Drug Delivery and Translational Research最新文献

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.

Heart failure (HF) has a serious impact on patients' lives and health. Gut microbiota plays an important role in the development of HF. Xinshuaining (XSN) preparation has a therapeutic effect on the HF. However, the mechanism of action of XSN in HF is still unclear. Our study aimed to explore the possible function and mechanism of XSN on HF induced by doxorubicin (DOX) in rats. DOX-induced HF rat models were prepared, grouped and treated. The ultrasound indexes of rat heart were measured before sampling, and the indexes of cardiac pathology, fibrosis degree, gut microbiota and metabolites were detected by ELISA, HE staining, Masson staining, immunohistochemistry, 16SrDNA sequencing, liquid chromatography-mass spectrometry (LC/MS) after sampling. XSN can significantly improve the cardiac function of HF rats, including increasing LVEF, LVFS, decreasing LVESD, LVESV, LVEDV levels, and at the same time, XSN can also reduce the heart weight index, reduce the cardiac histopathological damage and fibrosis. In addition, XSN can regulate the abundance and function of gut microbiota, inhibit the level of TMAO, and regulate plasma metabolites in HF rats. In conclusions, XSN improves cardiac function and delays the process of cardiac fibrosis in HF rats, and its mechanism may be related to the regulation of gut microbiota and metabolites.

Migraine, a prevalent neurological disorder, is known to significantly impact patients' quality of life. The effectiveness of oral medications is often hindered by nausea and vomiting, common migraine symptoms. In this study, a transdermal patch for the co-delivery of sumatriptan succinate and metoclopramide HCl was developed and evaluated, to offer a patient-friendly alternative for migraine management. This study evaluated the impact of chemical enhancers and hydrophilic formulations on drug permeation using dermatomed porcine ear skin. A combination of 25% w/w propylene glycol (PG) and 10% w/w dimethyl isosorbide (DMI) significantly enhanced the permeation of both drugs. Among four hydrophilic patch formulations, a matrix composed of a 1:3 ratio of polyvinylpyrrolidone (PVP) to hydroxypropyl methylcellulose (HPMC) demonstrated optimal drug delivery. Characterization tests, including coat weight, drug content uniformity, tack testing, and slide crystallization, were performed, all patches exhibited acceptable physical properties, including uniform drug content. The target therapeutic dose, equivalent to 4 mg subcutaneous injection of sumatriptan succinate and 10 mg oral metoclopramide HCL, was achieved within 8 h using a 60 cm² patch of the optimized formulation. Based on these findings, the developed transdermal patch could serve as a promising alternative for migraine management, potentially improving patient compliance and therapeutic outcomes.

Inflammation and impaired bone regeneration are major challenges in oral and maxillofacial surgery, necessitating the development of effective drug delivery systems. This study aimed to develop a hydrogel-based microneedle (MN) system for the controlled release of anti-inflammatory and osteogenic drugs. A hydrogel loaded with naproxen sodium (NAS) and dexamethasone sodium phosphate (DEX) using poloxamer 407 (NDgel) was prepared using a low-temperature method and optimized via the Box-Behnken design. The optimized hydrogel exhibited a gelation temperature of 30.87 ± 0.64℃, pH 7.92 ± 0.12, and viscosity 87.47 ± 5.66 cP. Physicochemical evaluations, including differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR), confirmed that NAS and DEX were incorporated in an amorphous form. The hydrogel was coated onto microneedles (NDgMN) via a dip-coating method and dried. In vitro drug release studies in artificial saliva showed NAS and DEX release rates of 21.7 ± 5.8% and 19.0 ± 1.8%, respectively, after 5 min. The NDgMN exhibited significantly enhanced permeability, with 48.5% and 48.7% permeability for NAS and DEX after 48 h, compared to 31.0% and 28.8% for the hydrogel alone. The IC₅₀ values of the drug solution and drug-containing gel were 123 µg/mL and 203.2 µg/mL, respectively. NDgel demonstrated concentration-dependent inhibition of nitrogen oxide (NO) production at 1-1000 µg/mL, and alkaline phosphatase (ALP) activity assays revealed a 1.2-fold increase at concentrations above 50 µg/mL. These findings suggest that hydrogel-coated MNs have potential as a novel drug delivery system for reducing inflammation and promoting osteocyte differentiation due to their enhanced permeability and bioactivity.

The use of fractional microporation to disrupt superficial skin is an effective approach to enhance drug absorption. This study analyzed and compared the effectiveness of fractional Er:YAG laser and radiofrequency microneedling (RM) in promoting skin penetration and hair follicle (HF) targeting of free or nanoencapsulated minoxidil and minocycline. Porcine skin delivery, with or without laser (3, 6, and 7 mJ) and RM (6.1, 10.2, and 20.4 mJ with a penetration depth of 0.5 or 1.0 mm), was investigated using in vitro permeation test (IVPT). The in vitro and in vivo antibacterial activity of the microporation-assisted minocycline-loaded nanocarriers was also conducted. The skin deposition and flux of free minoxidil were increased by 3- and 56-fold, respectively, with laser treatment at 7 mJ. The laser enhanced the deposition and flux of free minocycline by 25- and 40-fold compared to the untreated control, respectively. RM elevated the drug flux by 5‒18-fold compared to passive absorption. However, this enhancement effect was not observed in skin deposition. Nanostructured lipid carriers (NLC) and liposomes, with sizes of 81 and 76 nm, were produced and entrapped approximately 80% of the drugs, respectively. Microporation increased skin delivery of nanoencapsulated drugs, though this enhancement was less pronounced than that of the free drugs. Biodistribution observed through confocal microscopy showed that microporation increased the penetration depth of lipid-based nanocarriers into the dermis compared to passive diffusion. The nanocarriers were primarily distributed into the microchannels and transported into the surrounding dermal tissue. Minocycline uptake in HF increased from 0.03 to 0.16 and 0.20 nmol/cm² after the nanoencapsulation with NLC and liposomes, respectively. This uptake of NLC was further increased to 1.24 and 1.51 nmol/cm² by laser and RM treatment. The minocycline-loaded nanocarriers inhibited Cutibacterium acnes viability in both planktonic and biofilm forms more effectively than the free drug. The in vivo C. acnes infection model in mice exhibited an efficient bacterial eradication through microporation-mediated nanocarrier delivery. The microchannel closure in laser- and RM-treated skin occurred within 36 and 12 h, respectively, as indicated by transepidermal water loss (TEWL). These findings demonstrate that fractional laser and RM are promising strategies for improving skin- and HF-targeted absorption of nanoencapsulated drugs.