title: Non-ionic surfactant vesicles in pulmonary glucocorticoid delivery: characterization and interaction with human lung fibroblasts.
abstract: Non-ionic surfactant vesicles (NSVs) were proposed for the pulmonary delivery of glucocorticoids such as beclomethasone dipropionate (BDP) for the treatment of inflammatory lung diseases, e.g. asthma, chronic obstructive pulmonary disease and various type of pulmonary fibrosis. The thin layer evaporation method followed by sonication was used to prepare small non-ionic surfactant vesicles containing beclomethasone dipropionate. Light scattering experiments showed that beclomethasone dipropionate-loaded non-ionic surfactant vesicles were larger than unloaded ones and showed a significant (P<0.001) decrease of the zeta potential. The morphological analysis, by freeze-fracture transmission electron microscopy, showed the maintenance of a vesicular structure in the presence of the drug. The colloidal and storage stability were evaluated by Turbiscan Lab Expert, which evidenced the good stability of BDP-loaded non-ionic surfactant vesicles, thus showing no significant variations of mean size and no colloidal phase segregation. Primary human lung fibroblast (HLF) cells were used for in vitro investigation of vesicle tolerability, carrier-cell interaction, intracellular drug uptake and drug-loaded vesicle anti-inflammatory activity. The investigated NSVs did not show a significant cytotoxic activity at all incubation times for concentrations ranging from 0.01 to 1 μM. Confocal laser scanning microscopy showed vesicular carrier localization at the level of the cytoplasm compartment, where the glucocorticoid receptor (target site) is localized. BDP-loaded non-ionic surfactant vesicles elicited a significant improvement of the HLF intracellular uptake of the drug with respect to the free drug solution, drug/surfactant mixtures and empty vesicles used as references. The treatment of HLF cells with BDP-loaded non-ionic surfactant vesicles determined a noticeable increase of the drug anti-inflammatory activity by reducing the secretion of both constitutive and interleukin-1β-stimulated nerve growth factor (as inflammatory index) of 68% and 85%, respectively. Obtained data indicate that the investigated NSVs represent a promising tool as a pulmonary drug delivery system.
authors.affiliation: Department of Drug Chemistry and Technologies, Faculty of Pharmacy, University Sapienza, Rome, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Marianecci
authors.forename: Donatella
authors.initials: D
authors.lastname: Paolino
authors.forename: Christian
authors.initials: C
authors.lastname: Celia
authors.forename: Massimo
authors.initials: M
authors.lastname: Fresta
authors.forename: Maria
authors.initials: M
authors.lastname: Carafa
authors.forename: Franco
authors.initials: F
authors.lastname: Alhaique
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001507:Beclomethasone / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry*; D004355:Drug Stability; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D010316:Particle Size; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013499:Surface Properties; D013501:Surface-Active Agents / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D013501:Surface-Active Agents; D001507:Beclomethasone