Castelli Francesco, Sarpietro Maria Grazia, Ceruti Maurizio, Rocco Flavio, Cattel Luigi
Dipartimento di Scienze Chimiche, Università degli Studi di Catania, V.le Andrea Doria, 6, 95125 Catania, Italy.
Mol Pharm. 2006 Nov-Dec;3(6):737-44. doi: 10.1021/mp060059y.
Gemcitabine is an anticancer agent rapidly deaminated to the inactive metabolite 2',2'-difluorodeoxyuridine. Its stability as well as bioavailability can be increased by making prodrugs. A series of lipophilic prodrugs of gemcitabine were synthesized by linking the 4-amino group with valeroyl, lauroyl, and stearoyl linear acyl derivatives. We studied, by the differential scanning calorimetry technique, and compared the interaction of pure gemcitabine and its prodrugs with dimyristoylphosphatidylcholine and distearoylphosphatidylcholine vesicles with the aim of demonstrating if the gemcitabine prodrug is more able than the pure gemcitabine to interact with lipid vesicles employed both as model biomembranes and as carriers in the transport of 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 interaction with lipid bilayers, favoring the absorption through the lipid barriers and allowing the liposomes to work (when the prodrug is inserted inside the vesicles) as a lipophilic carrier which is able to deliver the drug near the cell surface. The use of different prodrugs modified in their lipophilic character, of different kinds of vesicles (multilamellar and unilamellar), and of different kinds of vesicles forming phospholipids permitted us to determine the better equilibrium between in-vesicle solubility and through-vesicle diffusion of the drug, important in the preformulative studies of antitumor carriers based on phospholipid formulations. Such studies suggest that the prodrug lipophilic tail should modulate the transport and the release of gemcitabine inside the cellular compartments, and the efficiency of the liposomal system is related to the length of the prodrug's acyl chain which has to match the phospholipid acyl chain allowing or retarding the migration through the lipid release device.
吉西他滨是一种抗癌药物，会迅速脱氨生成无活性的代谢产物2',2'-二氟脱氧尿苷。通过制备前药可以提高其稳定性和生物利用度。通过将4-氨基与戊酰基、月桂酰基和硬脂酰基线性酰基衍生物连接，合成了一系列吉西他滨的亲脂性前药。我们采用差示扫描量热法进行研究，并比较了纯吉西他滨及其前药与二肉豆蔻酰磷脂酰胆碱和二硬脂酰磷脂酰胆碱囊泡的相互作用，目的是证明吉西他滨前药是否比纯吉西他滨更能与用作模型生物膜和抗肿瘤药物运输载体的脂质囊泡相互作用。这些通过静态和动态量热测量进行的研究表明，前药亲脂性的增加改善了与脂质双层的相互作用，有利于通过脂质屏障的吸收，并使脂质体（当前药插入囊泡内部时）能够作为亲脂性载体发挥作用，将药物递送至细胞表面附近。使用亲脂性不同的不同前药、不同种类的囊泡（多层和单层）以及形成囊泡的不同种类磷脂，使我们能够确定药物在囊泡内的溶解度和通过囊泡的扩散之间的更好平衡，这在基于磷脂制剂的抗肿瘤载体的制剂前研究中很重要。此类研究表明，前药的亲脂性尾部应调节吉西他滨在细胞区室中的运输和释放，脂质体系统的效率与前药酰基链的长度有关，该长度必须与磷脂酰基链相匹配，从而允许或阻碍通过脂质释放装置的迁移。
