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.

Lipid–Drug Conjugate for Enhancing Drug Delivery

“…Lymphatic targeted delivery of antitumor agents has the potential to treat metastatic malignancies. 65,66 …”

“…An antitumor agent, SN38, was modified to improve its oral delivery by attaching undecanoate (C20). 66 The formation of lipophilic prodrug led to the increase in the uptake of drugs in enterocytes, resulting in more than doubled increase in drug permeation through the intestinal epithelium of rats.…”

Lipidic prodrug approach for improved oral drug delivery and therapy

“…The lymphatic system presents a reservoir for human immunodeficiency virus (HIV), such that the majority of HIV replication occurs in the intestinal lymphatic tissues . Examples of lymphatic‐targeted prodrugs designed to exploit this pathway include γ‐aminobutyric acid (GABA), TG‐MPA, chlorambucil, melphalan, closantel, SN‐38 (7‐ethyl‐10‐hydroxy camptothecin) …”

Antitumor efficacy of Folic Acid conjugated Polymeric Nanoparticles of SN-38 after oral delivery

“…It is the active metabolite of Irinotecan (CPT-11), which is a topoisomerase I inhibitor and is available commercially as Camptosar® [21][22][23] . It has poor aqueous solubility and poor oral bioavailability (8%) 24 . It is formed in the liver and tumors from CPT-11 but its metabolic conversion rate is less than 10% of the original volume of CPT-11 25 .…”

“…Folatereceptor-targeted SN-38 NPs was produced earlier using PLGA NPs covalently bound to Poly (ethylene glycol)-folate, which demonstrated more cytotoxicity on HT-29 cells as compared to control NPs [28][29][30] . These nanoparticles where given via the intravenous route and showed that the bioavailability of SN-38 was significantly increased 24,31 . However, oral delivery of nanoparticles is more practical as compared with the intravenous route because of greater convenience, cheaper cost, better patient compliance and further simplicity for long-standing treatment of chronic diseases 9,[32][33][34] .…”