Characterization of Lipophilic Gemcitabine Prodrug-Liposomal Membrane Interaction by Differential Scanning Calorimetry

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• 作者：Francesco Castelli ; Maria Grazia Sarpietro ; Maurizio Ceruti ; Flavio Rocco ; Luigi Cattel
• 刊名：Molecular Pharmaceutics
• 出版年：2006
• 出版时间：December 2006
• 年：2006
• 卷：3
• 期：6
• 页码：737 - 744
• 全文大小：156K
• 年卷期：v.3,no.6(December 2006)
• ISSN：1543-8392

文摘

Gemcitabine is an anticancer agent rapidly deaminated to the inactive metabolite2',2'-difluorodeoxyuridine. Its stability as well as bioavailability can be increased by makingprodrugs. A series of lipophilic prodrugs of gemcitabine were synthesized by linking the 4-aminogroup with valeroyl, lauroyl, and stearoyl linear acyl derivatives. We studied, by the differentialscanning calorimetry technique, and compared the interaction of pure gemcitabine and itsprodrugs with dimyristoylphosphatidylcholine and distearoylphosphatidylcholine vesicles withthe aim of demonstrating if the gemcitabine prodrug is more able than the pure gemcitabine tointeract with lipid vesicles employed both as model biomembranes and as carriers in the transportof antitumor drugs. These studies, carried out by static and kinetic calorimetric measurements,give evidence that the increase of the prodrug's lipophilic character improves the interactionwith lipid bilayers, favoring the absorption through the lipid barriers and allowing the liposomesto work (when the prodrug is inserted inside the vesicles) as a lipophilic carrier which is able todeliver the drug near the cell surface. The use of different prodrugs modified in their lipophiliccharacter, of different kinds of vesicles (multilamellar and unilamellar), and of different kinds ofvesicles forming phospholipids permitted us to determine the better equilibrium between in-vesicle solubility and through-vesicle diffusion of the drug, important in the preformulative studiesof antitumor carriers based on phospholipid formulations. Such studies suggest that the prodruglipophilic tail should modulate the transport and the release of gemcitabine inside the cellularcompartments, and the efficiency of the liposomal system is related to the length of the prodrug'sacyl chain which has to match the phospholipid acyl chain allowing or retarding the migrationthrough the lipid release device.