Cholyl-l-lysine-carboxylbutyryl adriamycin prodrugs targeting chemically induced liver injury

Abstract

By use of carboxylbutyryl as a linker, adriamycin (ADR) and cholyl-L-Lys (an anti-inflammatory agent) were covalently conjugated and N^α-cholyl-N^ε-(N-carbonylpropionoadriamycin)-L-Lys (BCBALys) was constructed as a liver-targeting nano-delivery system to release cholyl-L-Lys and protect the liver from CCl₄-induced injury. In ultrapure water and rat plasma, 10⁻⁶ M BCBALys formed nanoparticles of 42–231 nm in diameter and ∼116 nm in height. In a CCl₄-injured mouse model, however, only 2 µmol kg⁻¹ of BCBALys effectively protected the liver of the mice from injury, and the mouse liver histology showed no hepatic architecture loss and inflammatory cell infiltration. BCBALys selectively accumulated in the liver of CCl₄-injured mice, but not in other vital organs, and released cholyl-L-Lys. These data demonstrated that BCBALys exhibited high efficacy for treating CCl₄-induced liver injury in a targeted manner. The chemical mechanism of BCBALys nanoparticle formation and the pharmacological mechanism of BCBALys mouse liver protection from CCl₄-induced injury were also revealed by experiments.