title: Lipophilic Prodrugs of SN38: Synthesis and in Vitro Characterization toward Oral Chemotherapy.
abstract: SN38 (7-ethyl-10-hydroxy camptothecin) is a potent anticancer agent belonging to the camptothecin family; however, its oral delivery is extensively restricted by poor solubility in pharmaceutically acceptable excipients and low transmucosal permeability. Lipid-based carriers are well-known for their ability to improve oral absorption and bioavailability of lipid soluble and highly permeable compounds. Thus, this study has focused on improving solubility in lipid excipients, controlling stability, and enhancing transmucosal permeability of SN38 by specific chemical modification. To achieve these aims, a series of lipophilic prodrugs were designed and synthesized by esterification at the C10 and/or C20 positon(s) of SN38 with dietary fatty acids of diverse hydrocarbon chain lengths. The solubility of these novel prodrugs in long-chain triglycerides was increased up to 444-fold, and cytotoxicity was significantly reduced in comparison to SN38. The prodrugs were stable in simulated gastric fluids but exhibited different rates of hydrolysis (t1/2 < 5 min to t1/2 > 2 h) in simulated intestinal fluids (in the presence of enzymes) depending on the alkyl chain length and the position modified. A predictable reconversion of prodrugs to SN38 in plasma was also confirmed. On the basis of these studies, SN38-undecanoate (C20) was identified as the optimal prodrug. Finally, in vitro permeability and uptake studies in rat intestinal mucosal membrane using an Ussing chamber showed significant improvement in transepithelial drug transport and cellular uptake. Together, these results indicate that well designed lipophilic prodrugs have potential for the efficacious and safe oral delivery of SN38.
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors.forename: Vaskor
authors.initials: V
authors.lastname: Bala
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors.forename: Shasha
authors.initials: S
authors.lastname: Rao
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors.forename: Shudong
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmacy and Medical Sciences, University of South Australia , Adelaide, SA 5001, Australia.
authors.forename: Clive A
authors.initials: CA
authors.lastname: Prestidge
mesh_terms: D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods*; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D011355:Prodrugs / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry*; D053719:Tandem Mass Spectrometry
chemical_list: D011355:Prodrugs; D000077146:Irinotecan; D002166:Camptothecin
keywords: SN38 (7-ethyl-10-hydorxy camptothecin); cytotoxicity; drug delivery; lipophilic prodrug; permeability; simulated gastric/intestinal conditions