“…After 4 hours incubation, uptake was found ~15 times higher with CDXP-siRNA-NP than with free siRNA. These data demonstrate cationic lipidic prodrug nanoparticles possess the same capacity as cationic polymers to induce a high siRNA uptake by RAW264.7 cells compared to free siRNA (Bohr et al, 2020(Bohr et al, , 2017. Finally, TNF-α release inhibition was evaluated (Figure 7).…”
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.
“…After 4 hours incubation, uptake was found ~15 times higher with CDXP-siRNA-NP than with free siRNA. These data demonstrate cationic lipidic prodrug nanoparticles possess the same capacity as cationic polymers to induce a high siRNA uptake by RAW264.7 cells compared to free siRNA (Bohr et al, 2020(Bohr et al, , 2017. Finally, TNF-α release inhibition was evaluated (Figure 7).…”
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.
“…5 ) 72 , 88 , 91 . Owing to the similarities between DNA and RNA, many vectors tested for DNA delivery have been explored for drug delivery of siRNA to the lung against ALI/ARDS ( Table 2 ) 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 . Figure 5 The ideal delivery system for siRNA.…”
Section: Sirna Delivery Systems For Treatment Of Ali/ardsmentioning
confidence: 99%
“…However, PAMAM dendriplexes showed lower efficacy than non-complexed TNF- α siRNA on the 3 rd day, requiring more frequent administrations. This could be explained by the higher stability of the non-complexed siRNA and their deep penetration into the lung retarding their removal compared to dendriplexes that undergo fast mucociliary clearance 97 . Interestingly, Agnoletti et al 172 engineered inhalable dry powders of TNF- α siRNA-loaded G4 PAMAM dendriplexes embedded in microparticles formed of a saccharide matrix, aiming to avoid the unfavorable exhalation of nanoparticles and facilitate their transport.…”
Section: Sirna Delivery Systems For Treatment Of Ali/ardsmentioning
The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the clinical translation of siRNA is hampered by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.
“…Several researchers have developed NP-based nasal delivery, aiming to effecti and safely deliver small nucleic acid fragments with therapeutic or vaccine effects to ta cells [234]. Most animal experiments focus on intranasal instillation [235] and orotrac administration [236] to detect the efficacy of NP-siRNAs [236][237][238] (Table 3). Intravenous delivery can deliver therapeutic siRNAs directly to the liver via the circulatory system.…”
Section: Challenges Of Local Delivery Of Np-sirnas-the Importance Of ...mentioning
Since December 2019, a pandemic of COVID-19 disease, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread across the globe. At present, the Food and Drug Administration (FDA) has issued emergency approval for the use of some antiviral drugs. However, these drugs still have limitations in the specific treatment of COVID-19, and as such, new treatment strategies urgently need to be developed. RNA-interference-based gene therapy provides a tractable target for antiviral treatment. Ensuring cell-specific targeted delivery is important to the success of gene therapy. The use of nanoparticles (NPs) as carriers for the delivery of small interfering RNA (siRNAs) to specific tissues or organs of the human body could play a crucial role in the specific therapy of severe respiratory infections, such as COVID-19. In this review, we describe a variety of novel nanocarriers, such as lipid NPs, star polymer NPs, and glycogen NPs, and summarize the pre-clinical/clinical progress of these nanoparticle platforms in siRNA delivery. We also discuss the application of various NP-capsulated siRNA as therapeutics for SARS-CoV-2 infection, the challenges with targeting these therapeutics to local delivery in the lung, and various inhalation devices used for therapeutic administration. We also discuss currently available animal models that are used for preclinical assessment of RNA-interference-based gene therapy. Advances in this field have the potential for antiviral treatments of COVID-19 disease and could be adapted to treat a range of respiratory diseases.
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