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

Abstract

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.

Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts

“…Dexamethasone (Dex) is a synthetic glucocorticoid (GC) used widely for treating inflammatory and autoimmune diseases [ 1 , 2 ]. However, chronic Dex treatment is associated with adverse effects, including decreased bone mineral density and microarchitecture porosity, eventually leading to glucocorticoid-induced osteoporosis (GIOP) and osteonecrosis [ 3 – 5 ].…”

Breathing Micelles for Combinatorial Treatment of Rheumatoid Arthritis

“…Although the interplay of NO and CO in living organisms has been known for decades, [7] the simultaneous modulation of the concentrations of NO and CO for therapeutic purpose remains elusive. Moreover, recent studies revealed that macromolecular prodrugs were more efficient for RA treatment due to the extravasation through leaky vasculature and subsequent inflammatory cell‐mediated sequestration (ELVIS) in the arthritis joints [4a, 8] …”

Nanomedicines for the treatment of rheumatoid arthritis: State of art and potential therapeutic strategies

“…We have summarized the details of the inflammatory stimulus used for the development of bio-responsive delivery system in Table 4 107 , 108 , 109 , 110 , 111 , 112 . This section highlights recent advances in the application of stimulus-responsive drug delivery systems in RA treatments ( Table 5 ) 19 , 94 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 .…”