Camptothecin (CPT) shows potent anticancer activity through inhibition of topoisomerase I. However, its water insolubility and severe toxicity limit its clinical application. Coupling with bile acid moieties is a promising method for liver-targeted drug delivery, which takes advantage of the bile acid receptors on hepatocytes. In this study, we evaluated the potential liver targeting and stability of a deoxycholic acid-CPT conjugate (G2). The competitive inhibition of antitumor activity experiment based on bile acid transporters was performed using the MTT method. The effects of deoxycholic acid on uptake of G2 and CPT were assessed in 2D and 3D HepG2 cell models. The stability of G2 and CPT was evaluated in vitro (in simulated gastric fluid, simulated intestinal fluid, and fresh rat plasma). Finally, biodistribution of G2 and CPT was investigated in Kunming mice following oral administration. The results showed that deoxycholic acid pretreatment could significantly reduce the antitumor activity and cellular uptake of G2 in HepG2 cells, but had no distinct effects on CPT. Meanwhile, G2 exhibited better stability compared with CPT. More importantly, biodistribution study in mice demonstrated that the liver targeting index of G2 increased 1.67-fold than that of CPT. Overall, the study suggests that conjugation with deoxycholic acid is a feasible method to achieve liver targeting delivery of CPT.
Background
7-p-trifluoromethylphenyl-FL118 (FLQY2) is a camptothecin analog with excellent antitumor efficacy against various solid tumors. However, its poor solubility and low bioavailability limited the development of the drug. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), an emerging carrier for preparing solid dispersion (SD), encapsulated FLQY2 to circumvent the above limitations.
Results
In this project, FLQY2-SD was prepared by solvent evaporation method and self-assembled into micelles in aqueous solutions owing to the amphiphilic nature of Soluplus®. The physicochemical characterizations demonstrated that FLQY2 existed in a homogeneous amorphous form in SD and was rapidly dissolved. The micelles did not affect cytotoxicity or cellular uptake of FLQY2 in vitro, and the oral bioavailability was increased by 12.3-fold compared to the FLQY2 cyclodextrin suspension. The pharmacokinetics of FLQY2-SD showed rapid absorption, accumulation in the intestine, and slow elimination via fecal. Metabolite identification studies showed 14 novel metabolites were identified, including 12 phase I metabolites (M1–M12) and 2 phase II metabolites (M13–M14), of which M2 (oxidation after decarboxylation) and M7 (dioxolane ring cleavage) were the primary metabolites in the positive mode and negative mode, respectively. The tumor growth inhibition rate (TGI, 81.1%) of FLQY2-SD (1.5 mpk, p.o./QW) in tumor-bearing mice after oral administration was higher than that of albumin-bound Paclitaxel (15 mpk, i.v./Q4D) and Irinotecan hydrochloride (100 mpk, i.p./QW).
Conclusions
The successful preparation, pharmacokinetics, and pharmacodynamics studies of FLQY2-SD showed that the solubility and bioavailability of FLQY2 were improved, which facilitated the further druggability development of FLQY2.
Graphical Abstract
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