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. 2022 Jun 30;14(7):1392.
doi: 10.3390/pharmaceutics14071392.

Celecoxib Microparticles for Inhalation in COVID-19-Related Acute Respiratory Distress Syndrome

Monica-Carolina Villa-Hermosilla  1 , Sofia Negro  1   2 , Emilia Barcia  1   2 , Carolina Hurtado  3 , Consuelo Montejo  3 , Mario Alonso  1 , Ana Fernandez-Carballido  1   2
Affiliations

Celecoxib Microparticles for Inhalation in COVID-19-Related Acute Respiratory Distress Syndrome

Monica-Carolina Villa-Hermosilla et al. Pharmaceutics. .

Abstract

Inhalation therapy is gaining increasing attention for the delivery of drugs destined to treat respiratory disorders associated with cytokine storms, such as COVID-19. The pathogenesis of COVID-19 includes an inflammatory storm with the release of cytokines from macrophages, which may be treated with anti-inflammatory drugs as celecoxib (CXB). For this, CXB-loaded PLGA microparticles (MPs) for inhaled therapy and that are able to be internalized by alveolar macrophages, were developed. MPs were prepared with 5% and 10% initial percentages of CXB (MP-C1 and MP-C2). For both systems, the mean particle size was around 5 µm, which was adequate for macrophage uptake, and the mean encapsulation efficiency was >89%. The in vitro release of CXB was prolonged for more than 40 and 70 days, respectively. The uptake of fluorescein-loaded PLGA MPs by the RAW 264.7 macrophage cell line was evidenced by flow cytometry, fluorescence microscopy and confocal microscopy. CXB-loaded PLGA MPs did not produce cytotoxicity at the concentrations assayed. The anti-inflammatory activity of CXB (encapsulated and in solution) was evaluated by determining the IL-1, IL-6 and TNF-α levels at 24 h and 72 h in RAW 264.7 macrophages, resulting in a higher degree of reduction in the expression of inflammatory mediators for CXB in solution. A potent degree of gene expression reduction was obtained with the developed CXB-loaded MPs.

Keywords: COVID-19; PLGA; celecoxib; inhalation; macrophages; microparticles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
SEM microphotographs and particle size distributions of formulations. (a) MP-C1, (b) MP-C2, (c) MP-0 and (d) MP-F.
Figure 2
Figure 2
Cumulative amounts (±SD) of CXB released from CXB-loaded PLGA MPs (MP-C1 and MP-C2) at pH 5 and pH 7.4.
Figure 3
Figure 3
Cell viability results (±SD) obtained after the incubation of macrophages with formulations MP-0, MP-C1, MP-C2, CXB-S1 (12 µg/mL), CXB-S2 (24 µg/mL) and CXB-S3 (48 µg/mL). PC: positive control (live macrophages), NC: negative control (dead macrophages).
Figure 4
Figure 4
Intensity of fluorescence plots obtained for formulation MP-F at 1 h (b), 5 h (d) and 24 h (f), and their respective controls at 1 h (a), 5 h (c) and 24 h (e). MP-F: FITC-loaded PLGA MPs. FITC: fluorescein-5-isothiocyanate.
Figure 5
Figure 5
Fluorescence microscopy images of RAW 264.7 macrophages acquired at different times after incubation with formulation (a) MP-F: 1 h, (b) 5 h and (c) 24 h. MP-F: FITC-loaded PLGA MPs. FITC: fluorescein-5-isothiocyanate.
Figure 6
Figure 6
Confocal images of phagocytosis of formulation MP-F obtained at (a) 24 h and (b) 72 h. MP-F: FITC-loaded PLGA MPs. FITC: fluorescein-5-isothiocyanate.
Figure 7
Figure 7
Mean concentrations (±SD) of (a) IL-1, (b) IL-6 and (c) TNF-α obtained after incubating macrophages with formulations MP-0, MP-C1, MP-C2, MP-C2-L and CXB solution for 24 h and 72 h. Mock: control cells. * p < 0.05.
Figure 8
Figure 8
mRNA gene expression levels of (a) IL-1, (b) IL-6 and (c) TNF-α obtained after incubation for 72 h with formulations MP-0, MP-C1, MP-C2, MP-C2-L and CXB solution. Mock: control. NC: negative control.
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