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.
Keywords:
Dexamethasone; Modular; Nanomedicine; Prodrugs; Rheumatoid Arthritis; pH-Sensitive.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetone / analogs & derivatives
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Acetone / pharmacokinetics
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Acetone / therapeutic use*
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / therapeutic use*
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Arthritis, Rheumatoid / drug therapy*
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Arthritis, Rheumatoid / pathology
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Dexamethasone / analogs & derivatives
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Dexamethasone / pharmacokinetics
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Dexamethasone / therapeutic use*
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Mice
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Nanomedicine
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Nanoparticles / analysis
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Nanoparticles / chemistry
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Nanoparticles / therapeutic use*
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Prodrugs / chemistry
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Prodrugs / pharmacokinetics
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Prodrugs / therapeutic use*
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RAW 264.7 Cells
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Rats
Substances
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Anti-Inflammatory Agents
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Prodrugs
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Acetone
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Dexamethasone