ABSTRACT
With the aim of improving the topical delivery of the antineoplastic drug 5-fluorouracil (5FU), it was loaded into ultradeformable liposomes composed of soy phosphatidylcholine and sodium cholate (UDL-5FU). The liposome populations had a mean size of 70 nm without significant changes in 56 days, and the ultradeformable formulations were up to 324-fold more elastic than conventional liposomes. The interaction between 5FU and the liposomal membrane was studied by three methods, and also release profile was obtained. UDL-5FU did penetrate the stratum corneum of human skin. At in vitro experiments, the formulation was more toxic on a human melanoma-derived than on a human keratinocyte-derived cell line. Cells captured liposomes by metabolically active processes. In vivo toxicity experiments were carried out in zebrafish (Danio rerio) larvae by studying the swimming activity, morphological changes, and alterations in the heart rate after incubation. UDL-5FU was more toxic than free 5FU. Therefore, this nano-formulation could be useful for topical application in deep skin precancerous lesions with advantages over current treatments. This is the first work that assessed the induction of apoptosis, skin penetration in a Saarbrücken penetration model, and the toxicological effects in vivo of an ultradeformable 5FU-loaded formulation.
Subject(s)
Antineoplastic Agents/administration & dosage , Fluorouracil/administration & dosage , Nanoparticles/administration & dosage , Administration, Cutaneous , Administration, Topical , Adult , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Apoptosis/drug effects , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Drug Compounding , Drug Liberation , Female , Fluorouracil/chemistry , Fluorouracil/toxicity , Heart Rate/drug effects , Humans , Keratinocytes/drug effects , Larva/drug effects , Larva/physiology , Liposomes , Melanoma/drug therapy , Motor Activity/drug effects , Nanoparticles/chemistry , Nanoparticles/toxicity , Phosphatidylcholines/administration & dosage , Phosphatidylcholines/chemistry , Phosphatidylcholines/toxicity , Skin/metabolism , Skin Absorption , Sodium Cholate/administration & dosage , Sodium Cholate/chemistry , Sodium Cholate/toxicity , Zebrafish/physiologyABSTRACT
BACKGROUND/AIMS: The current study compared the effects of intratracheal administration of different lipopolymeric vectors on lung function and histology in normal mice. METHODS: Forty-eight BALB/c mice were randomly divided into 8 groups (6/group). All animals received intratracheal instillation of the following suspensions: polymerized [(A) 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC):1,2-bis-(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8,9PC):1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), (B) DMPC:DC8,9PC:stearylamine (SA), (C) DMPC:DC8,9PC:myristoylcholine chloride (MCl)]; nonpolymerized [(D) DMPC:DC8,9PC:DOTAP, (E) DMPC:DC8,9PC:SA, (F) DMPC:DC8,9PC:MCl] together with plasmid DNA; vehicle (control), and pDsRed2-N1 plasmid DNA (DNA). At 24 h, the survival rate, lung mechanics (resistive and viscoelastic pressure, static elastance) and morphometry were analyzed. RESULTS: The survival rate was 50% in D, 40% in E and F, and 100% in the CTRL, DNA, A, B and C groups. Animals from groups D, E, and F that died presented diffuse pulmonary hemorrhagic capillaritis. Lung mechanics, the fraction of normal and collapsed alveoli, as well as the number of polymorphonuclear and mononuclear cells in lung tissue were similar in all surviving mice. CONCLUSION: Intratracheal instillation of polymerized particles is safe compared with nonpolymerized formulations and may be used for future gene/drug therapy.
Subject(s)
Drug Carriers , Polymers/administration & dosage , Trachea , Animals , Base Sequence , DNA Primers , Mice , Mice, Inbred BALB C , Real-Time Polymerase Chain Reaction , Respiratory Mechanics , Spectrophotometry, UltravioletABSTRACT
Risperidone is an approved antipsychotic drug belonging to the chemical class of benzisoxazole. This drug has low solubility in aqueous medium and poor bioavailability due to extensive first-pass metabolism and high protein binding (>90%). As new strategies to improve treatments efficiency are needed, we have studied cationic G4 PAMAM dendrimers' performance to act as efficient nanocarriers for this therapeutic drug. In this respect, we explored dendrimer-risperidone complexation dependence on solvent, temperature, pH and salt concentration, as well as in vitro cytotoxicity measured on L929 cell line and human red blood cells. The best dendrimer-risperidone incorporation was achieved when a mixture of 70:30 and 90:10 v/v chloroform:methanol was used, obtaining 17 and 32 risperidone molecules per dendrimer, respectively. No cytotoxicity on L929 cells was found when dendrimer concentration was below 3 × 10(-2) µM and risperidone concentration below 5.1 µM. Also, no significant hemolysis or morphological changes were observed on human red blood cells. Finally, attempting to obtain an efficient drug delivery system for risperidone, incorporation in G4 PAMAM dendrimers was optimized, improving drug solubility with low cytotoxicity.
