Synthesis and Characterization of New Liver Targeting 5‐Fluorouracil‐Cholic Acid Conjugates

Abstract

The objective of this work was to develop a liver-specific antihepato carcinoma agent. A series of 5-fluorouracil / cholic acid conjugates (5-FU-cholic acid conjugates) were prepared and tested for their chemical characteristics and bio-distribution properties. The in-vitro stability trial showed 5-FU-cholic acid conjugates could be completely hydrolyzed by heating at 70 degrees C in an acidic solution, pH = 1, for 5 min. The fast and complete hydrolysis of these compounds could be compatible with a fast separation and analysis method to shorten the analysis time. The decomposition speeds of the 5-FU-cholic acid conjugates in different organs of mice at several time points after oral administration were evaluated by measuring the concentrations of regenerated 5-FU in organ tissue. The results were compared with those of the controls, which was a group of mice orally taking 5-FU. The concentrations of 5-FU in mice liver tissue were remarkably increased after oral administration of the prodrugs, and were much larger than if only orally administered 5-FU. The results suggested the feasibility to improve therapeutic efficiency of liver targeting treatments by using cholic acid as the vector of drugs.

Renal targeted delivery of triptolide by conjugation to the fragment peptide of human serum albumin

“…Carbodiimide chemistry was then applied to conjugate the succinylated TP to the PF-A 299-585 fragment via an amide bond. Ester bond linkages are known to be vulnerable to plasma esterases, and indeed are a favored strategy for producing prodrugs to allow for the ready reversion of parent compound in vivo [25][26][27]. Plasma hydrolysis of TPS-PF-A 299-585 to TP is, however, undesirable for our purpose as it would prematurely curtail the function of PF-A 299-585 as a renal targeting carrier.…”

Synthesis and in vitro evaluation of bile acid prodrugs of floxuridine to target the liver

“…When orally administered to rats, valylchenodeoxycholate increased the bioavailability of acyclovir from 25% to 48% (31), showing the potential for increased oral drug bioavailability by exploitation of the enterohepatic circulation of bile acids. Additionally, a 5-FU conjugate of cholic acid was shown to have increased mouse liver concentrations of 5-FU, compared with when 5-FU itself was dosed (34). …”

Steroid-Based Supramolecular Systems and their Biomedical Applications: Biomolecular Recognition and Transportation

“…In this case, a valine linker between cholic acid and acyclovir could be cleaved upon esterase hydrolysis and release acyclovir [76]. Later, other bile acid-based prodrugs such as cholic acid-cytarabine conjugates [77], cholic acid-5-fluorouracil (FU) conjugates [78], and bile acid-tamoxifen conjugates [79] were developed. The bile acid-based prodrug transport systems showed improved drug absorption, membrane permeation, as well as the "trojan horse" effect [80] that largely increased the bioavailability of the antitumor drugs.…”