE: To determine the cloud point of a variety of nonionic surfactants and to search for means to raise the surfactant cloud point in liquid formulations. METHODS: Cloud points of nonionic surfactants were determined visually in a water bath. Organic compounds, many of which have been used as pharmaceutical excipients, were tested initially for effect on the cloud point of poloxamine 908. Four effective cloud point boosters (CPBs) from different structural classes were further tested on additional surfactants. RESULTS: A number of compounds can raise the cloud point of nonionic surfactants. These cloud point boosters are classified into two categories: nonionic and ionic. The nonionic CPBs include poly(ethylene glycols), propylene glycol, methanol, ethanol, isopropanol, and 2-hydroxypropyl-beta-cyclodextrin. They are effective at molar concentrations. The ionic CPBs include anionic and cationic surfactants, charged phospholipids, long chain fatty acids, and bile salts. They are effective at millimolar concentrations. CONCLUSIONS: The cloud point of nonionic surfactants used in liquid formulations can be modulated through the proper choice of excipient.
Assuntos
Excipientes/química , Tensoativos/química , Álcoois/química , Soluções Tampão , Carboidratos/química , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos/química , Etilenodiaminas/química , Ácidos Graxos/química , Ionóforos/química , Íons , Tamanho da Partícula , Fosfolipídeos/química , Polietilenoglicóis/química , Solubilidade , TemperaturaRESUMO
PURPOSE: To study the effects of formulation variables on the physical stability of a submicron crystal (nanocrystal) suspension under steam sterilization conditions. METHODS: Suspensions of ethyl diatrizoate nanocrystals were prepared by wet milling in the presence of the surfactant poloxamine 908. Particle size distribution and zeta potential were measured by photon correlation spectroscopy. RESULTS: On heating, the mean particle size of the nanocrystal suspension remained essentially unchanged up to 110 degrees C, the cloud point of the stabilizing surfactant, but increased significantly above that temperature. The increase in particle size was a result of particle aggregation rather than crystal growth. Adding a cloud point booster to the suspension significantly minimized the particle aggregation at high temperatures. The purity of poloxamine 908 and the tonicity agent and buffer salt used also affected the heat stability of the suspension, the latter agents apparently through altering the surfactant cloud point. CONCLUSIONS: The aggregation of the ethyl diatrizoate nanocrystalline suspension under steam sterilization conditions was a result of phase separation of the stabilizing surfactant at its cloud point. When formulated with a cloud point booster to prevent the phase-separation, the suspension maintained its physical stability under steam sterilization without any significant change in particle size distribution.