Combining dexamethasone and TNF-α siRNA within the same nanoparticles to enhance anti-inflammatory effect

Abstract

We propose to combine two therapeutic anti-inflammatory approaches with different mechanisms of action in a single drug delivery system consisting of cationic dexamethasone palmitate nanoparticles (CDXP-NP) associated with TNF-α siRNA. The CDXP-NPs are obtained by the solvent emulsion evaporation technique using dexamethasone palmitate, a prodrug of dexamethasone, associated with a cationic lipid, DOTAP. Their physicochemical properties as well as their ability to bind siRNA were evaluated through gel electrophoresis and siRNA binding quantification. SiRNA cellular uptake was assessed by flow cytometry and confocal microscopy on RAW264.7 macrophages. TNF-α inhibition was determined on LPS-activated RAW264.7 macrophages. Stable and monodisperse nanoparticles around 100 nm with a positive zeta potential (+59mV) were obtained with an encapsulation efficiency of the prodrug of 95%. A nitrogen/phosphate (N/P) ratio of 10 was selected that conferred the total binding of siRNA to the nanoparticles. Using these CDXP-siRNA-NPs, the siRNA was strongly internalized by RAW264.7 macrophage cells and localized within the cytoplasm. On the LPS-induced RAW264.7 macrophages, a larger inhibition of TNF-α was observed with CDXP-siRNA-NPs compared to CDXP-NPs alone. In conclusion, from these data, it is clear that a combination of DXP and TNF-α siRNA therapy could be a novel strategy and optimized alternative approach to cure inflammatory diseases.

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

“…These nanoparticles were shown in vitro to produce a synergistic anti-inflammatory effect which could allow reducing the given dose of each drug. 33 Subsequent histologic analyses of the tibiotalar and forefoot joints confirmed the above results. They revealed a significant reduction of synovial hyperplasia and infiltration in the dendriplexes group compared to the control (PBS) group (Figure 7A,B).…”

“…However, it encouraged us to design a promising nanoparticle formulation combining palmitate dexamethasone and anti-TNF-α siRNA. These nanoparticles were shown in vitro to produce a synergistic anti-inflammatory effect which could allow reducing the given dose of each drug …”

Solid Lipid–Polymer Hybrid Nanoplatform for Topical Delivery of siRNA: In Vitro Biological Activity and Permeation Studies

“…Stronger red fluorescence intensity was observed for siRNA Alexa ® 647 in keratinocyte cells (HaCaT) compared to fibroblast cells In fact, the strategy of releasing siRNA from SLPHN-0.15% PEI, SLPHNs-0.25% PEI, and Lipofectamine™ resulted in 5-fold higher fluorescence (p < 0.001) compared with naked siRNA. These findings suggest that the developed SLPHNs associated with PEI promote cell internalization through endocytosis due to their opposite charge to the cell membrane [55], allowing transfection of siRNA, a molecule that has limited cell penetration due to its hydrophilicity, high molecular weight, and negative charge [66,67].…”

Glucocorticoids-based prodrug design: Current strategies and research progress

“…Limethason®, a lipid emulsion injection loaded with DXP, has been available in Japan since 1988 for treating arthritis [146] , [147] , [148] . Encouraged by this, DXP-related drug delivery systems have gained much attention from researchers, such as emulsions [ 149 , 150 ], liposomes [ 12 , 145 , 151 , 152 ], lipid nanoparticles [ 147 , [153] , [154] , [155] , [156] ], and microparticles [157] . Representatively, Daull et al prepared DXP emulsion and preliminarily evaluated its sustained-release effect after intravitreous injection [149] .…”

“…For example, the DXP liposomes were demonstrated by Hu et al to accumulate to a higher extent in joints and have a stronger anti-inflammatory effect in inhibiting arthritis [152] . In addition, some DXP nanoparticles, such as lipid nanoparticles [ 153 , 158 ], polymer nanoparticles [159] , and low-density lipoprotein nanoparticles [160] , have also been used for anti-inflammatory, age-related macular degeneration and anti-tumor applications. For example, DXP nanoparticles were employed to treat age-related macular degeneration [159] .…”