Improving dexamethasone drug loading and efficacy in treating arthritis through a lipophilic prodrug entrapped into PLGA-PEG nanoparticles

Abstract

Targeted delivery of dexamethasone to inflamed tissues using nanoparticles is much-needed to improve its efficacy while reducing side effects. To drastically improve dexamethasone loading and prevent burst release once injected intravenously, a lipophilic prodrug dexamethasone palmitate (DXP) was encapsulated into poly(DL-lactide-co-glycolide)-polyethylene glycol (PLGA-PEG) nanoparticles (NPs). DXP-loaded PLGA-PEG NPs (DXP-NPs) of about 150 nm with a drug loading as high as 7.5% exhibited low hemolytic profile and cytotoxicity. DXP-NPs were able to inhibit the LPS-induced release of inflammatory cytokines in macrophages. After an intravenous injection to mice, dexamethasone (DXM) pharmacokinetic profile was also significantly improved. The concentration of DXM in the plasma of healthy mice remained high up to 18 h, much longer than the commercial soluble drug dexamethasone phosphate (DSP). Biodistribution studies showed lower DXM concentrations in the liver, kidneys, and lungs when DXP-NPs were administered as compared with the soluble drug. Histology analysis revealed an improvement in the knee structure and reduction of cell infiltration in animals treated with the encapsulated DXP compared with the soluble DSP or non-treated animals. In summary, the encapsulation of a lipidic prodrug of dexamethasone into PLGA-PEG NPs appears as a promising strategy to improve the pharmacological profile and reduce joint inflammation in a murine model of rheumatoid arthritis.

Amphiphilic Phosphorus Dendrons Associated with Anti-inflammatory siRNA Reduce Symptoms in Murine Collagen-Induced Arthritis

“…The sequence dependence was confirmed by comparing anti-TNF-α siRNA-associated C17P10 dendriplexes and control siRNA-associated C17P10 dendriplexes. This effect was equivalent to the one observed in our previous studies using dexamethasone palmitate, as a nanoprodrug or entrapped in poly­(lactide- co -glycolide) nanoparticles . In both cases, a reduction of the arthritis score was detected after three intravenous administrations of 1 mg/kg of the prodrug delivered by the nanocarriers.…”

“…This effect was equivalent to the one observed in our previous studies using dexamethasone palmitate, as a nanoprodrug 31 or entrapped in poly(lactide-co-glycolide) nanoparticles. 32 In both cases, a reduction of the arthritis score was detected after three intravenous administrations of 1 mg/kg of the prodrug delivered by the nanocarriers. Of course, the intracellular target is entirely different for both types of drugs, siRNA and dexamethasone.…”

Sustained inhibition of CC-chemokine receptor-2 via intraarticular deposition of polymeric microplates in post-traumatic osteoarthritis

“…This appears to be in line with similar drug delivery systems previously developed for diverse medical applications by the authors [ 14 , 16 , 29 , 30 ] and with the commercially available ZILRETTA microparticles, returning a nominal drug load of 25% for the synthetic corticosteroid triamcinolone acetonide [ 31 , 32 ]. Indeed, a higher EE of up to 80% could be obtained by using drug conjugates, such as dexamethasone palmitate, as recently documented by Fattal and his group [ 33 ].…”

Reprogramming Metabolism of Macrophages as a Target for Kidney Dysfunction Treatment in Autoimmune Diseases

“…The patient’s renal function must be paid attention to over time, with intervention when necessary, or renal protection drugs given while treating rheumatoid arthritis. In addition, targeted delivery of anti-inflammatory medications that encapsulate the drug into a high-molecular polymer such as PLGA-PEG NPs appears to be a promising strategy to reduce finite side effects and improve the drug utilization rate [ 155 ]. However, this method remains controversial because it only focuses on a single factor and cannot completely avoid damage to other tissues.…”