Antioxidant polymeric prodrug microparticles as a therapeutic system for acute liver failure

Acetaminophen (APAP) is the most widely used analgesic and its overdose, intentional or unintentional, is known to cause massive oxidative stress and liver tissue damages characterized by hepatocellular apoptosis and hemorrhagic necrosis, leading to acute liver failure (ALF). There has been great interest in the use of antioxidant and anti-inflammatory drugs for the effective treatment of ALF. Manganese porphyrin (MnP), a nonpeptidyl mimic of superoxide dismutase is a promising compound with antioxidant activity, but its application is curtailed by a short half-life in blood. We have recently developed a new family of biodegradable and antioxidant polymeric prodrug, poly(vanilly1 alcohol-co-oxalate) (PVAX), which is able to scavenge H2O2 and release antioxidant and anti-inflammatory vanillyl alcohol. In this work, we developed MnP-loaded PVAX particles and evaluated their potential as antioxidant and anti-inflammatory therapeutic agents for APAP-induced ALP. PVAX particles and MnP showed synergistic antioxidant and anti-inflammatory activities in macrophages stimulated with LPS (lipopolysaccharide). Animal studies using a mouse model of APAP-induced ALF revealed that MnPloaded PVAX particles significantly reduced the serum ALT level and protected liver damages. We anticipated that MnP-loaded PVAX particles have great potential as a therapeutic agent for oxidative stress-associated diseases such as APAP-induced ALF. (c) 2014 Elsevier Ltd. All rights reserved.