Modular Acid-Activatable Acetone-Based Ketal-Linked
Nanomedicine by Dexamethasone Prodrugs for Enhanced Anti-Rheumatoid
Arthritis with Low Side Effects
Given
the physically encapsulated payloads with drug burst release
and/or low drug loading, it is critical to initiate an innovative
prodrug strategy to optimize the design of modular nanomedicines.
Here, we designed modular pH-sensitive acetone-based ketal-linked prodrugs of dexamethasone (AKP-dexs) and formulated them as nanoparticles.
We comprehensively studied the relationships between AKP-dex structure
and properties, and we selected two types of AKP-dex-loaded nanoparticles
for in vivo studies on the basis of their size, drug loading, and
colloidal stability. In a collagen-induced arthritis rat model, these
AKP-dex-loaded nanoparticles showed higher accumulation in inflamed
joints and better therapeutic efficacy than free dexamethasone phosphate
with less-severe side effects. AKP-dex-loaded nanoparticles may be
useful for treating other inflammatory diseases and thus have great
translational potential. Our findings represent an important step
toward the development of practical applications for acetone-based
ketal-linked prodrugs and are useful in the design of modular nanomedicines.