Modulation of release and pharmacokinetics from nanoscale lipid prodrugs of dexamethasone with variable linkage chemistry.

In an attempt to tune drug release and subsequent pharmacokinetics once administered intravenously, we have synthesized three lipid-drug conjugates (LDCs) of dexamethasone (DXM) each possessing a different lipid-drug chemical linkage: namely ester, carbamate and carbonate. These LDCs were thoroughly characterized before being turned into nanoscale particles by an emulsion-evaporation process using DSPE-PEG (Distearoyl-sn-Glycero-3-Phosphoethanolamine-N-(methoxy(polyethylene glycol)-2000) as the only excipient. Spherical nanoparticles (NPs) of about 140-170 nm, with a negative zeta potential, were obtained for each LDC and exhibited good stability upon storage at 4 °C for 45 days with no recrystallization of LDCs observed.

Emerging nanoparticle platforms to improve the administration of glucocorticoids.

Glucocorticoids (GC) are common drugs used to treat acute and chronic inflammatory diseases, whose prolonged use can result in severe side effects hampering their efficacy. In addition, the pharmacokinetics, and biodistribution of GC are inadequate to support high efficacy with reduced toxicity. Following the marketing of GC prodrugs, new GC prodrug entities, and conjugates, have been developed.

Hyaluronic acid-conjugated liposomes loaded with dexamethasone: A promising approach for the treatment of inflammatory diseases.

Dexamethasone is a well-known anti-inflammatory drug readily used to treat many lung diseases. However, its side effects and poor lower airway deposition and retention are significant limitations to its usage. In this work, we developed lipid nanoparticulate platforms loaded with dexamethasone and evaluated their behavior in inflammatory lung models in vitro and in vivo.

Interplay between mucus mobility and alveolar macrophage targeting of surface-modified liposomes.

Alveolar macrophages play a crucial role in the initiation and resolution of the immune response in the lungs. Pro-inflammatory M1 alveolar macrophages are an interesting target for treating inflammatory and infectious pulmonary diseases. One commune targeting strategy is to use nanoparticles conjugated with hyaluronic acid, which interact with CD44 overexpressed on the membrane of those cells.

Interspecies comparison of plasma metabolism and sample stabilization for quantitative bioanalyses: Application to (R)-CE3F4 in preclinical development, including metabolite identification by high-resolution mass spectrometry.

The CE3F4 is an inhibitor of the type 1 exchange protein directly activated by cAMP (EPAC1), which is involved in numerous signaling pathways. The inhibition of EPAC1 shows promising results in vitro and in vivo in different cardiac pathological situations like hypertrophic signaling, contributing to heart failure, or arrhythmia. An HPLC-UV method with a simple and fast sample treatment allowed the quantification of (R)-CE3F4.

Nanomedicine-based delivery strategies for nucleic acid gene inhibitors in inflammatory diseases.

Thanks to their abilities to modulate the expression of virtually any genes, RNA therapeutics have attracted considerable research efforts. Among the strategies focusing on nucleic acid gene inhibitors, antisense oligonucleotides and small interfering RNAs have reached advanced clinical trial phases with several of them having recently been marketed. These successes were obtained by overcoming stability and cellular delivery issues using either chemically modified nucleic acids or nanoparticles.

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

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.

Treatment of acute lung inflammation by pulmonary delivery of anti-TNF-α siRNA with PAMAM dendrimers in a murine model.

To improve the efficacy of nucleic acid-based therapeutics, e.g., small interfering RNA (siRNA), transfection agents are needed for efficient delivery into cells.