Enhanced Liver Targeting of Camptothecin via Conjugation with Deoxycholic Acid

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 ac...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2019-03, Vol.24 (6), p.1179
Main Authors: Xiao, Linxia, Yu, Endian, Yue, Hanlin, Li, Qingyong
Format: Article
Language:English
Subjects:
Accuracy
Acids
Antitumor activity
Bile
bile acid
biodistribution
Camptothecin
Cell culture
Colorectal cancer
Conjugation
Cytotoxicity
Deoxycholic acid
DNA topoisomerase
Drug delivery
Evaluation
Hepatocytes
Investigations
Liver
liver targeting
Oral administration
Ovarian cancer
Plasma
Stability analysis
Toxicity
Two dimensional models
uptake
Water pollution effects
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Summary: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 ( ). 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 and CPT were assessed in 2D and 3D HepG2 cell models. The stability of and CPT was evaluated in vitro (in simulated gastric fluid, simulated intestinal fluid, and fresh rat plasma). Finally, biodistribution of 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 in HepG2 cells, but had no distinct effects on CPT. Meanwhile, exhibited better stability compared with CPT. More importantly, biodistribution study in mice demonstrated that the liver targeting index of 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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules24061179