Search Results (2,043)

Objective: Current pharmacological treatments for prostate diseases are limited by poor drug penetration into the prostate and systemic adverse effects. This study evaluated whether a novel vas-deferens injection device could improve targeted delivery of levofloxacin to the prostate. Methods: Healthy adult male Sprague–Dawley rats received a single dose of levofloxacin by either intravenous administration (IV) or trans-vas-deferens administration using a novel disposable device (VS). Plasma and prostate samples were collected from 0.5 to 24 h and analyzed by LC-MS/MS. Iodixanol micro-CT imaging was used to visualize the local delivery pathway. Pharmacokinetic evaluation included observed composite-profile Cmax/Tmax, AUC0-24, and fT. Time-dependent tissue selectivity was evaluated through partial AUC analyses, prostate-to-plasma exposure ratios, and pointwise concentration ratios. A bioequivalence-style framework was applied to compare relative exposure parameters using geometric mean ratios (GMRs) with the 80.00–125.00% reference interval. Exploratory PK/PD evaluation combined literature-derived free-drug fractions (fut_plasma = 0.55, fut_prostate = 0.080) to estimate fAUC/MIC against representative uropathogens, supplemented by Monte Carlo simulation (n = 5000) to estimate probability of target attainment (PTA) at an fAUC/MIC ≥ 30 threshold. Results: Imaging confirmed selective distribution within the reproductive tract after vas-deferens delivery. In plasma, VS substantially reduced systemic exposure compared with IV: Cmax was 4.74 μg/mL (VS) versus 10.72 μg/mL (IV), and AUC0-24 was 15.47 versus 28.59 μg·h/mL. In the prostate, VS maintained comparable or numerically higher exposure: Cmax was 61.96 μg/g (VS) versus 52.02 μg/g (IV), and AUC0-24 was 235.77 versus 208.77 μg·h/g. The tissue distribution factor fT was substantially elevated in VS (2.26; 95% CI: 1.58–3.19) compared with IV (1.06; 95% CI: 0.89–1.30). Bioequivalence-style analysis demonstrated that plasma GMRs for AUC0-24 and Cmax fell well below 80%, confirming reduced systemic burden, while prostate GMRs were maintained, and the prostate-to-plasma AUC ratio GMR was increased. Time-dependent partial AUC analyses revealed that VS significantly elevated the prostate-to-plasma exposure ratio. PK/PD evaluation showed that at 24 h, prostate fAUC/MIC against Enterobacteriaceae (MIC = 0.5 μg/mL) was 37.7 (VS) versus 33.4 (IV), with corresponding PTA values of 97% and 94%, while plasma fAUC/MIC remained substantially lower in the VS group. Conclusions: Trans-vas-deferens administration of levofloxacin via a novel injection device effectively reduced systemic drug exposure while maintaining or enhancing prostate tissue concentrations, thereby widening the therapeutic window and reducing systemic drug exposure. Full article

Background/Objectives: Magnetotactic bacteria therapy is an emerging active intratumoral drug delivery platform in which drug-loaded, magnetically responsive bacteria are injected into a tumor and navigated through its microenvironment toward defined targets using an external magnetic field, fundamentally distinct from passive intratumoral injection. No endoscopic ultrasound (EUS)- or ultrasound (US)-guided delivery workflow for MTBT has been described, and five critical technical prerequisites for clinical translation remain unaddressed: three-body image registration, minimum contrast concentration for cone-beam computed tomography (CBCT) bolus localization, needle repositioning accuracy, optimal fiducial strategy, and EUS/US procedural feasibility within the magnetic guidance apparatus. Methods: In three healthy female swine, we tested an image-guided intratumoral workflow at pancreatic and rectal sites. Gold rod fiducials were implanted under EUS in two animals and via transabdominal/endorectal US in one animal. A needle was navigated toward the implanted fiducial group using real-time gold-fiducial shine-through, and 2 mL of saline mixed with iodine contrast (Isovue-370) at 15%, 10%, or 5% v/v (one concentration per animal) was injected. Scan with CBCT was acquired before and after injection; fiducials, needle tip, and contrast bolus were segmented in 3D Slicer and their centroids compared to quantify targeting accuracy. Contrast visibility and artifact were scored by an expert radiologist on a five-point Likert scale. EUS feasibility within the magnetic apparatus was assessed using a full-scale cardboard replica of the CuraDrone PolarTrak. Results: Five percent v/v Isovue-370 was the minimum concentration for reliable CBCT bolus identification (280–360 HU; 1:1 injection-to-volume ratio). Needle repositioning accuracy was ≤2 cm in 5/6 sites using fiducial shine-through guidance. Gold rod fiducials served a dual role: CBCT tumor registration and real-time EUS/US navigation, not previously described for intratumoral injection. EUS was feasible within the PolarTrak with defined workflow adaptations. Conclusions: This pilot study demonstrates the technical feasibility of an EUS/US–CBCT workflow for MTBT, yielding quantitative, actionable parameters for first-in-human trial design. These feasibility findings, obtained in a small healthy animal cohort, are intended to inform the design of subsequent clinical studies. Full article

In-vivo diabetes detection of glucose was sought using square-wave anodic stripping voltammetry (SW), with bismuth-immobilized carbon nanotube paste electrode (BCE), and skin tattoo painted wearable circuits. The optimum analytical results indicated sensitivity of 0.0781 μg/L peak signals on the BCE. The raw voltammogram was approached within the in vivo detection ranges of 10–90 μg/L, with preconcentration times of 50 s attained. The relative standard deviation was micro ranges under optimum conditions. The analytical detection limit (S/N) was attained at a nano range of 5.5 nM. The handmade microsensor was directly used in vivo on the living fish brain and human urine. The method was applied at real time in vivo, without requiring any pretreatment and other ionic electrolyte solutions. It can be used for medicinal and other materials requiring biological-fluid detection in real time. This study was designed to be suitable for real-time unmanned remote diagnosis and therapeutic drug injection into the body, micro-needle long-term administration, wearable artificial skin tattoo sensor, and real-time control. In addition, the glasses monitor was designed to be suitable for multitasking and multi-user control sensing. Full article

Background/Objectives: Long-acting injectable aqueous suspensions based on fatty acid prodrugs offer a compelling strategy for chronic disease management. However, the selection of optimal alkyl chain length remains largely empirical, as its influence on prodrug performance is highly system-dependent and lacks predictive guidelines. Methods: Three aripiprazole prodrugs with different alkyl chain lengths were synthesized and characterized using ¹H-NMR spectroscopy and single-crystal X-ray diffraction. A series of physicochemical assessments was performed, including melting point, solubility, lipophilicity, solid-state stability, and plasma stability. The prodrugs were subsequently formulated as aqueous suspensions, which were evaluated for particle size, morphology, release behavior, cytotoxicity, and cellular uptake. Finally, intramuscular administration in rats was carried out to investigate pharmacokinetic profiles and local tolerability. Results: Physicochemical characterization revealed that chain elongation progressively reduced the melting point, solubility, wettability, and solid-state stability of these prodrugs, whereas their flexibility, lipophilicity, and plasma stability correspondingly increased. After wet milling and intramuscular administration in rats, all suspensions sustained drug release for up to one month with good tolerability. Notably, the aripiprazole lauroxil formulation exhibited superior bioavailability and a shortened subtherapeutic interval, enabling the rapid attainment of therapeutic concentrations while effectively mitigating a prolonged pharmacokinetic tail. Conclusions: These findings reinforce the favorable profile of aripiprazole lauroxil as a lead candidate and demonstrate that isostructural packing facilitates the reliable prediction of chain length–property correlations across diverse fatty acid-prodrug systems, thus providing a valuable reference for rational alkyl chain selection in the design of fatty acid-based LAI suspensions. Full article

Objectives: The present study was designed to repurpose aripiprazole (AR) as an antifungal drug for the management of topical candidiasis using a bioadhesive sponge incorporating a hyaluronic acid (HA)-, ceramide-, and terpene-based vesicular nanosystem (HCT-NS). Methods: AR-loaded HCT-NS were formulated by the modified ethanol injection method with varying amounts of HA, ceramide, and two types of terpenes. The formulation optimization of AR-loaded HCT-NS was carried out by a full factorial design. The responses evaluated were zeta potential (ZP), particle size (PS), and entrapment efficiency (EE). Results: The optimized AR-loaded HCT-NS has 5 mg of HA, 10 mg of ceramide, and fenchone, which showed spherical vesicles with EE of 81.21 ± 0.01%, PS of 223.25 ± 11.25 nm, polydispersity index (PDI) of 0.492 ± 0.003, and ZP of −27.74 ± 0.04 mV. The optimum HCT-NS showed a greater drug release in comparison to the AR suspension. In addition, the selected HCT-NS exhibited good bioadhesive characteristics and stayed stable during storage. Confocal laser scanning microscopy confirmed the penetration of the fluorescently optimized HCT-NS via the skin. Further, the scanning electron microscope image indicates the porous structure of the formed sponge. In vivo evaluations for the optimum HCT-NS sponge showed a good antifungal impact against Candida albicans. The safety of topical treatment was confirmed by histopathological examination. Conclusions: Taken together, the results here suggest that the AR-loaded HCT-NS sponge showed potent antifungal activity against Candida albicans fungal infection. Full article

GLP-1 receptor (GLP-1R) agonists, widely used for diabetes and obesity management, have shown preclinical and clinical promise as potential therapeutics for neurological conditions. Until 2026, all U.S. Food and Drug Administration (FDA)-approved GLP-1 drugs were peptide-based, with most requiring daily or weekly subcutaneous injections. Despite their large size and low brain penetrance, several peptide-based GLP-1 drugs are in clinical trials for neurologic indications. Recently, the FDA approved orforglipron as the first small-molecule, non-peptide, orally bioavailable human GLP-1 receptor agonist, and it may offer advantages over peptide-based counterparts. We hence evaluated whether it possesses similar neurotrophic, neuroprotective, and anti-inflammatory attributes. Herein, we utilized human-derived neuronal and microglial cell lines to investigate these properties. Orforglipron activated cAMP signaling and shielded neuronal cells from excitotoxic glutamate and oxidative stress, which are common in neurodegenerative diseases and injuries. Additionally, orforglipron effectively mitigated LPS- and glutamate-induced proinflammatory protein secretion (IL-6, IL-8, and MCP-1) from a human microglial cell line. Actions were replicated under insulin resistance—a potential cause of neurodegenerative conditions—in which orforglipron significantly upregulated phosphorylation of protein kinase B (Akt), providing an additional neuroprotective mechanism. Measured orforglipron brain uptake in rat was low (brain/plasma and CSF/plasma ratios: 0.0078), and in the ballpark of peptide-based GLP-1 drugs. Nevertheless, orforglipron may provide potential value in specific neurological conditions. Full article

Thermoresponsive polymeric prodrugs represent a promising strategy for localized and sustained in vivo drug delivery. In this work, two polyethylene glycol (PEG)-based dexamethasone (Dex) prodrugs with different Dex contents were synthesized using a four-arm PEG scaffold. Prodrug 1, containing four Dex molecules, showed high aqueous solubility but no thermoresponsive gelation behavior. In contrast, eight-Dex Prodrug 2 exhibited temperature-dependent aggregation and formed hydrogels in aqueous media. The viscosity of the Prodrug 2 hydrogel was reduced by introducing 10% ethanol as a cosolvent, enabling an injectable formulation that rapidly forms a hydrogel depot upon contact with aqueous media. The hydrogel provides gradual Dex release via the cleavage of the acid-labile hydrazone bond linking Dex to the PEG. In a monosodium iodoacetate (MIA)-induced osteoarthritis (OA) pain model, intra-articular (IA) injection of Prodrug 2 produced rapid and sustained pain relief for up to 28 days. These findings indicate that the hydrogel-forming four-arm PEG-based Dex prodrug offers a potentially effective approach for prolonged local corticosteroid (CS) delivery, applicable to the treatment of many local pathologies, including OA and OA pain. Full article

Colon cancer is one of the leading causes of death, requiring advanced therapies that need models for developing new drugs. Conventional cell culture models do not accurately and precisely reproduce the complexity of the tumor microenvironment, limiting their usefulness in research and therapy development. To address this weakness, patient-derived organoids have emerged as promising in vitro models. The implementation of these organoid-based models into more physiologically relevant systems is expected to improve their clinical relevance. Thus, integrating these organoids into microfluidic chips acting as bioreactors will likely improve the predictive response of therapies in personalized medicine. In this article, we report the development of a new colon cancer organoid-on-a-chip model that enables the in vitro culture of patient-derived colon cancer organoids under continuous culture media flow. We demonstrate how the developed organoids were derived from tumor biopsies of patients with colorectal cancer, expanded in standard three-dimensional (3D) culture, and cultured inside the microfluidic chips. The microfluidic chip chambers are designed to house organoids in a controlled environment, allowing the injection of therapies and monitoring by optical microscopy in real time. The in vitro therapies tested were a combination of drugs based on 5-fluorouracil and oxaliplatin at different concentrations. As a result, we demonstrate for the first time that this model proves the capability of this technology for in vitro testing colon cancer therapies. Full article

Intratympanic (IT) injection of corticosteroids is a standard clinical treatment for sensorineural hearing loss; however, achieving both biocompatibility and efficient cochlea drug delivery remains a significant challenge. Herein, we engineered a novel drug nanocrystal (NS)-loaded thermo-reversible hydrogel (NS-TG) system of dexamethasone-21-palmitate (DEX-P), a lipophilic prodrug of dexamethasone (DEX), for improved IT delivery. NSs with a mean diameter of 835.0 nm were fabricated using a dual centrifugation process with polyvinyl alcohol as the stabilizer. The NS-TG system, comprising NSs in a 19% (w/v) Poloxamer 407 hydrogel, exhibited rapid gelation (2–3 min) and a 31-fold increase in drug solubility (1.57 ± 0.02 mg/mL) compared to NS alone, through micellar solubilization. In vitro cytotoxicity assays in HEI-OC1 cells revealed that NS-TG is highly biocompatible, maintaining cell viability, whereas the commercial lipid emulsion (Lipothason^®) induced significant cytotoxicity. In vivo pharmacokinetic evaluation in mice revealed that IT NS-TG provided superior cochlear drug absorption compared to DEX-SP solutions and DEX-P NS, despite showing lower absorption than the lipid emulsion. These findings suggest that the DEX-P NS-TG system, pending further investigation, could serve as a promising platform for cochlear steroidal delivery, offering an optimal balance between delivery efficiency and local safety for treating inner ear diseases. Full article

Despite significant biomedical advances in the prevention of mother-to-child transmission (MTCT) of HIV, residual transmission and suboptimal maternal outcomes persist across Europe. The challenge is no longer primarily virological but structural: aggregated ART coverage indicators mask important discontinuities across the perinatal care pathway. This scoping review maps evidence on clinical and psychosocial dimensions of the perinatal HIV pathway among adult women living with HIV (WLHIV) in Europe, and identifies key gaps in their integration across the continuum of care. Following PRISMA-ScR guidelines, five databases were searched for studies published between 2010 and 2026. Of 1881 records identified, 109 met inclusion criteria. Findings were synthesized thematically using an inductively developed framework spanning preconception through long-term postpartum outcomes. MTCT rates declined from approximately 1–1.2% in the mid-2000s to below 0.5% in recent data, and vaginal delivery rates increased markedly with sustained viral suppression. However, persistent inequalities remain among younger women, migrants, and those with histories of injecting drug use. Stigma, migration-related vulnerability, mental health difficulties, constrained disclosure, and socioeconomic insecurity shape engagement with care, influencing treatment continuity, retention, and virological outcomes, particularly during the postpartum period. Equitable perinatal HIV outcomes require integrated care models that combine clinical HIV and obstetric services with mental health support, social needs screening, and migration-sensitive services to address the structural conditions shaping care trajectories. A substantial proportion of WLHIV in Europe originate from high-prevalence regions, making perinatal HIV in this context a direct interface between global infectious disease burden and migration health. Addressing care in European settings therefore contributes to broader global health equity goals in HIV elimination. The protocol was pre-registered on Open Science Framework with registration number: 10.17605/OSF.IO/9BZGY. Full article

Pulmonary drug delivery has become a vital route for both local and systemic treatments because of the unique structure and function of the respiratory system. Unlike oral and injectable dosage forms, inhalation offers a non-invasive, direct route to deliver medicines to the lungs, bypassing gastric degradation and first-pass hepatic metabolism. Common forms such as aerosols, solutions, suspensions, and dry powders are frequently used to treat respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD). However, their effectiveness is often limited by physiological and biopharmaceutical barriers, such as mucociliary clearance, enzymatic degradation, and nonspecific deposition, which reduce drug retention and bioavailability. These issues are especially critical for poorly soluble or sensitive molecules, leading to lower drug concentrations at the target site and necessitating frequent dosing. To address these challenges, advanced nanoparticle-based delivery systems are being developed to improve drug stability, targeting, and controlled release within the lungs. At the same time, computational methods, including deposition modeling, physiologically based pharmacokinetic (PBPK) simulations, and AI-driven optimization, are increasingly used in formulation development to predict in vivo performance and boost translational success. This review covers the physiological and biological barriers to pulmonary drug delivery, explores major inhalation routes and dosage forms, and discusses new therapeutic strategies and nanoparticle platforms. It also highlights the growing role of in silico modeling and AI in accelerating the design and optimization of pulmonary treatments, while addressing current challenges, limitations, and regulatory issues in translating pulmonary nanomedicine into clinical practice. Full article

Xanthohumol (XN), a prenylated chalcone isolated from Humulus lupulus L., exhibits a wide range of biological activities, including antioxidant, anti-inflammatory, and chemopreventive effects. However, its therapeutic application is limited by poor aqueous solubility, low chemical stability, and rapid clearance from the systemic circulation. The present study aimed to develop and characterize a novel nano-sized drug-delivery system for XN that combines favourable colloidal stability, efficient encapsulation, sustained release, and reduced recognition by macrophages (“stealth-like” properties). To achieve this, XN-loaded cationic liposomes were coated with two marine polysaccharides, iota-carrageenan (CAR) and fucoidan (FUC), followed by Ca²⁺-mediated cross-linking. Liposomes were prepared by the ethanol injection method, and formulation parameters were optimized using a 2³ + 1 full factorial design. Surface modification and cross-linking conditions were further optimized through polyelectrolyte titration and a Taguchi L9 orthogonal array. The resulting nanocarriers were evaluated for particle size, polydispersity, ζ-potential, encapsulation efficiency, release behavior, and cellular uptake. Both coatings significantly prolonged XN release compared with uncoated liposomes, with CAR-coated vesicles providing the most sustained release (≈55% over 48 h). In RAW264.7 macrophages, 50 µg/mL CAR-coated liposomes reduced cellular uptake by approximately 74% following 1-h incubation relative to uncoated controls and maintained this reduction over 2 h whereas FUC-coated vesicles afforded only transient early evasion. The cross-linked iota-carrageenan coating thus represents a promising strategy for conferring stable “stealth-like” characteristics to XN-loaded liposomes intended for prolonged drug delivery. Full article

With a lifetime risk estimated to be 1 in 8 in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide and the second leading cause of cancer deaths in women. More importantly, current evidence suggests that in women aged <45 years, breast cancer is unquestionably the leading cause of cancer-related deaths. Hormonal therapy has an established role in the treatment of breast cancer. Hormonal therapy aims at preventing the stimulation of mitogenic estrogen-dependent pathways. Hormonal therapy can be performed through blocking the production of estrogens or through blocking the action of estrogens upon tumor cells. The action of estrogens upon tumor cells can be blocked through selective estrogen receptor modulators (SERMs) or through selective estrogen receptor downregulators (SERDs). Estrogen receptor mutation (ESR1 mutation) is one of the common mechanisms by which breast cancer becomes resistant to additional therapies from SERMs or aromatase inhibitors. Fulvestrant, an injectable anti-estrogen, is the SERD commonly used. Fulvestrant has no agonistic activity and causes degradation of the estrogen receptor. This agent is more active in postmenopause than premenopause and is indicated in the treatment of advanced breast cancer in case of disease progression during or after tamoxifen. Oral SERDs are being rapidly developed to replace fulvestrant with the potential of higher efficacy and lower toxicities. Novel agents such as complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and selective estrogen receptor covalent antagonists (SERCAs) are also promising therapies. This manuscript focuses on recent advances in the development of drugs targeting the estrogen receptor. Full article

Intradermal injections of anti-canine immunoglobulin E (IgE) in healthy dogs have been utilized in preclinical drug testing to evaluate the efficacy of anti-allergic drugs used to treat canine atopic dermatitis (AD). However, the molecular effects of established canine anti-allergic drugs on this acute canine IgE-mediated atopic model remain largely uninvestigated. The objective of this study was to characterize the effect of proactive oclacitinib and prednisolone treatments on the immune and skin barrier transcriptome of IgE-mediated late-phase reactions (LPRs) in an acute model of canine AD. Sixteen healthy adult research-bred beagles were randomized to receive either oclacitinib or prednisolone orally for six days, followed by an intradermal anti-canine IgE injection. Biopsies were collected 24 h post-injection for RNA isolation and sequencing; previously analyzed transcriptomes (healthy skin, saline-injected skin, IgE lesions without drug modulation) from the same colony of dogs served as controls. Administration of prednisolone and oclacitinib prior to intradermal anti-IgE injections reduced the number of differentially expressed genes (DEGs) in 24 h samples to 1251 and 1471, respectively. Both treatments resulted in a decrease in expression of several significantly upregulated T helper-(Th)1 (e.g., MX1, OAS1, STAT1), Th2 (e.g., CCL13, CCL8, IL13RA1, IL-33, IL5RA, OSM), chemokine and receptor (e.g., CCL19, CCL2, CCL3, CCR1, CCR3) genes in comparison to the untreated IgE-mediated lesions. Interestingly, only prednisolone treatment significantly reduced IL-13 upregulation, an important gene in the Th2 immune response. In conclusion, both prednisolone and oclacitinib reduced the transcriptomic changes observed in the acute lesions of the canine IgE-induced atopic dermatitis model, with prednisolone inducing a broader inhibitory immune response. Full article

In this work, we develop a coupled multiphysics model that integrates polymer carriers exhibiting time-dependent thixotropic structural recovery with Darcy flow, linear Biot poroelasticity and advection–diffusion transport in a spherically symmetric, isotropic and homogeneous tissue domain. The formulation explicitly links rheological evolution to pressure-driven flow, interstitial deformation and solute transport through a unified framework, enabling systematic prediction of post-injection behavior. Unlike conventional approaches that assume constant carrier properties, the present model incorporates a time-dependent viscosity evolution, capturing the transition from an initially shear-thinned state to a recovered, highly viscous structure. Numerical simulations using hydroxypropyl methylcellulose and methotrexate parameters as representative components demonstrate that rapid post-injection viscosity recovery suppresses pressure-driven transport and diffusion, thereby enhancing local drug retention near the injection site. A systematic sensitivity analysis identifies the equilibrium viscosity as the dominant parameter controlling spatial localization, whereas tissue mechanical properties exert a comparatively minor influence. An effectiveness metric based on the Kullback–Leibler divergence reveals a tumor-size-dependent trade-off between spatial coverage and retention. The proposed framework thus introduces a predictive tool for analyzing coupled rheological-transport interactions and for the rational design and optimization of thixotropy-enhanced local chemotherapy strategies. Full article