Larissa Gomes dos Reis

Hyaluronic acid (HA) is a polymer with unique biological properties that has gained in interest over the years, with applications in pharmaceutical, cosmetic, and biomedical fields; however, its widespread use has been limited by its short half-life. Therefore, a new cross-linked hyaluronic acid was designed and characterized using a natural and safe cross-linking agent, such as arginine methyl ester, which provided improved resistance to enzymatic action, as compared to the corresponding linear polymer. The antibacterial profile of the new derivative was shown to be effective against S. aureus and P. acnes, making it a promising candidate for use in cosmetic formulations and skin applications. Its effect on S. pneumoniae, combined with its excellent tolerability profile on lung cells, also makes this new product suitable for applications involving the respiratory tract.

Hyaluronic acid (HA), an excellent biomaterial with unique bio properties, is currently one of the most interesting polymers for many biomedical and cosmetic applications. However, several of its potential benefits are limited as it is rapidly degraded by hyaluronidase enzymes. To improve the half-life and consequently increase performance, native HA has been modified through cross-linking reactions with a natural and biocompatible amino acid, Ornithine, to overcome the potential toxicity commonly associated with traditional linkers. 2-chloro-dimethoxy-1,3,5-triazine/4-methylmorpholine (CDMT/NMM) was used as an activating agent. The new product (HA–Orn) was extensively characterized to confirm the chemical modification, and rheological analysis showed a gel-like profile. In vitro degradation experiments showed an improved resistance profile against enzymatic digestions. Furthermore, in vitro cytotoxicity studies were performed on lung cell lines (Calu-3 and H441), which showed no cytotoxicity.

Inhalation therapy for respiratory disorders is being increasingly delivered via dry powder inhalers (DPIs), which are breath-actuated devices that deliver pharmaceutical drug particles to the lungs. The motion of inhalation air, produced when a patient inhales through this device, supplies all energy for the entrainment, de-agglomeration, and dispersion of powder drug agglomerates into a fine drug particle aerosol. The aerosol performance is directly related to the fluid-mechanics of a given DPI device. These flow mechanisms are complex as they depend on the device design, inhalation flow rate, and the properties of the dry powder formulation used. Among these, the role of device design is crucial as it significantly affects not only the generation and properties of delivered aerosol, but also the capability of targeted regional drug deposition.

Purpose Computational Fluid Dynamics (CFD) simulations are performed to investigate the impact of adding a grid to a two-inlet dry powder inhaler (DPI). The purpose of the paper is to show the importance of the correct choice of closure model and modeling approach, as well as to perform validation against particle dispersion data obtained from in-vitro studies and flow velocity data obtained from particle image velocimetry (PIV) experiments. Methods CFD simulations are performed using the Ansys Fluent 2020R1 software package. Two RANS turbulence models (realisable k − ε and k − ω SST) and the Stress Blended Eddy Simulation (SBES) models are considered. Lagrangian particle tracking for both carrier and fine particles is also performed. Results Excellent comparison with the PIV data is found for the SBES approach and the particle tracking data are consistent with the dispersion results, given the simplicity of the assumptions made. Conclusions This work shows the importance of selecting the correct turbulence modelling approach and boundary conditions to obtain good agreement with PIV data for the flow-field exiting the device. With this validated, the model can be used with much higher confidence to explore the fluid and particle dynamics within the device.

Airway stents are used to treat obstructive central airway pathologies including palliation of lung cancer, but face challenges with granulation tissue growth. Paclitaxel is a chemotherapy drug tha...

Introduction: Respiratory diseases are leading causes of death in the world, still inhalation therapies are so far being the largest fail in drug development. There is an evident need to develop new therapies. Biomolecules represent a potential therapeutic agent in this regard, however their translation to the clinic is hindered by the lack of tools to efficiently deliver these molecules. Cell penetrating peptides (CPPs) have arisen as a potential strategy for intracellular delivery that could theoretically enable the translation of new therapies. Areas covered: In this review, the use of CPPs as a strategy to deliver different molecules (also called cargoes) to treat lung-related diseases will be the focus. A brief description of these molecules and the innovative methods in designing new CPPs is presented. Then, the delivery of different cargoes (proteins, peptides, poorly soluble drugs and nucleic acids) using CPPs is discussed, focusing on its benefits to treat different respiratory diseases like inflammatory disorders, cystic fibrosis and lung cancer. Expert opinion: The advantages of using CPPs to deliver biomolecules and poorly soluble drugs to the lungs is evident. This field has vastly advanced in the past few years towards targeted intracellular delivery, although further studies are needed to fully understand its potential and limitations in vitro and in vivo.

The combination of nanoparticles (NPs) and cell-penetrating peptide (CPP) represents a new opportunity to develop plasmid DNA (pDNA) delivery systems with desirable properties for lung delivery. In this study, poly(lactide-co-glycolide) (PLGA) NPs containing pDNA were formulated with and without CPP using a double-emulsion technique. NPs were characterized in regards of size, surface charge, release profile, pDNA encapsulation efficiency and pDNA integrity. Cellular uptake, intracellular trafficking, uptake mechanism and pDNA expression were assessed in both A549 and Beas-2B cells. Manufactured PLGA-NPs efficiently encapsulated pDNA with approximately 50% released in the first 24 h of incubation. Addition of CPP was essential to promote NP internalization in both cell lines, with 83.85 ± 1.2% and 96.76 ± 1.7% of Beas-2B and A549 cells, respectively, with internalized NP–DNA–CPP after 3 h of incubation. Internalization appears to occur mainly via clathrin-mediated endocytosis, with other pathways also being used by the different cell lines. An endosomal-escape mechanism seems to happen in both cell lines, and eGFP expression was observed in Beas-2B after 96 h of incubation. In summary, the NP–DNA–CPP delivery system efficiently encapsulated and protected pDNA structure and is being investigated as a promising tool for gene delivery to the lungs.

The use of cell-penetrating peptides (CPPs) in combination with nanoparticles (NPs) shows great potential for intracellular delivery of DNA. Currently, its application is limited due to the potential toxicity and unknown long-term side effects. In this study NPs prepared using a biodegradable polymer, poly(lactic–co–glycolic acid (PLGA) in association with a CPP, was assessed on two lung epithelial cell lines (adenocarcinomic human alveolar basal epithelial cells (A549) and normal bronchial epithelial cells (Beas-2B cells)). Addition of CPP was essential for intracellular internalization. No effects were observed on the mitochondrial activity and membrane integrity. Cells exposed to the NPs–DNA–CPP showed low inflammatory response, low levels of apoptosis and no activation of caspase-3. Increase in necrotic cells (between 10%–15%) after 24 h of incubation and increase in autophagy, induced by NPs–DNA–CPP, are likely to be related to the lysosomal escape mechanism. Although oxidative stress is one of the main toxic mechanisms of NPs, NPs–DNA–CPP showed decreased reactive oxygen species (ROS) production on Beas-2B cells, with potential antioxidant effect of CPP and no effect on A549 cells. This NP system appears to be safe for intracellular delivery of plasmid DNA to the lung epithelial cells. Further investigations should be conducted in other lung-related systems to better understand its potential effects on the lungs.