Reactive oxygen species-responsive cinnamaldehyde prodrugs for the treatment of acute and chronic inflammatory diseases

Abstract

Inflammation is closely related to the etiology and pathogenesis of various acute and chronic diseases like ulcerative colitis (UC) and rheumatoid arthritis (RA). Anti-inflammation is a promising approach for inflammatory disease management. To overcome the systemic toxicity of traditional anti-inflammatory medicines, drug delivery systems responsive to high level of reactive oxygen species (ROS) in inflammatory microenvironment have been developed to increase drug accumulation at inflamed sites. However, most of current ROS-sensitive drug delivery systems also exist some problems, including low drug loading capacity, premature release and reduced drug pharmacological activity. One encouraging strategy is the delivery of prodrugs. Therefore, ROS-responsive prodrug delivery systems were developed in this thesis for inflammatory disease therapy.

The overall purpose of this study was to develop simple yet effective ROS-responsive prodrug systems with high drug loading capacity, controlled drug release and good biosafety for the treatment of acute and chronic inflammatory diseases. Two ROS-responsive prodrug strategies were developed in this thesis project, including ROS-sensitive drug-drug conjugate and ROS-responsive polymer-drug conjugate. Cinnamaldehyde (CA), a food additive approved by Food and Drug Administration (FDA), was chosen as the anti-inflammatory agent in the project due to its excellent anti-inflammation, biosafety and functional chemical structure.

The first strategy was to design a ROS-responsive drug-drug conjugate, captopril-cinnamaldehyde (CAPT-CA) prodrug, to increase each drug’s stability and protect their pharmaceutical activities. The ROS-responsive chemical bond, thioacetal bond, could be cleaved by ROS, followed by the release of two free active drugs without byproduct generation. The prodrug was easily obtained via one-step reaction and verified by a systemic characterization. CAPT-CA showed a powerful anti-inflammatory effect and good cell viability in vitro.

In the second strategy, a ROS-sensitive polymeric prodrug was developed. Anti-inflammatory drug, CA, was chemically conjugated in the polymer chain via a ROS-responsive thioacetal linker. CA was release upon oxidative stress activation. This system exhibited an excellent anti-inflammation and ROS scavenge ability in vitro. Animal studies verified that the system attenuated clinical disease activity and controlled pathogenesis of inflammation in both acute UC and chronic RA mouse models with good biocompatibility.

To conclude, two prodrug systems were designed in this project, showing the potential of being developed as effective and safe therapeutic agents for the treatment of inflammatory diseases in clinic. Future studies will be focused on the assessment of pharmacodynamics and toxicology and exploring the possibility of clinical trials.