Enhanced Liver Targeting of Camptothecin via Conjugation with Deoxycholic Acid

Abstract

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.

Transporter-Targeted Bile Acid-Camptothecin Conjugate for Improved Oral Absorption

“…39) The extent of biliary excretion of a compound may be affected by many physicochemical factors, such as molecular weight, polarity, sex, chemical structure and metab-olism. 40) Furthermore, the extent of some compounds varies widely with species. It has been reported the threshold molecular-weight for humans is approximately 500-600, while 325 is the minimum molecular-weight for the rat.…”

Physiology and Physical Chemistry of Bile Acids

“…Recently dihydroartemisinin–UDCA derivatives were reported to improve the cytotoxicity of dihydroartemisinin towards leukemia cells [ 90 ] and hepatocellular carcinoma [ 91 ]. A deoxycholic acid-Camptothecin conjugate [ 92 ] was recently proved by Xiao et al to enhance the targeted delivery of anticancer molecules in liver by exploiting the specific BA-BA receptors interaction. A series of nucleoside [ 93 ] and platinum(II) [ 94 ]-BADs were screened to test the cytotoxic activity in different tumor cell lines.…”

Bile Acid Conjugates with Anticancer Activity: Most Recent Research

“…Better inhibition, enhanced stability. [35,36] The anticancer profiles of bile acid-nucleoside hybrids were reported in the last decade. The 1,2,3-triazole scaffold was chosen to connect bile acids to deoxyadenosine-nucleoside analogues via click chemistry and the corresponding hybrids were evaluated for their cytotoxicity against a panel of four different human cancer cell lines and normal fibroblast cells (Scheme 1) [28].…”

“…Stability studies in blood rat serum of hybrid 45 showed that conjugation actually stabilizes CPT, resulting in an increase of hybrid half-life to up to 24 h, compared to a 2.3-h half-life of CPT alone. More recently, the same authors demonstrated in vitro and in vivo that DC-CPT hybrid 46 was more stable than CTP alone, and that its potential to target liver was remarkably enhanced by deoxycholic bile acid conjugation [36].…”