Drug Delivery with Hyaluronic Acid-Coated Polymeric Micelles in Liver Fibrosis Therapy
Yuta Yoshizaki, Manami Yamasaki, Takuya Nagata, Kengo Suzuki, Rio Yamada, Takuma Kato, Nobuo Murase, Akinori Kuzuya, Akira Asai, Kazuhide Higuchi, Kosuke Kaji, Hitoshi Yoshiji, Yuichi Ohya
Abstract
Developing delivery vehicles that achieve drug accumulation in the liver and transferability into hepatic stellate cells (HSCs) across the liver sinusoidal endothelium is essential to establish a treatment for hepatic fibrosis. We previously developed hyaluronic acid (HA)-coated polymeric micelles that exhibited affinity to liver sinusoidal endothelial cells. HA-coated micelles possess a core–shell structure of self-assembled biodegradable poly( l -lysine)- b -poly(lactic acid) AB-diblock copolymer (PLys + - b -PLLA), and its exterior is coated with HA through polyion complex formation via electrostatic interaction between anionic HAs and cationic PLys segments. In this study, we prepared HA-coated micelles entrapping olmesartan medoxomil (OLM), an anti-fibrotic drug, and evaluated their possibility as drug delivery vehicles. HA-coated micelles exhibited specific cellular uptake into LX-2 cells (human HSC line) in vitro. In vivo imaging analysis after intravenous ( i.v .) injection of HA-coated micelles into mice revealed that the micelles exhibited high accumulation in the liver. Observation of mouse liver tissue sections suggested that HA-coated micelles were distributed in liver tissue. Furthermore, i.v . injection of HA-coated micelles entrapping OLM showed a remarkable anti-fibrotic effect against the liver cirrhosis mouse model. Therefore, HA-coated micelles are promising candidates as drug delivery vehicles for the clinical management of liver fibrosis.