Dexamethasone and Dexamethasone Phosphate: Effect on DMPC Membrane Models.

Dexamethasone (Dex) and Dexamethasone phosphate (Dex-P) are synthetic glucocorticoids with high anti-inflammatory and immunosuppressive actions that gained visibility because they reduce the mortality in critical patients with COVID-19 connected to assisted breathing. They have been widely used for the treatment of several diseases and in patients under chronic treatments, thus, it is important to understand their interaction with membranes, the first barrier when these drugs get into the body. Here, the effect of Dex and Dex-P on dimyiristoylphophatidylcholine (DMPC) membranes were studied using Langmuir films and vesicles. Our results indicate that the presence of Dex in DMPC monolayers makes them more compressible and less reflective, induces the appearance of aggregates, and suppresses the Liquid Expanded/Liquid Condensed (LE/LC) phase transition. The phosphorylated drug, Dex-P, also induces the formation of aggregates in DMPC/Dex-P films, but without disturbing the LE/LC phase transition and reflectivity. Insertion experiments demonstrate that Dex induces larger changes in surface pressure than Dex-P, due to its higher hydrophobic character. Both drugs can penetrate membranes at high lipid packings. Vesicle shape fluctuation analysis shows that Dex-P adsorption on GUVs of DMPC decreases membrane deformability. In conclusion, both drugs can penetrate and alter the mechanical properties of DMPC membranes.

Interaction between Pharmaceutical Drugs and Polymer-Coated Fe3O4 Magnetic Nanoparticles with Langmuir Monolayers as Cellular Membrane Models.

Surface modification of magnetic nanoparticles (MNPs) has been reported to play a significant role in determining their interactions with cell membranes. In this research, the interactions between polymer functionalized (chitosan, CHI or diethylamino-ethyl dextran, DEAE-D) Fe3O4 MNPs, pharmaceutical drugs and model cell membranes were investigated by Langmuir isotherms and adsorption measurements. In this study, 1,2-distearoyl-sn-glycerol-3-phosphate (DSPA) phospholipid monolayers were used as cell membrane models. Insertion experiments demonstrate that diclofenac (DCFN) is not absorbed at the air-water interface, whereas triflupromazine (TFPZ) has a MIP (maximum insertion pressure) of 35 m Nm-1. The insertion of composites MNPs:TFPZ or DCFN has larger MIP values, indicating that the MNPs are adsorbed on the monolayer with the drugs. An Fe3O4@CHI:DCFN composite presented an MIP of 39 m Nm-1 and Fe3O4@DEAE-D:DCFN presented an impressive MIP of 67 mNm-1. In the case of TFPZ, the enhancement in the MIP values is also evident, being 42 mNm-1 for Fe3O4@CHI:TFPZ and 40 mNm-1 for Fe3O4@DEAE-D:DCFN composite. All MNPs:drugs composites have MIP values greater than commonly accepted membrane pressure values, indicating that MNPs:drugs can penetrate a cellular membrane. The fact that the composite MNPs:drugs present greater MIP values than separated compounds indicates that polymer-coated MNPs can act as good drug delivery systems.

Hyaluronic Acid-Dexamethasone Nanoparticles for Local Adjunct Therapy of Lung Inflammation.

The delivery of a dexamethasone formulation directly into the lung appears as an appropriate strategy to strengthen the systemic administration, reducing the dosage in the treatment of lung severe inflammations. For this purpose, a hyaluronic acid-dexamethasone formulation was developed, affording an inhalable reconstituted nanosuspension suitable to be aerosolized. The physico-chemical and biopharmaceutical properties of the formulation were tested: size, stability, loading of the spray-dried dry powder, reconstitution capability upon redispersion in aqueous media. Detailed structural insights on nanoparticles after reconstitution were obtained by light and X-ray scattering techniques. (1) The size of the nanoparticles, around 200 nm, is in the proper range for a possible engulfment by macrophages. (2) Their structure is of the core-shell type, hosting dexamethasone nanocrystals inside and carrying hyaluronic acid chains on the surface. This specific structure allows for nanosuspension stability and provides nanoparticles with muco-inert properties. (3) The nanosuspension can be efficiently aerosolized, allowing for a high drug fraction potentially reaching the deep lung. Thus, this formulation represents a promising tool for the lung administration via nebulization directly in the pipe of ventilators, to be used as such or as adjunct therapy for severe lung inflammation.