Hyaluronic Acid-Bilirubin Nanoparticles as a Tumor Microenvironment Reactive Oxygen Species-Responsive Nanomedicine for Targeted Cancer Therapy

Abstract

Seonju Lee, Seon Ah Lee, Jongyoon Shinn, Yonghyun Lee College of Pharmacy, Ewha Womans University, Seoul, 03760, South KoreaCorrespondence: Yonghyun Lee, College of Pharmacy, Ewha Womans University, Seoul, 03760, South Korea, Email [email protected]: The tumor microenvironment (TME) has attracted considerable attention as a potential therapeutic target for cancer. High levels of reactive oxygen species (ROS) in the TME may act as a stimulus for drug release. In this study, we have developed ROS-responsive hyaluronic acid-bilirubin nanoparticles (HABN) loaded with doxorubicin (DOX@HABN) for the specific delivery and release of DOX in tumor tissue. The hyaluronic acid shell of the nanoparticles acts as an active targeting ligand that can specifically bind to CD44-overexpressing tumors. The bilirubin core has intrinsic anti-cancer activity and ROS-responsive solubility change properties.Methods & Results: DOX@HABN showed the HA shell-mediated targeting ability, ROS-responsive disruption leading to ROS-mediated drug release, and synergistic anti-cancer activity against ROS-overproducing CD44-overexpressing HeLa cells. Additionally, intravenously administered HABN-Cy5.5 showed remarkable tumor-targeting ability in HeLa tumor-bearing mice with limited distribution in major organs. Finally, intravenous injection of DOX@HABN into HeLa tumor-bearing mice showed synergistic anti-tumor efficacy without noticeable side effects.Conclusion: These findings suggest that DOX@HABN has significant potential as a cancer-targeting and TME ROS-responsive nanomedicine for targeted cancer treatment.Keywords: tumor microenvironment, reactive oxygen species, hyaluronic acid-bilirubin nanomedicine, stimuli-responsive nanomedicine

Keywords

• tumor microenvironment
• reactive oxygen species
• hyaluronic acid-bilirubin nanomedicine
• stimuli-responsive nanomedicine