Synthesis, analysis, in vitro characterization, and in vivo disposition of a lamivudine-dextran conjugate for selective antiviral delivery to the liver.

ABSTRACT

A liver-selective prodrug (3TCSD) of the antiviral drug lamivudine (3TC) was developed and characterized. 3TC was coupled to dextran ( approximately 25 kDa) using a succinate linker, and the in vitro and in vivo behavior of the conjugate was studied using newly developed size-exclusion and reversed-phase analytical methods. Synthesized 3TCSD had a purity of >99% with a degree of substitution of 6.5 mg of 3TC per 100 mg of the conjugate. Furthermore, the developed assays were precise and accurate in the concentration ranges of 0.125-20, 0.36-18, and 1-50 microg/mL for 3TC, 3TC succinate (3TCS), and 3TCSD, respectively. In vitro, the conjugate slowly released 3TC in the presence of rat liver lysosomes, whereas it was stable in the corresponding buffer. In vivo in rats, conjugation of 3TC to dextran resulted in 40- and 7-fold decreases in the clearance and volume of distribution of the drug, respectively. However, the accumulation of the conjugated 3TC in the liver was 50-fold higher than that of the parent drug. The high accumulation of the conjugate in the liver was associated with a gradual and sustained release of 3TC in the liver. These studies indicate the feasibility of the synthesis of 3TCS-dextran and its potential use for the selective delivery of 3TC to the liver.