Modular Acid-Activatable Acetone-Based Ketal-Linked Nanomedicine by Dexamethasone Prodrugs for Enhanced Anti-Rheumatoid Arthritis with Low Side Effects

Xu, Y (Xu, Yang)^{[ 1,2 ]} ; Mu, JQ (Mu, Jingqing)^{[ 1,2 ]} ; Xu, ZK (Xu, Zunkai)^{[ 1,2 ]} ; Zhong, HP (Zhong, Haiping)^{[ 1,2 ]} ; Chen, ZQ (Chen, Ziqi)^{[ 1,2 ]} ; Ni, AK (Ni, Qankun)^{[ 3,4 ]} ; Liang, XJ (Liang, Xing-Jie)^{[ 3,4 ]} ; Guo, ST (Guo, Shutao)^{[ 1,2 ]}

NANO LETTERS, 2020, 20(4): 2558-2568

DOI: 10.1021/acs.nanolett.9b05340

摘要

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 anomedicines.