Frontiers in drug delivery最新文献

GLP-1 receptor agonists ((GLP-1 RAs) are currently receiving a lot of attention because of their impact in diabetes, weight loss and other areas. While GLP-1 RAs in injectable form are highly efficacious, further work is required to develop oral versions which can deliver these peptides efficiently without requiring use of excessively high doses. This paper describes the ability of an oral peptide delivery formulation, Axcess™, to enhance uptake of GLP-1 receptor agonists via the intestine, resulting in changes in insulin and glucose blood levels indicative of biopotencies of 9% for exendin-4 and 14.8% for semaglutide in preclinical models. The route of delivery suggests that the peptides will be able to interact with the GLP-1 receptors on the vagal afferents of the intestine, as is the case for native GLP-1 in healthy individuals. GLP-1 receptor agonists administered via this route will be a valuable addition to the therapeutic modalities available for treatment of diabetes and obesity.

Fungal infections, though affecting healthcare globally, receive insufficient attention in clinical and academic settings. Invasive fungal infections, particularly caused by combat wounds, have been identified as a critical threat by the US Department of Defense. Monotherapy with traditional antifungals is often insufficient, and so combination therapies are explored to enhance treatment efficacy. However, systemic combination treatments can result in severe adverse effects, suggesting the need for localised delivery systems, such as drug-loaded electrospun patches, to administer antifungals directly to the infection site. This proof-of-concept study hypothesised that dual amorolfine and terbinafine therapy slowly releasing from electrospun patches would be an effective way of eradicating Candida albicans when the patch was applied directly to the fungal colony. The feasibility of creating electrospun materials loaded with amorolfine and terbinafine for combination antifungal therapy was investigated. Electrospinning was used to fabricate polycaprolactone (PCL) patches with varying drug loadings (2.5%, 5%, and 10% w/w) of amorolfine and terbinafine either individually or in combination. The incorporation of both drugs in the fibres was confirmed, with the drugs predominantly in an amorphous state. Results showed that combination therapy patches had a significantly greater and prolonged antifungal effect compared to monotherapy patches, with larger zones of inhibition and sustained efficacy over at least 7 days. This study therefore demonstrates that PCL-based electrospun patches containing amorolfine and terbinafine provide superior antifungal activity against C. albicans compared to monotherapy patches. This approach could lower required drug doses, reducing adverse effects, and enhance patient compliance due to prolonged drug release, leading to more effective antifungal therapy.

Psychotropics are currently developed and marketed with a limited understanding of their mechanism of action. The notion that protein kinase C (PKC) activity is highly relevant to learning and memory function stems from experiments in the 1980s, which associated protein kinase alpha (pka) and pkc to animal models of associative learning, opening an area of exploration for psychotropic development. The PKC family consists of several isoforms, including PKC alpha, beta1, beta1, gamma, delta and epsilon among others. In particular, PKC gamma (PRKCG) is highly brain-expressed and is singled out as a candidate for modulation in psychiatric illness. With hundreds of identified substrates, PRKCG affects multiple pathways relevant for regulation of neuronal health. In this review, converging lines of evidence are presented in the context of psychotropic drug action, which point to downregulation of PKC activity as a potential common mechanism across several psychiatric disorders. Using this mechanism through more targeted psychotropic action may then be used to develop agents that further ameliorate psychiatric symptom expression. Psychotropics including fluoxetine, tricyclics, lithium, valproate, ketamine and others are explored in relation to their effect of PKC, finding that across all drugs examined, a downregulation with chronic-but not acute-use constitutes their putative effect in ameliorating symptoms. This effect is compounded by findings that suggest that PKCs, and PRKCG in particular, promote neuroplastic effects by their downregulation. This effect is in contrast to PKC activators, which have been used in neurodegenerative disorders such as Alzheimer's disease. Cross-disorder mechanisms need to continue to be explored in neuropsychiatric illness and targeted treatments developed in turn to address treatment-resistant conditions.

The risk of infection remains a significant concern with cardiovascular implantable electronic devices, necessitating the development of new strategies. This study explores the efficacy of a novel antibiotic-eluting biologic envelope designed to mitigate infection risk through localized antibiotic delivery while preserving the regenerative properties of biological matrix. Antibiotics, rifampin and minocycline, are released through polymer discs, ensuring extended drug release. Utilizing an established model of infection in a New Zealand White rabbit, the study assessed performance against Gram-positive bacterial strains, including common pathogens such as Staphylococcus aureus and S. epidermidis associated with CIED infections, and Gram-negative bacterial strains. Results demonstrated strong antibacterial activity, achieving complete eradication of bacterial colonies and greater than 6-log reductions in colonization for all strains. Pharmacokinetic analysis revealed sustained local antibiotic concentrations at the implantation site for up to 14 days, with minimal systemic exposure, demonstrating the advantages of localized drug delivery. Health outcomes in the antibiotic bioenvelope group were significantly improved, with no signs of infection or abnormal body temperatures, in contrast to the control group. Macroscopic examinations post-necropsy confirmed the absence of infection at the implantation sites of animals receiving the antibiotic bioenvelope. The combination of localized antibiotic delivery in a regenerative matrix positions the antibiotic bioenvelope as a promising solution for preventing CIED-related infections.

RNA therapy is a rapidly expanding field and has great promise in achieving targeted gene silencing and contributing to personalized medicine. However, the delivery of RNA molecules into targeted organs or cells is still challenging. To overcome this hurdle, a number of nanocarriers with pros and cons have been developed. This study was designed to develop a simple and cost-effective approach to functionalize biodegradable magnetic iron nanoparticles (MNPs) for cell-specific siRNA delivery. MNPs were synthesized based on co-precipitation and further functionalized with sodium citrate and polyethyleneimine (PEI) followed by material characterization using TEM, FTIR, and Zeta potential. The citrate and PEI-coated MNPs were further conjugated with CD31 antibody and complexed with siRNA using a linker-free approach. siRNA-loaded MNPs successfully knocked down the expression of GAPDH in human endothelial cells (ECs) and NOTCH3 in human vascular smooth muscle cells (VSMCs). In an EC and VSMC co-culture system under shear stress to mimic blood flow, siRNA and CD31 conjugated MNPs specifically targeted and delivered siRNA into the ECs. Our approach represents a versatile platform that could be adopted for targeted general siRNA delivery.

[This corrects the article DOI: 10.3389/fddev.2024.1407304.].