Search

Self-assembled hyaluronic acid-based nanogels are versatile drug carriers due to their biodegradable nature and gentle preparation conditions, making them particularly interesting for delivery of peptide therapeutics. This study aims to elucidate the relation between peptide structure and encapsulation in a nanogel. Key peptide properties that affect encapsulation in octenyl succinic anhydride-modified hyaluronic acid nanogels were identified as we explored the effect on nanogel characteristics using 12 peptides with varying charge and hydrophobicity. The size and surface properties of the microfluidics-assembled peptide-loaded nanogels were evaluated using dynamic light scattering, laser Doppler electrophoresis, and small angle neutron scattering. Additionally, the change in peptide secondary structure upon encapsulation in nanogels, their release from the nanogels, and the in vitro antimicrobial activity were assessed. In conclusion, the more hydrophobic peptides showed stronger binding to the nanogel carrier and localized internally rather than on the surface of the nanogel, resulting in more spherical nanogels with smoother surfaces and slower release profiles. In contrast, cationic and hydrophilic peptides localized at the nanogel surface resulting in fluffier nanogel structures and quick and more complete release in biorelevant medium. These findings emphasize that the advantages of nanogel delivery systems for different applications depend on the therapeutic peptide properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The integrity of the intestinal mucus barrier is crucial for human health, as it serves as the body's first line of defense against pathogens. However, postnatal development of the mucus barrier and interactions between maturity and its ability to adapt to external challenges in neonatal infants remain unclear. In this study, we unveil a distinct developmental trajectory of the mucus barrier in preterm piglets, leading to enhanced mucus microstructure and reduced mucus diffusivity compared to term piglets. Notably, we found that necrotizing enterocolitis (NEC) is associated with increased mucus diffusivity of our large pathogen model compound, establishing a direct link between the NEC condition and the mucus barrier. Furthermore, we observed that addition of sodium decanoate had varying effects on mucus diffusivity depending on maturity and health state of the piglets. These findings demonstrate that regulatory mechanisms governing the neonatal mucosal barrier are highly complex and are influenced by age, maturity, and health conditions. Therefore, our results highlight the need for specific therapeutic strategies tailored to each neonatal period to ensure optimal gut health., (© 2024. The Author(s).)

Amyloid protein aggregates are not only associated with neurodegenerative diseases and may also occur as unwanted by-products in protein-based therapeutics. Surfactants are often employed to stabilize protein formulations and reduce the risk of aggregation. However, surfactants alter protein-protein interactions and may thus modulate the physicochemical characteristics of any aggregates formed. Human insulin aggregation was induced at low pH in the presence of varying concentrations of the surfactant polysorbate 80. Various spectroscopic and imaging methods were used to study the aggregation kinetics, as well as structure and morphology of the formed aggregates. Molecular dynamics simulations were employed to investigate the initial interaction between the surfactant and insulin. Addition of polysorbate 80 slowed down, but did not prevent, aggregation of insulin. Amyloid spherulites formed under all conditions, with a higher content of intermolecular beta-sheets in the presence of the surfactant above its critical micelle concentration. In addition, a denser packing was observed, leading to a more stable aggregate. Molecular dynamics simulations suggested a tendency for insulin to form dimers in the presence of the surfactant, indicating a change in protein-protein interactions. It is thus shown that surfactants not only alter aggregation kinetics, but also affect physicochemical properties of any aggregates formed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Oral delivery of therapeutic peptides is hampered by their large molecular size and labile nature, thus limiting their permeation across the intestinal epithelium. Promising approaches to overcome the latter include co-administration with carrier peptides. In this study, the cell-penetrating peptide penetratin was employed to investigate effects of co-administration with insulin and the pharmacologically active part of parathyroid hormone (PTH(1-34)) at pH 5, 6.5, and 7.4 with respect to complexation, enzymatic stability, and transepithelial permeation of the therapeutic peptide in vitro and in vivo. Complex formation between insulin or PTH(1-34) and penetratin was pH-dependent. Micron-sized complexes dominated in the samples prepared at pH-values at which penetratin interacts electrostatically with the therapeutic peptide. The association efficiency was more pronounced between insulin and penetratin than between PTH(1-34) and penetratin. Despite the high degree of complexation, penetratin retained its membrane activity when applied to liposomal structures. The enzymatic stability of penetratin during incubation on polarized Caco-2 cell monolayers was pH-dependent with a prolonged half-live determined at pH 5 when compared to pH 6.5 and 7.4. Also, the penetratin-mediated transepithelial permeation of insulin and PTH(1-34) was increased in vitro and in vivo upon lowering the sample pH from 7.4 or 6.5 to 5. Thus, the formation of penetratin-cargo complexes with several molecular entities is not prerequisite for penetratin-mediated transepithelial permeation a therapeutic peptide. Rather, a sample pH, which improves the penetratin stability, appears to optimize the penetratin-mediated transepithelial permeation of insulin and PTH(1-34).

Bacterial biofilm represents a protected mode of bacterial growth that significantly enhances the resistance to antibiotics. Poly lactic-co-glycolic acid (PLGA)-based nanoparticle delivery systems have been intensively investigated to combat the bacterial biofilms-associated infections. However, some drawbacks associated with current PLGA-based nanoformulations (e.g. the relatively low drug loading capability, premature burst release and/or incapability of on-demand release of cargos at the site of action) restrict the transition from the lab research to the clinical applications. One potent strategy to overcome the above-mentioned limitations is exploiting the unique properties of carbon quantum dots (CQDs) and combining CQDs with the conventional PLGA nanoparticles. In the present study, the CQDs were innovatively incorporated into PLGA nanoparticles by using a microfluidic method. The resulting CQD-PLGA hybrid nanoparticles presented good loading capability of azithromycin (a macrolide antibiotic, AZI) and tobramycin (an aminoglycoside antibiotic, TOB), and stimuli-responsive release of the cargos upon laser irradiation. Consequently, AZI-loaded CQD-PLGA hybrid nanoparticles showed chemo-photothermally synergistic anti-biofilm effects against P. aeruginosa biofilms. Additionally, the CQD-PLGA hybrid nanoparticles demonstrated good biocompatibility with the eukaryotic cells. Overall, the proof-of-concept of CQD-PLGA hybrid nanoparticles may open a new possibility in chemo-photothermal therapy against bacterial biofilms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Essentials Knowledge of the interplay between FVIII and VWF pharmacokinetics (PK) is lacking. We characterized the capacity-limited PK of FVIII and VWF. The PK model described the PK of FVIII and VWF over a broad range of rFVIII doses. High-dose rFVIII treatment can reduce the endogenous VWF levels., Background: Understanding of the pharmacokinetics (PK) interplay between factor VIII (FVIII) and von Willebrand factor (VWF) following high-dose FVIII treatment is lacking., Objectives: To characterize the PK of recombinant FVIII (rFVIII), VWF, and the rFVIII:VWF complex in hemophilia A rats following intravenous administration of rFVIII using PK modeling. A second aim was to investigate the effect of high daily dosing and constant expression of rFVIII on VWF exposure using PK simulations., Methods: We developed a population PK model based on the principles of target-mediated drug disposition modeling, using data on total rFVIII and VWF plasma concentrations, and the rFVIII:VWF complex luminescent oxygen channeling immunoassay signal in hemophilia A rats following intravenous administration of rFVIII (17.5, 100, 1000, and 5000 IU kg -1 ). Additionally, we evaluated the influence of high-dose rFVIII treatment on the exposure of VWF using PK simulations., Results: The plasma concentration-time profiles of total rFVIII and VWF, and the luminescent oxygen channeling immunoassay signal-time profiles of the rFVIII:VWF complex were adequately described using a two-compartment quasi-steady-state target-mediated drug disposition model (K ss  = 0.14 nmol L -1 ). The elimination half-life of the rFVIII:VWF complex was dependent on the unbound plasma concentration of rFVIII. Additionally, we showed that high-dose rFVIII treatment may significantly reduce the endogenous VWF levels., Conclusions: We developed a population-based PK model describing the time-course of total rFVIII, total VWF, and the rFVIII:VWF complex over a broad range of rFVIII doses in hemophilia A rats., (© 2019 Novo Nordisk A/S. Journal of Thrombosis and Haemostasis published by Wiley Periodicals Inc. on behalf of International Society on Thrombosis and Haemostasis.)

Bacterial biofilm-associated chronic sinusitis in cystic fibrosis (CF) patients caused by Pseudomonas aeruginosa infections and the lack of available treatments for such infections constitute a critical aspect of CF disease management. Currently, inhalation therapies to combat P. aeruginosa infections in CF patients are focused mainly on the delivery of antimicrobials to the lower respiratory tract, disregarding the sinuses. However, the sinuses constitute a reservoir for P. aeruginosa growth, leading to re-infection of the lungs, even after clearing an initial lung infection. Eradication of P. aeruginosa from the respiratory tract after a first infection has been shown to delay chronic pulmonary infection with the bacteria for up to two years. The challenges with providing a suitable treatment for bacterial sinusitis include: (i) identifying a suitable antimicrobial compound; (ii) selecting a suitable device to deliver the drug to the sinuses and nasal cavities; and (iii) applying a formulation design, which will mediate delivery of a high dose of the antimicrobial directly to the site of infection. This review highlights currently available inhalable antimicrobial formulations for treatment and management of biofilm infections caused by P. aeruginosa and discusses critical issues related to novel antimicrobial drug formulation design approaches., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the writing of the manuscript, and in the decision to publish the results.