title: Supramolecular organization of S12363-liposomes prepared with two different remote loading processes.
abstract: The S12363 anticancer drug was encapsulated into liposomes in an attempt to increase its therapeutic index. Loading of S12363 was achieved using two different processes based on the formation of either a pH gradient or an ammonium gradient between the acidic inner liposomal compartment and the basic outer phase. High encapsulation yields (>90%) were obtained using both processes for sphingomyelin/cholesterol/cholesterol-PEG vesicles. Spectrofluorimetry measurements have shown that liposomes were characterized by an internal pH around 4 for both loading processes. This internal pH was stable over a period of at least 20 days. Differential scanning calorimetry coupled with time-resolved synchrotron X-ray diffraction was used to study the drug/carrier supramolecular organization. In ammonium sulfate, S12363 was inserted into the bilayer in the vicinity of the polar headgroup. In citrate buffer, S12363 was mainly adsorbed at the water-lipid interface. The drug partitioning into the membrane was inhomogeneous and led to the formation of drug-rich and drug-poor domains. This effect was enhanced in the presence of cholesterol, especially in ammonium sulfate. To conclude, for both processes, the encapsulated drug was found inside the liposome aqueous core but strongly interacting with the membrane.
authors.affiliation: Université Paris-Sud 11, UMR CNRS 8612, 5 rue J.B. Clément, 92290 Châtenay-Malabry, France. caroline.chemin@u-psud.fr
authors.forename: Caroline
authors.initials: C
authors.lastname: Chemin
authors.forename: Jean-Manuel
authors.initials: JM
authors.lastname: Péan
authors.forename: Claudie
authors.initials: C
authors.lastname: Bourgaux
authors.forename: Georg
authors.initials: G
authors.lastname: Pabst
authors.forename: Patrick
authors.initials: P
authors.lastname: Wüthrich
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
authors.forename: Michel
authors.initials: M
authors.lastname: Ollivon
mesh_terms: D000645:Ammonium Sulfate; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D055592:Biophysical Phenomena; D002021:Buffers; D002152:Calorimetry, Differential Scanning; D019343:Citric Acid; D020285:Cryoelectron Microscopy; D016503:Drug Delivery Systems; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D013050:Spectrometry, Fluorescence; D014748:Vinca Alkaloids / Q000008:administration & dosage* / Q000737:chemistry; D014961:X-Ray Diffraction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002021:Buffers; D008081:Liposomes; D014748:Vinca Alkaloids; C064005:S 12363; D019343:Citric Acid; D000645:Ammonium Sulfate