Pharmacokinetics and Biodistribution of Polymeric Nanoparticles Loaded with a Small Molecule Drug in Mice with Alcoholic Liver Disease Article (Faculty180)

cited authors

  • Ma, Jingyi; Pan, Qiaoyu; Mahto, Sohan; Ramanathan, Raghu; Shaikh, Altab; Kumar, Virender; Tan, Chalet; Mahato, Ram I

description

  • We recently demonstrated the therapeutic efficacy of a novel phosphodiesterase 4B (PDE4B) inhibitor, KVA-D88, loaded in mPEG--P(CB--LA) polymeric nanoparticles (NPs) for alcohol-associated liver disease (AALD) treatment. In this study, we investigated the pharmacokinetics (PK) parameters and biodistribution at whole body and organ (liver) levels of this nanoformulation compared to the KVA-D88 free drug as well as their in vivo efficacies. Following administration, KVA-D88 was distributed to all major organs, with the highest accumulation in the liver and kidney and the lowest accumulation in the brain when loaded into NPs, as quantified using LC-MS/MS after a single intravenous injection in a mouse model with AALD induced by Lieber-DeCarli. Compared to the free drug, KVA-D88-loaded NPs demonstrated significantly higher area under the curve (AUC), maximum plasma concentration (), and mean residence time (MRT), while the clearance (CI) and volume of distribution (Vss) were significantly lower: 6581.07 vs 3987.24 ng/mL × h (AUC), 4503.13 vs 2947.08 ng/mL (),1.81 vs 1.57 h (MRT), 725.01 vs 1253.45 mL/h/kg (CI), and 1372.81 vs 1963.01 mL/kg (Vss). In addition, the hepatic drug concentration and proportion of the initial dose of KVA-D88 loaded NPs were reduced in the AALD mice compared to those in healthy mice. Though NP treatment exhibited superior efficacy compared to the free drug, we did not observe a significant difference between the nontargeting NPs and hepatocytes or Kupffer cell-targeting NPs. Our study proved that mPEG--P(CB--LA) polymeric NPs effectively improved the PK and biodistribution profiles of KVA-D88, highlighting the potential of this nanoformulation as an effective treatment strategy for AALD.

authors

publication date

  • 2025

published in

start page

  • 5473

end page

  • 5484

volume

  • 22