International Journal of Pharmaceutics最新文献

Diabetic foot ulcers are a severe complication of diabetes mellitus, characterized by chronicity and high risk of infection. Their effective management requires wound-specific dressings, as no universal system adequately addresses the full spectrum of wounds. Hydrogel dressings offer promising local therapeutic strategies; however, materials combining mechanical robustness, prolonged drug release, and microenvironment modulation remain limited. Herein, we present a rational design strategy for a physically crosslinked, multi-component PVA-based hydrogel membrane incorporating metformin hydrochloride (MET) as the active pharmaceutical ingredient. Although conventionally administered orally, MET has been increasingly recognized for its anti-inflammatory and pro-regenerative properties, supporting its repurposing for localized wound applications. The developed dressings were comprehensively characterized in terms of rheology, pH modulation, morphology (optical microscopy, SEM), mechanical performance, liquid uptake, MET release, cytocompatibility, and in vitro antibacterial and anti-inflammatory activity. An optimized hydrogel formulation based on PVA (Mw ∼ 195,000 Da) and six freeze-thaw cycles (-80 °C/∼22 °C) exhibited high elasticity (ε > 380%), tensile strength (σ ∼ 0.23 MPa), and minimal permanent deformation (ε ≤ 3%). It enabled prolonged MET release over 72 h while maintaining a mildly acidic environment (pH ∼ 5.5-6.3) favorable for wound healing. Compared with commercial drug-free hydrogel dressings, the optimized formulation showed superior mechanical strength, pH-modulating capacity, antibacterial activity against Escherichia coli and Pseudomonas aeruginosa, as well as attenuation of IL-6 expression in LPS-stimulated keratinocytes, indicating anti-inflammatory activity. Collectively, these findings highlight the early-stage potential of MET-loaded solid-sheet hydrogels as multifunctional dressings for chronic, low-exudate diabetic foot ulcers.

Vascular calcification (VC), a critical pathological complication in chronic kidney disease, type 2 diabetes mellitus, and atherosclerosis, is also a major risk factor for adverse cardiovascular events. Once considered a passive age-related process, VC is now recognized as a highly dynamic and multifactorial process involving an array of biological events, including oxidative stress, cellular phenotypic differentiation, and disruptions in calcium-phosphate homeostasis, among others. To date, no specific pharmacological therapies for VC have been established. Existing drug candidates in VC clinical trials often exhibit limitations like short half-lives and poor targeting efficiency, and systemic drug administration is limited by low efficacy and a high risk of adverse effects, which hinders clinical translation. In recent years, nanomaterials have emerged as promising therapeutic strategies to mitigate the dynamic pathological process of VC by virtue of microenvironment-responsive release, multi-target synergistic regulation, and precise enrichment at lesion sites, with the potential to overcome barriers to clinical translation. This review consolidates the pathophysiological mechanisms of VC, systematically evaluates recent advances in nanomaterial-based VC therapies, and analyzes future research directions based on existing evidence, with the goal of providing a theoretical foundation and innovative strategies to overcome current clinical barriers in VC management.

Aerogels, defined as low-density solid materials with high porosities, open pore structures, and high specific surface areas, have shown increasing interest among the scientific and industrial communities. The engineering of aerogels in the form of spherical particles has been well documented for several applications and recent studies have highlighted the promising potential of use them as new drug delivery systems. Therefore, this review article consolidates the recent progress on aerogel particle technology by providing a comprehensive and focused synthesis of the state-of-the-art of aerogel particle design specifically intended to enhance biocompatibility, stability, and targeted drug delivery. The engineering technologies presented, based on droplets production and on the milling technology, are critically discussed, highlighting critical aspects used to control their features. Moreover, surface modification and coating techniques are critically examined as tools to enhance biocompatibility, colloidal stability, and targeted delivery. Then, key results in the diverse biomedical applications, namely for oral, skin and pulmonary drug delivery, were discussed. In oral delivery, their capacity to improve drug loading and enable sustained release is emphasized. In skin delivery, aerogels show potential to enhance dermal permeation and provide a sustained release. For pulmonary administration, their low density and aerodynamic properties make them ideal for deep lung deposition. By bridging particle engineering with therapeutic functionality, this review highlights the unique features and advantages of aerogel particles to become the next-generation aerogel-based therapeutic systems. Finally, the current challenges to be addressed and future trends are identified.

There is increasing interest in the delivery of chemicals to or through the oral buccal mucosa to avoid first-pass metabolism by the liver or the use of needles, which are associated with oral or parenteral administration. Moreover, buccal mucosa is several times more permeable than skin, making it an attractive route for controlled drug delivery via mucoadhesive films, tablets, and patches. Developing in silico models to predict rates of chemical permeation would greatly expediate experimental discovery to clinical use. However, predicting chemical permeation through the buccal mucosa is challenging due to limited availability of ex vivo human tissue for experimentation. Previously, we used tissue engineered buccal mucosa to parameterise an in silico model of buccal chemical permeation using partial differential equations, fitted to in vitro generated chemical permeation data of chemicals with known physiochemical properties. Here, we describe a new approach to predict in vivo permeation from in vitro data. The importance of the permeability barrier is included explicitly in the in silico models by parameterising from in vitro permeation experiments on buccal epithelium with fully formed or deficient permeability barriers. In vivo predictions are made by mapping mechanistic parameters, fitted to in vitro data, to in vivo cell geometry including cell layer thicknesses, cell-sizes and extracellular space. The predictions are tied to a physiologically-based pharmacokinetic model for whole-body chemical distribution that is validated against in vivo data. This combined in vitro-in silico approach has the potential to reduce animal experimentation and improve in vivo predictions for human buccal mucosa.

Platelets, once regarded solely as mediators of hemostasis and thrombosis, are now recognized as active participants in tumor biology. A growing body of evidence indicates that tumors can reprogram circulating platelets into tumor-educated platelets (TEPs) through molecular cargo exchange, intraplatelet RNA processing, and receptor remodeling. These processes reshape platelet transcriptomic and proteomic profiles and endow TEPs with functional properties that support tumor progression. This review critically examines the molecular mechanisms underlying platelet education, including extracellular vesicle-mediated biomolecule transfer, spliceosome-associated RNA reprogramming, and tumor-induced alterations in platelet surface receptors. We then analyze how these molecular changes translate into key pro-tumorigenic functions, such as promotion of angiogenesis, induction of anoikis resistance via the RhoA-MYPT1-PP1-YAP1 axis, facilitation of immune evasion, and enhancement of metastatic dissemination. Beyond mechanistic insights, we evaluate the translational relevance of TEPs as a liquid biopsy biosource and as a potential therapeutic target. Particular attention is given to current limitations, including the specificity of TEP RNA signatures across cancer types, methodological heterogeneity in platelet isolation and profiling, and the unresolved distinction between causal reprogramming and passive biomolecule uptake. Collectively, this review positions TEPs as a biologically informative but methodologically challenging interface between tumor biology and clinical oncology, highlighting both their diagnostic promise and the critical barriers that must be overcome for their integration into precision cancer management.

Tofacitinib citrate (TC), a selective inhibitor of Janus kinase 1/3 (JAK1/3), has gained attention as a potential treatment option for vitiligo, although systemic adverse effects remain a concern with oral therapy. To address this limitation, the current study focused on the development of a tofacitinib citrate-loaded nanoemulsion (TC-NE) incorporating black seed oil (BSO), a major source of thymoquinone (TQ), which was engineered under the shed of D-Optimal statistical mixture design using a high-energy ultrasonication method. TC-NE exhibited a droplet size of 41.68 ± 0.2  nm, a PDI of 0.132 ± 0.004, and a zeta (ζ) potential of -31.9 ± 0.057  mV. Later, TC-NE was transformed into tofacitinib citrate-loaded nanoemulgel (TC-NEG) and characterized under a set of stringent in vitro and in vivo parameters for pharmaceutical and therapeutic efficacy analysis. Additionally, molecular docking studies revealed strong binding affinities of TC and TQ with JAK1 and JAK3 receptors, yielding docking scores of -8.339 kcal/mol and 6.092 kcal/mol for TC, and -9.36 kcal/mol and -7.31 kcal/mol for TQ, respectively. Next, the therapeutic efficacy of TC-NEG was tested against monobenzone-induced experimental vitiligo in C57BL/6 male mice. It demonstrated superior worth in the vitiligo area scoring index (VASI), melanogenesis, and attenuation of oxidative stress markers. Following this, TC-NEG also demonstrated noteworthy melanogenic activity in histological sections, Fontana-Masson (F-M) staining, and Lillie staining. TC-NEG caused significant down-regulation of JAK1 (One-way ANOVA, P < 0.001) and JAK3 (One-way ANOVA, P < 0.0001) in experimental vitiligo. Next, the relative transcriptional levels of JAK1, JAK3, and IFN-γ were also measured using the RT-PCR technique. Treatment with TC-NEG produced marked suppression of JAK1, JAK3, and IFN-γ gene expressions by 3.47-fold, 4.3-fold, and 3.65-fold in experimental vitiligo. Hence, TC-NEG enriched with TQ provided synergistic efficacy against experimental vitiligo due to diminution of oxidative stress, reduction in melanocyte damage, and augmentation of anti-inflammatory activity owing to inhibition of pro-inflammatory JAK/STAT pathway. In conclusion, TC-NEG may be a promising therapeutic modality for translating into a clinically viable pharmaceutical product.

Oral drug administration, preferred for patient compliance and convenience, encounters significant bioavailability challenges arising from complex physicochemical, physiological, and formulation-related barriers. Traditional models for evaluating absorption exhibit limitations in physiological relevance and predictive accuracy. This review critically examines evolving methodologies for oral drug absorption assessment, from classical permeability assays to emerging predictive platforms, emphasizing integration of mechanistic research with predictive modeling to advance intelligent platforms and clinical translation. While classical permeability models including parallel artificial membrane permeability assay (PAMPA), Caco-2, Ussing chambers, and intestinal perfusion remain indispensable for early screening, their limited physiological relevance and inability to elucidate mechanistic pathways constrain predictive accuracy. Mechanistic approaches such as lymphatic transport studies and advanced tracking techniques using fluorescence, Single Photon Emission Computed Tomography (SPECT), or Positron Emission Tomography (PET) imaging reveal critical biological pathways but suffer from scalability challenges. Emerging platforms provide transformative potential, as organoid-on-a-chip offer physiologically relevant and high-throughput alternatives, while integrated computational modeling enables multiscale prediction, from molecular interactions to systemic pharmacokinetics. Future oral absorption assessment requires converging in vitro biomimetics, computational modeling, and Artificial intelligence (AI) within unified platforms. Achieving this requires standardized in vitro models, robust data integration, and alignment with regulatory to accelerate translational drug development.

Manganese-based nanozymes have garnered significant research interest owing to their unique physicochemical properties. Their structures and morphologies can be precisely tailored, offering broad applicability. These materials exhibit novel magnetic and optical characteristics, endowing them with substantial potential in magnetic and optical applications. Furthermore, they have demonstrated excellent catalytic activity alongside favorable biodegradability, establishing a robust foundation for their utilization in catalysis and biomedicine. This review systematically summarizes the synthesis methodologies, catalytic mechanisms, biomedical applications, and future prospects of manganese-based nanozymes. It particularly highlights their applications and underlying mechanisms in tumor therapy and biosensing and detection. Future research endeavors should prioritize optimizing synthesis protocols, expanding the scope of application domains, and exploring their potential in areas such as drug delivery, biosensing, and environmental monitoring.

Fully synthetic exosome-mimetics (FSEMs) represent a nature-inspired drug delivery system designed to replicate the key physicochemical and biological properties of natural exosomes, while offering the potential to address limitations in scalability and reproducibility associated with natural exosomes. In this study, we prepared FSEMs at the laboratory scale. We loaded them with (-)-epigallocatechin-3-gallate (EGCG) and microRNA-23a (miR-23a), aiming to co-deliver therapeutic small molecules and nucleic acids for the treatment of melanoma. FSEMs were fabricated using three methods: thin-film hydration, ethanol injection, and microfluidics. They were surface-functionalized with either CD9, a tetraspanin involved in membrane fusion, or TSP-1, an adhesion protein promoting cellular interactions. Through physicochemical characterization via dynamic light scattering, we found that FSEMs were ∼ 100 nm in size, of low polydispersity (∼0.2) and showed a negative zeta potential (∼-55 mV). Both EGCG and miR-23a were efficiently encapsulated. SDS-PAGE analysis confirmed successful protein incorporation and correct positioning. In vitro release studies showed minimal premature leakage, supporting their suitability for cellular uptake-mediated delivery. When tested on melanoma cells (MDA-MB-435) and progenitor human dermal fibroblasts (FE002-SK2), FSEMs selectively killed melanoma cells while sparing fibroblasts. Importantly, EGCG within FSEMs was more effective than the free compound. Compared to conventional DOTAP-based liposomes, FSEMs were more selective and induced less off-target cytotoxicity. This study presents a proof-of-concept for fully synthetic, protein-functionalized FSEMs as dual carriers for both chemical and gene-based agents, offering a safer and potentially more effective alternative to traditional cationic liposomes. These results lay the groundwork for future in vivo validation and translational cancer research.

Inhalation-based delivery can efficiently transport monoclonal antibodies (mAbs) to the lungs for respiratory and other diseases. While several attempts have been made to develop inhaled formulations of mAbs in the nebulized or dry powder form, these formulations typically rely on high quantities of sugar stabilizers. While sugars can stabilize the mAbs during processing and storage, they are characterized by high hygroscopicity, which could hamper product physical stability in certain drug product configurations and requires aggressive moisture protection during storage and use. The addition of stabilizing excipients like sugars may also lead to a higher powder burden for high-dose therapies. Additionally, sugars may react adversely with certain mAbs via reactions such as the Maillard reaction. This study aimed at delivering mAbs in -lipid-based formulations and abrogate potential storage issues that limit typical sugar-based formulations by reducing hygroscopicity and cohesivity while maintaining high doses of the mAb. The broader goal was to evaluate if the dry powder formulation approach could enable a patient-friendly system that allows a minimal number of inhalations to achieve therapeutic efficacy by increasing the payload of IgG, reducing excipients, in each actuation. Anti-streptavidin IgG1 antibody was used as a model biologic and a series of formulations were prepared using one representative lipid, amino acid, and surfactant in different compositions. A "mixture design of experiments" was utilized to identify stability and dose constraints using these excipients when processed via spray drying. Three formulations containing high IgG content (50 %, 73 %, and 79 % w/w) were chosen for further characterization and assessment of storage stability. The prepared IgG powders exhibited excellent aerosol performance, with over 80 % fine particle fraction and more than 85 % emitted fraction. The powders also had reduced moisture sorption relative to control powders. Additionally, size exclusion chromatography showed that the powders remained stable for at least one month under accelerated conditions (e.g., 40°C with 75 % relative humidity). These findings suggest lipid-based mAb formulations can provide enhanced physical stability to the protein, while exhibiting superior aerosol performance and hence may offer promise for dry powder inhaled therapies.