Drug Delivery and Translational Research最新文献

Atopic dermatitis (AD) is a chronic inflammatory skin condition characterized by immune dysregulation and a disrupted gut-skin axis. Emerging evidence suggests that the gut microbiota and their metabolites play a critical role in pathogenesis and potential treatment of AD. However, therapeutic strategies targeting the gut microbiota that aim to alleviate AD remain underexplored. Therefore, this study investigated the potential of bovine colostrum-derived extracellular vesicles (BCEVs) to ameliorate AD symptoms by modulating the gut microbiota and intestinal metabolites. AD was induced in mice using 2,4-dinitrochlorobenzene, followed by the oral administration of BCEVs. Skin lesions were assessed histologically to evaluate disease severity. Allergic and immune responses were measured by analyzing serum immunoglobulin E (IgE) levels and cytokine profiles, including interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-α). Gut microbiota composition was determined using 16 S rRNA gene sequencing, and the metabolomic profiling of intestinal samples was performed using gas chromatography-mass spectrometry to identify metabolites. BCEV treatment significantly alleviated skin lesions and reduced the serum IgE levels and the imbalance in IL-4 and TNF-α levels associated with AD induction. Gut microbiota analysis revealed that BCEVs restored microbial dysbiosis and improved the abundance of beneficial bacteria, and metabolomic analysis demonstrated elevated levels of lactic acid and other metabolites. These findings suggest that BCEVs alleviate AD symptoms by rebalancing the gut microbiota and intestinal metabolomes. This study emphasizes the importance of targeting the gut-skin axis as a novel strategy for AD treatment and provides evidence for the therapeutic potential of BCEVs in skin-related immune disorders.

Hydrogel-forming microarray patches (MAPs) offer a minimally invasive platform for transdermal drug delivery, enabling systemic absorption of active pharmaceutical ingredients. Unlike dissolving MAPs, which deposit their entire polymer matrix into the skin, hydrogel-forming MAPs remain intact upon removal, reducing polymer exposure while delivering higher drug doses than dissolving or coated MAPs. Moreover, they have demonstrated excellent biocompatibility and do not cause skin or systemic issues, even with repeated application in humans. This study assessed the leachable and extractable compounds from hydrogel-forming MAPs composed of Gantrez^® S-97, PEG 10,000, and sodium carbonate under various conditions. Under physiological conditions (37°C in water), minimal PEG 10,000 leaching (10.4 ± 2.0%) and negligible Gantrez^® S-97 extraction (< 2%) confirmed the hydrogel matrix's stability and safety. However, stress testing in DMSO at 70°C led to increased PEG 10,000 extraction (up to 32.9 ± 6.1%) and minor Gantrez^® S-97 degradation, likely due to ester hydrolysis. These findings highlight the robustness of hydrogel-forming MAPs, ensuring minimal systemic exposure to unbound polymers while maintaining effective drug delivery. The results support their potential for chronic therapeutic applications requiring repeated dosing. Further clinical studies are needed to validate these findings, facilitating regulatory approval and broader adoption across diverse medical applications.

Insulin-binding B cells are implicated in Type 1 Diabetes (T1D) pathology. Antigen-specific immunotherapy (ASIT) holds promise in T1D. However, ASIT-targeted suppression of insulin-binding B cells is hampered by insulin's hormonal activity and the resulting binding and endocytosis of insulin by insulin receptors (INSR). To evaluate ASIT strategies that target insulin-binding B cells in vivo, non-hormonally active insulin variants are needed. In this work, we aimed to improve upon prior non-hormonal insulin variants by making mutations to the insulin precursor, proinsulin, and including a c-terminal sortase (SrtA) tag (LPETGGHG) to enable facile site-selective bioconjugation to scaffolds or payloads. Of the insulin variants investigated that retained low-nM binding to the murine-derived insulin autoantibody mAb 125, proinsulin(F25D)-SrtA had the lowest INSR binding and activity and the greatest fibrillation resistance. Compared to desoctapeptide insulin, a previously proposed non-hormonal insulin variant, proinsulin(F25D)-SrtA demonstrated 50-fold lower INSR binding and 100-fold greater fibrillation lag time. However, insulin(F25D)-SrtA bound to the anti-insulin antibody 12M4 isolated from a presymptomatic T1D individual, whereas proinsulin(F25D)-SrtA and desoctapeptide insulin did not, highlighting the potential for anti-insulin B cells to develop in human T1D that would escape this ASIT moiety. The characteristics of proinsulin(F25D)-SrtA make it a well-suited non-hormonal insulin variant for insulin-binding B cell targeting and warrants additional study with other anti-insulin B cell specificities derived from T1D individuals.

This study aimed to design and evaluate the clinical efficacy of a new patented portable multifunctional medical nebulizer. The portable multifunctional nebulizer, constructed using medical-grade PVC, incorporates four main systems: a nebulization system, a particle size adjustment mechanism, a heating unit, and a power storage system. This study employed a comparative experimental design. A conventional medical nebulizer, commonly used in a tertiary hospital, was selected as the control group, while the newly developed portable multifunctional nebulizer served as the experimental group. Each group underwent 30 experimental runs, with controlled variables across all tests. Key parameters assessed included initial mist emission time, nebulization rate, particle size distribution, medication splash loss, residual drug volume, and noise levels. The particle size distribution was measured using dynamic light scattering (DLS) technology, while medication loss was calculated by capturing mist spillover and measuring residual drug volume. Noise levels during stable nebulization were recorded using a sound level meter. The experimental group demonstrated the production of smaller, more uniform nebulized particles, reduced medication splash loss, decreased residual drug volume, and lower noise emissions. Statistically significant differences (P < 0.05) were observed across all parameters when compared to the control group. The multifunctional medical nebulizer consistently generates particles within a size range of 120-160 nm, improving drug delivery to target organs, minimizing medication loss, and reducing operational noise. This innovative design represents a significant advancement in the clinical application of respiratory therapy.

Helicobacter pylori (H. pylori) have infected about 50% of the world's population and is a leading cause of gastrointestinal diseases, including gastritis, peptic ulcer, and stomach cancer. Current treatment regimens often fail to completely eradicate the bacteria due to the failure of antibiotics to penetrate into stomach's inner mucosa, where the bacteria reside. Additional factors such as the ability of the organism to neutralize the stomach's acidic environment and biofilm formation further contribute to treatment failure leading to antibiotic resistance. These challenges underscore the urgent need for new treatment options and strategies to combat H. pylori effectively. The current review delivers an overview of the pathophysiology of H. pylori, the limitations of the current regimens, and the potential of nanoemulsion as a smart carrier addressing the limitations associated with H. pylori treatment. The nanoemulsion offers specific advantages like mucoadhesion potential, targeted delivery, controlled release, and co-delivery options that ultimately results in an enhancement of bioavailability of the antibiotics to H. pylori, which resides in the inner walls of the stomach mucosa. Further, the ability of nanoemulsions to encapsulate the drug molecules helps in protecting the antibiotics from the stomach acidity facilitating drug stability. In conclusion, the review highlights the importance of tapping this unexplored potential of nanoemulsion as a promising drug delivery option for the treatment of H. pylori infection.

A shift towards the subcutaneous (S.C.) delivery of protein therapeutics is enabling patient-centric at-home self-administration. To circumvent the volume constraints of the S.C. route of delivery, protein therapeutics are required to achieve ever higher concentrations to administer doses beyond 1 g. Aqueous technologies rarely concentrate above 175 mg/mL and endure syringability and stability complications. Elektrofi's novel non-aqueous microparticle suspensions enable such ultra-high concentration delivery of protein therapeutics subcutaneously. In this work, we demonstrate the bioequivalence of high-concentration suspensions compared to their aqueous counterparts in a rodent model. The 500 mg/mL concentration iteration of the injection was injectable in 20 s with forces below 20 N. We also demonstrate comparable subcutaneous clearance of the suspension test articles to the aqueous comparator. To the best of our knowledge, this work is the first to report comparable efficacy and immunogenicity of microparticle suspensions to the aqueous comparator formulation. The model commercially available reagents serve as a glimpse into the performance of the Elektrofi technology which is in the process of advancing into the clinic with a multitude of biopharma partnerships.

Hypertension is a global health challenge associated with significant morbidity and mortality resulting from vascular inflammation and endothelial dysfunction. Chronic hypertension is characterised by endothelial dysfunction, oxidative stress, immune cell recruitment, and cytokine release, all of which exacerbate vascular inflammation. Despite the availability of various antihypertensive therapies, limitations such as drug resistance and suboptimal targeting hinder their efficacy and reveal their side effects. Nanoparticle-based strategies could present innovative solutions by enabling precise drug delivery, minimising off-target effects, and enhancing therapeutic outcomes. Dual-targeting approaches that focus on molecular mechanistic pathways for managing hypertension using nanoparticle-based methods allow targeted modulation of inflammatory pathways as well. This advancement aids in redefining the management of vascular inflammation as a transformative frontier in antihypertensive therapy, addressing the unmet need for targeted, efficient, and patient-tailored treatment strategies. This review outlines the inflammatory pathophysiology underlying vascular hypertension and underscores the necessity of integrating knowledge gaps while inspiring innovative approaches to combat hypertension effectively. It concludes by identifying potential obstacles and solutions to overcome in order to successfully translate such nano-derived therapies into clinical practice applications.

Breast cancer is the most diagnosed cancer and the second leading cause of cancer death in women. Although treatments with major anti-cancer modalities are largely successful, resistance to treatments including widely applied radiation therapy (RT) can occur due largely to the multifaceted mechanisms in the tumor microenvironment (TME). The present work investigated the ability of Polymer-Lipid-Manganese Dioxide Nanoparticles (PLMD) to overcome hypoxia-associated radioresistant mechanisms and enhance RT-induced immunogenic cell death (ICD) and anti-tumor immunity for inhibiting growth of primary and distant tumors (the abscopal effect). The results showed that PLMD plus RT significantly inhibited the clonogenic survival of murine EMT6 and 4T1 breast cancer cells under hypoxic condition compared to RT alone. Analysis of ICD biomarkers revealed that PLMD profoundly enhanced RT-induced ICD compared to RT alone in EMT6 and 4T1 cells under hypoxic conditions but not under normoxic conditions. In a syngeneic murine breast tumor model with 4T1 orthotopic tumor, the PLMD treatment reduced tumor hypoxia significantly; PLMD + RT combination therapy increased infiltration of cytotoxic CD8⁺ T cells and CD86⁺ macrophages and decreased infiltration of immunosuppressive Tregs and CD163⁺ macrophages, as compared to RT alone. Importantly, the PLMD + RT treatment generated an abscopal effect in a tumor growth experiment using a double-tumor model, where the growth of an untreated tumor was inhibited by treatment of a tumor grown on the opposite side. Overall, the PLMD + RT induced an anti-tumor immune response that inhibited both primary and distant tumor growths and extended median survival in the tumor model.

Extravascular injection represents the predominant modality for contemporary drug administration. Needle injection (NI), a 180-year-old technology, provides a low-cost and effective method for delivering small-molecule drugs. However, it often results in low bioavailability for biomacromolecular drugs. Recently, needle-free jet injection (NFJI) technology has shown promise in enhancing bioavailability by promoting greater drug dispersion at delivery. However, application of the technology in clinical settings impeded by its limitations in tunability and controllability of the initial dispersion. To better understand drug dispersion at delivery, Initial Dispersion Rate (IDR) as a quantitative metric was introduced in this work. Computational Fluid Dynamics (CFD), alongside an in vitro nanosponge-gel model, were employed to investigate the correlation between IDR and various fluid properties and injection parameters. The impact of IDR on pharmacokinetics of biomacromolecular drugs was revealed in the study. Guided by a comprehensive study of IDR, a novel micro-needle jet injection (MNJI) technology was developed. In vivo animal studies demonstrated that MNJI could achieve superior injection efficiency and controllable dispersion compared to NFJI and NI. Furthermore, modifying MNJI configurations enabled tunable IDR, thereby achieving desired bioavailability for biomacromolecular drugs. To the best of our knowledge, IDR was introduced for the first time as a quantitative metric to evaluate extravascular injection efficiency, while MNJI was the first extravascular drug delivery technology that could achieve controllable and tunable dispersion at delivery.