Acute inflammatory diseases are a major cause of death in the world, and effective treatments are greatly needed. Microparticles formulated from polyketals have great potential to enhance the treatment of inflammatory diseases by targeting therapeutics to macrophages. However, existing polyketals have slow hydrolysis rates, which limit their applications in treating acute inflammatory diseases.

In this study, we demonstrated that the hydrolysis kinetics of aliphatic polyketals can be accelerated by increasing their hydrophilic/hydrophobic balance. Aliphatic polyketals of varying hydrophobicity were synthesized, via the acetal exchange reaction, and their hydrolysis kinetics were investigated at the pH values of 4.5 and 7.4. In particular, one polyketal copolymer, PK3, was developed, which had a hydrolysis half-life of 2 days at pH 5 and 22 days at pH 7.4. Microparticles formulated from PK3 should be suitable for treating acute inflammatory diseases because they will hydrolyze and release therapeutics rapidly in the acidic phagolysosomes of macrophages.

Microparticles were formulated with PK3, which encapsulated the anti-inflammatory drug, imatinib. In vivo experiments demonstrated that PK3 microparticles, which encapsulated imatinib significantly improve the efficacy of imatinib in treating acute liver failure. We anticipate that aliphatic polyketals will have numerous applications for the treatment of acute inflammatory diseases, such as traumatic brain injury (TBI), given their pH sensitivity, tunable hydrolysis kinetics, and biocompatible degradation products.