Local Delivery of Azithromycin Nanoformulation Attenuated Acute Lung Injury in Mice.

Humanity has suffered from the coronavirus disease 2019 (COVID-19) pandemic over the past two years, which has left behind millions of deaths. Azithromycin (AZ), an antibiotic used for the treatment of several bacterial infections, has shown antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as against the dengue, Zika, Ebola, and influenza viruses. Additionally, AZ has shown beneficial effects in non-infective diseases such as cystic fibrosis and bronchiectasis. However, the systemic use of AZ in several diseases showed low efficacy and potential cardiac toxicity. The application of nanotechnology to formulate a lung delivery system of AZ could prove to be one of the solutions to overcome these drawbacks. Therefore, we aimed to evaluate the attenuation of acute lung injury in mice via the local delivery of an AZ nanoformulation. The hot emulsification-ultrasonication method was used to prepare nanostructured lipid carrier of AZ (AZ-NLC) pulmonary delivery systems. The developed formulation was evaluated and characterized in vitro and in vivo. The efficacy of the prepared formulation was tested in the bleomycin (BLM) -mice model for acute lung injury. AZ-NLC was given by the intratracheal (IT) route for 6 days at a dose of about one-eighth oral dose of AZ suspension. Samples of lung tissues were taken at the end of the experiment for immunological and histological assessments. AZ-NLC showed an average particle size of 453 nm, polydispersity index of 0.228 ± 0.07, zeta potential of -30 ± 0.21 mV, and a sustained release pattern after the initial 50% drug release within the first 2 h. BLM successfully induced a marked increase in pro-inflammatory markers and also induced histological changes in pulmonary tissues. All these alterations were significantly reversed by the concomitant administration of AZ-NLC (IT). Pulmonary delivery of AZ-NLC offered delivery of the drug locally to lung tissues. Its attenuation of lung tissue inflammation and histological injury induced by bleomycin was likely through the downregulation of the p53 gene and the modulation of Bcl-2 expression. This novel strategy could eventually improve the effectiveness and diminish the adverse drug reactions of AZ. Lung delivery could be a promising treatment for acute lung injury regardless of its cause. However, further work is needed to explore the stability of the formulation, its pharmacokinetics, and its safety.

Safe and effective aerosolization of in vitro transcribed mRNA to the respiratory tract epithelium of horses without a transfection agent.

Vaccines and therapeutics using in vitro transcribed mRNA hold enormous potential for human and veterinary medicine. Transfection agents are widely considered to be necessary to protect mRNA and enhance transfection, but they add expense and raise concerns regarding quality control and safety. We found that such complex mRNA delivery systems can be avoided when transfecting epithelial cells by aerosolizing the mRNA into micron-sized droplets. In an equine in vivo model, we demonstrated that the translation of mRNA into a functional protein did not depend on the addition of a polyethylenimine (PEI)-derived transfection agent. We were able to safely and effectively transfect the bronchial epithelium of foals using naked mRNA (i.e., mRNA formulated in a sodium citrate buffer without a delivery vehicle). Endoscopic examination of the bronchial tree and histology of mucosal biopsies indicated no gross or microscopic adverse effects of the transfection. Our data suggest that mRNA administered by an atomization device eliminates the need for chemical transfection agents, which can reduce the cost and the safety risks of delivering mRNA to the respiratory tract of animals and humans.

Antiviral potential of plant polysaccharide nanoparticles actuating non-specific immunity.

The development of high-end targeted drugs and vaccines against modern pandemic infections, such as COVID-19, can take a too long time that lets the epidemic spin up and harms society. However, the countermeasures must be applied against the infection in this period until the targeted drugs became available. In this regard, the non-specific, broad-spectrum anti-viral means could be considered as a compromise allowing overcoming the period of trial. One way to enhance the ability to resist the infection is to activate the nonspecific immunity using a suitable driving-up agent, such as plant polysaccharides, particularly our drug Panavir isolated from the potato shoots. Earlier, we have shown the noticeable anti-viral and anti-bacterial activity of Panavir. Here we demonstrate the pro-inflammation activity of Panavir, which four-to-eight times intensified the ATP and MIF secretion by HL-60 cells. This effect was mediated by the active phagocytosis of the Panavir particles by the cells. We hypothesized the physiological basis of the Panavir proinflammatory activity is mediated by the indol-containing compounds (auxins) present in Panavir and acting as a plant analog of serotonin.

Overcoming the paracetamol dose challenge with wrinkled mesoporous carbon spheres.

Paracetamol is the most commonly used antipyretic and analgesic drug in the world. The key challenge in paracetamol therapy is associated with the frequency of the dosing. Depending on the gastric filling within 10-20 min paracetamol is released and rapidly absorbed from the gastrointestinal tract. Therefore, it must be taken three or four times a day. To address the dose challenge it is desirable that the paracetamol release profile follows the zero-order kinetic model (constant rate of drug release per unit time). This goal can be achieved by using a suitable porous carrier system. Herein, non-toxic wrinkled mesoporous carbons with unique morphology were synthesized via the hard template method as new carriers for paracetamol. These particles can precisely modulate the release of paracetamol over 24 h in a simulated gastric fluid according to the zero-order kinetic model completely eliminating the initial burst release. Overall, these systems could significantly enhance the bioavailability of paracetamol and prolong its therapeutic effect in numerous diseases such as cold, flu, COVID-19, and severe pain.