Selective targeting of the anti-viral agent lamivudine to the liver
Chimalakonda, Krishna Chaitanya
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Lamivudine (3TC) is a negative enantiomer of 2’-deoxy-3’-thiacytidine, which is used in the treatment of hepatitis B virus (HBV) infection. It is desirable to selectively deliver the antiviral drugs used in the treatment of HBV infection to their site of action (liver). In this study, a liver-selective dextran prodrug (3TCSD) of the antiviral drug lamivudine (3TC) was developed and characterized. 3TC was coupled to dextran (~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 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 µg/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 forty- and seven-fold decreases in the clearance and volume of distribution of the drug, respectively. However, the accumulation of the conjugated 3TC in the liver was fifty-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. In addition to the liver, kidney was the only other organ where high concentrations of the conjugate were found. In contrast to the liver and kidneys, the concentrations of the conjugate and/or regenerated 3TC were very low or undetectable in the lungs, spleen, and heart after 3TCSD injection. These studies indicate the feasibility of the synthesis of 3TC-succinate-dextran and its potential use for the selective delivery of 3TC to the liver.