Search Results (2,397)

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) cause recurrent skin infections that are difficult to treat because of the limited solubility and permeability of acyclovir (ACV). This study developed electrospun polymeric membranes based on polycaprolactone (PCL), poly(lactic acid) (PLA), and cellulose acetate (CA) as controlled ACV delivery systems using uniaxial and coaxial fiber architectures. In the coaxial configuration, ACV-loaded PCL was used as the core and a PLA/CA blend as the shell. Continuous, randomly oriented, bead-free fibers with diameters ranging from 0.68 ± 0.32 µm to 1.45 ± 0.57 µm were obtained. Spectroscopic and thermal analyses confirmed successful drug incorporation, polymer compatibility, and good thermal stability. Coaxial membranes exhibited improved mechanical properties compared with uniaxial systems. Drug release studies showed a prolonged, pH-dependent profile, with greater ACV release at pH 7.3 than at pH 5.5, indicating the effective modulation of drug diffusion by the shell layer. Release kinetics were mainly governed by diffusion and anomalous transport mechanisms. All membranes maintained a cell viability above 80%, demonstrating good in vitro cytocompatibility. These findings support the potential of coaxial electrospun membranes for controlled antiviral drug delivery in skin applications. Full article

Antibody–drug conjugates (ADCs) have emerged as a powerful class of targeted therapeutics in many clinical areas, such as in oncology. Despite their efficacy, the onset of adverse events has been a major drawback in their clinical use. Among other explanations, the clinical performance of the ADCs has been associated with the chemistry of the linker connecting the antibody and payload. Linkers determine plasma stability, intracellular activation, and payload diffusibility, thereby influencing the therapeutic index, off-tumour toxicity, and by-stander activity. Mechanistic insights increasingly show that linker–payload properties govern catabolite permeability and intratumoral distribution, particularly in antigen-heterogeneous settings. Current developments include enzyme-cleavable and tumour-selective linkers, polarity-modulating masking strategies, alternative self-immolative spacers, and dual-trigger systems designed to enhance selectivity and decouple efficacy from toxicity. In parallel, linker behaviour intersects with broader mechanisms of tumour resistance. This review focuses on understanding these processes, which are essential for designing the next generation of linkers capable of improving stability, safety, and long-term therapeutic effectiveness across diverse tumour contexts. Full article

Nanostructured drug-delivery materials—liposomes, polymeric nanoparticles, dendrimers, and inorganic carriers—have become central to pharmaceutical strategies for crossing the blood–brain barrier (BBB), where most candidate therapeutics fail to reach their targets. Their biological performance hinges on a coupled chain of vascular transport, BBB translocation, tissue diffusion, cellular uptake, and intracellular release, each of which is shaped by the nanocarrier’s size, surface chemistry, charge, and ligand functionalization. Physiologically based pharmacokinetic (PBPK) models describe this chain mechanistically but are limited by parameter uncertainty, simplified representations of the BBB, and coarse regional resolution. Machine learning (ML) can close these gaps by extracting nonlinear structure–transport–exposure relationships from heterogeneous experimental and clinical datasets. This review examines emerging ML–PBPK hybrid frameworks for predicting the brain biodistribution of nanostructured drug carriers. We compare regression, kernel, and deep learning approaches for parameter inference, model correction, and surrogate modeling; assess strategies for feature selection, uncertainty quantification, and interpretability; and discuss documented failure cases that bound the conditions under which these methods can be trusted. The review closes with recommendations on dataset standardization, software platform selection, and the responsible use of generative AI in pharmaceutical modeling, thus providing guidance for translating nanostructured material design into safer, more effective brain-targeted therapies. Full article

Nanoparticle-laden contact lenses (CLs) represent a promising strategy for ocular drug delivery. Nanocarriers built from hyaluronic acid and chitosan offer a biomimetic alternative to synthetic polymers, by combining the lubricating property of hyaluronic acid with the mucoadhesive property of chitosan. However, achieving sustained drug release without compromising lens properties remains challenging, and the influence of lens material and replacement modality is unclear. This study evaluated methotrexate (MTX)-loaded chitosan/hyaluronic acid (CS/HA) nanoparticles incorporated into silicone hydrogel CLs with different replacement modalities, assessing their effect on drug release kinetics. Daily replacement lenses (Senofilcon A and Delefilcon A) released 26 ± 4% and 33 ± 5% of MTX after 24 h, respectively. The monthly lens Lehfilcon A showed slower diffusion-controlled release, with only 15 ± 2% released at 24 h and a 64 ± 3% cumulative release after 31 days (p < 0.01). Nanoparticle incorporation improved drug retention and reduced initial drug loss compared with lenses loaded with only MTX. Monthly lenses demonstrated sustained delivery potential, supporting prolonged ocular therapy, while daily lenses may be better suited for short-term treatment. These findings reinforce the value of bioinspired nanocarriers, mimicking natural retention mechanisms of the ocular surface, for next-generation therapeutic CLs. Full article

Autonomous microrobot teams have significant potential for distributed drug delivery, cooperative vascular intervention, and parallelized biomedical diagnostics. However, coordinated control in cardiovascular environments remains challenging due to partial observability, limited communication bandwidth, and hydrodynamically coupled pulsatile blood flow. This paper introduces Decentralized Hemodynamic-Aware Multi-Agent Reinforcement Learning (DH-MARL), a distributed learning and control framework in which individual microrobots learn decentralized policies from local observations while graph-based attention mechanisms model inter-agent interactions during centralized training. The proposed framework integrates turbulence-aware adaptive exploration, reduced-order hydrodynamic interaction modeling, diffusion-based local communication, and hemodynamic-aware counterfactual credit assignment to improve cooperative learning and role specialization in dynamic vascular environments. A scalable Unity-based simulator supporting coupled pulsatile flow for up to 32 agents was developed for training and evaluation. Our experimentalresults cover four therapeutic scenarios: distributed drug delivery, cooperative clot dispersion, stenosis mapping, and vessel bottleneck traversal. For 16-agent teams, DH-MARL reaches an 88.7% team success rate. This performance exceeds independent single-agent controllers and centralized MAPPO baselines, and inter-robot collision rates remain below 4%. The learned policies generalize to unseen team sizes with minimal performance degradation, highlighting the scalability and robustness of the proposed decentralized control strategy. These simulation-level results demonstrate the feasibility of distributed reinforcement learning and graph-based coordination as a control paradigm for future multi-agent microrobot systems in biomedical environments. The results also provide a foundation for the calibration of subsequent microfluidic, ex vivo, and preclinical experiments. Full article

Background/Objectives: Rice bran wax (RBW), a natural hydrophobic byproduct of rice bran oil refining, was evaluated as a lipid matrix former for the sustained oral delivery of diclofenac sodium (DFS). Methods: Matrix tablets containing 100 mg DFS and 45–60% (w/w) RBW, corresponding to 180–240 mg RBW per 400 mg tablet, were prepared using five techniques: simple mixing, dry granulation, extrusion–spheronization, partial melt granulation, and melt granulation. These techniques were selected to represent progressively different thermal, mechanical, and solvent-processing histories, ranging from simple physical blending to high-shear wet processing and extensive distribution of molten wax. Results: Processing method, wax concentration, and thermal sintering significantly influenced matrix structure and drug release. Scanning electron microscopy of the processed powders and granules indicated that melt granulation produced more extensively integrated wax-containing structures, although the internal continuity of the tablet matrix was not directly examined. FTIR and DSC analyses showed no evidence of major drug–excipient interactions and confirmed the retention of a detectable RBW melting transition. Melt granulation produced the greatest release retardation, followed by partial melt granulation, while extrusion–spheronization and dry granulation showed broadly similar release-retarding performance, and simple mixing was the least effective. The optimized formulation, containing 55% (w/w) RBW, prepared by melt granulation and sintered at 80 °C for 2 h, showed sustained release consistent with diffusion through the hydrophobic matrix. It met the dissolution limits specified in the USP–NF monograph for Diclofenac Sodium Extended-Release Tablets and showed a dissolution profile that was broadly comparable to that of the commercial reference product based on descriptive profile analysis. During a preliminary 4-week accelerated stability study, no statistically significant changes were observed in the physicochemical properties subjected to inferential analysis, while friability remained below 1%. The 55MG2 formulation also retained a broadly comparable dissolution profile, although a modest increase in drug release was observed. Conclusions: These findings support the potential of RBW as a natural lipid excipient for controlled oral drug delivery. Full article

Leaves of Mitragyna speciosa Korth. (M. speciosa), commonly known as Kratom, are rich in alkaloids, with mitragynine as the main bioactive compound. This study presents a technique for the entrapment of ethanolic Kratom leaf extract within bacterial cellulose (BC) films and the subsequent controlled release of mitragynine. Kratom leaves were dried, ground, and extracted by maceration in 95% ethanol at 35 °C for 72 h. The extract was incorporated into the BC matrix via the immersion method, followed by air-drying at room temperature (~32 °C). BC’s highly porous structure facilitates sustained mitragynine absorption and entrapment within a tight nanofibrillar network. The mitragynine content in the BC films ranged from 9.1 to 23.3 mg/g, allowing for the evaluation of its effects on film properties and drug release performance. Release studies were conducted using Franz diffusion cells, with acetate buffer (pH 5.5) and phosphate buffer (pH 7.4) as receptor phases. Consistent with its higher solubility in acidic conditions, mitragynine showed greater release in acetate buffer, particularly within the first 0–12 h. The release profile depended on both mitragynine loading and time. The mitragynine-loaded BC films exhibited strong antimicrobial activity, achieving 100% reduction of Staphylococcus aureus and Escherichia coli. In vitro studies using L929 mouse fibroblast cells demonstrated that the films were noncytotoxic. The films also promoted proliferation and viability of normal human epidermal keratinocytes. Overall, the mitragynine-loaded BC films support skin cell growth and attachment and exhibit antibacterial, antioxidant, and anti-inflammatory properties, highlighting their potential as candidates for wound healing applications. Full article

Periodontitis, a chronic inflammatory disease driven by plaque biofilm, is a leading cause of tooth loss in adults worldwide. Effective treatment requires not only infection and inflammation control but, more critically, functional regeneration of the periodontal ligament, cementum, and alveolar bone. Periodontal regeneration, however, is a highly ordered, multi-stage biological cascade involving temporally coordinated phases of blood clot formation, inflammatory regulation, tissue formation, and remodeling. Conventional single-drug or mixed-delivery strategies cannot distinguish the distinct demands of each healing phase and fail to replicate this natural rhythm. Sequential controlled-release systems address this gap by delivering multiple bioactive agents (antimicrobials, immunomodulators, and growth factors) in a programmed order tailored to the healing cascade, enabling precise modulation of the periodontal microenvironment and orderly tissue regeneration. This review systematically summarizes advances in these systems, classifying material platforms into four categories: (1) diffusion-barrier and degradation-kinetics systems, including multilayer films, core–shell fibers, porous microspheres, and microneedle arrays; (2) stimuli-responsive systems triggered by pH, matrix metalloproteinases, reactive oxygen species, or exogenous physical stimuli; (3) cell and extracellular vesicle-based systems exploiting the inflammatory tropism of M2 macrophage-derived exosomes for targeted immune reprogramming; and (4) asymmetric structural designs achieving spatiotemporal coordination of physical and biochemical signals through hierarchical architectures. These systems follow an anti-infection/anti-inflammation first, osteogenesis later therapeutic logic, circumventing temporal antagonism among bioactive factors. However, significant challenges hinder clinical translation, including individualized prediction of release kinetics, long-term biocompatibility of carrier materials, material retention under dynamic oral conditions, translational limitations of animal models, and precise regulation of complex factor networks. Future progress will likely depend on multi-responsive and logic-gated systems, deeper integration of biotechnology and immunomodulation, personalized precision medicine, AI-driven material design, and robust clinical translational research. Full article

Drug release from long-acting intravitreal implants is governed by the coupled effects of diffusion, hydrolysis-driven erosion, and progressive shrinkage of the polymeric matrix. To capture these mechanisms, we solve the diffusion equation in a cylindrical domain whose radius decreases according to the hydrolytic degradation kinetics of PLGA, which follow a pseudo-first-order behaviour in aqueous excess. The resulting formulation combines a modal Bessel expansion with an erosion-controlled time transformation, allowing the evolving geometry and the attenuation of the diffusion modes to be incorporated in a fully mechanistic manner. Within this framework, the shrinkage parameter p quantifies the rate of erosion-induced geometric evolution and enables an accurate reconstruction of the experimental dexamethasone release profile. The solution reproduces both the initial fast-release phase and the extended depletion tail from which the characteristic times $t_{0.50}=264.3\mathrm{h}$ and $t_{0.90}=996.5\mathrm{h}$ are extracted, providing compact and physically meaningful indicators of the transition between early and late kinetic regimes. Overall, the approach offers a robust and interpretable description of drug release from shrinking polymeric systems and is directly applicable to the design of long-acting intravitreal therapies. Full article

Post-operative infections remain a challenge in implant surgery, leading to prolonged treatment, increased costs, and implant failure. Localized antibiotic-delivery coatings are a promising strategy to reduce infection risk while maintaining biocompatibility. Here, we evaluate cold atmospheric pressure plasma (CAP) spraying as a solvent-free method to deposit polyvinyl alcohol (PVA) layers containing amikacin on stainless steel and to identify plasma parameters that control release and antibacterial activity. A 3 × 3 factorial design varied nozzle distance (15, 20, 25 mm) and speed (10, 15, 20 cm/s). Surface morphology was assessed by optical microscopy, amikacin release quantified by HPLC-HRMS, and antibacterial activity tested against Staphylococcus aureus and Escherichia coli using Kirby–Bauer disc diffusion. Two-way ANOVA with Tukey post hoc tests and nonparametric validation were applied. Cold plasma spraying speed significantly affected drug release, whereas distance and the interaction term were not significant. Lower spraying speeds produced thicker, more porous coatings with greater cumulative release and larger inhibition zones. Drug release profiles were best described by Weibull and first-order models, showing an initial burst followed by sustained release. These findings indicate that CAP spraying enables solvent-free fabrication of antibiotic-loaded PVA coatings with tunable release, and optimizing spraying speed improves coating mass, drug delivery, and antibacterial performance. Full article

Imperatorin (IPT) is a naturally occurring coumarin with recognized antioxidant and anti-aging properties; unfortunately, its poor water solubility and low oral bioavailability severely limit its practical use. To get around these issues, we formulated IPT-loaded NLCs using grape seed oil and glyceryl monostearate—both food-grade excipients—with the goal of enhancing oral absorption. Optimized IPT@NLCs were prepared by high-pressure homogenization, featuring uniform spherical morphology, an average particle size of 186.63 ± 1.65 nm, a PDI of 0.188 ± 0.008, an encapsulation efficiency of 99.54 ± 0.10%, and a drug loading capacity of 9.08 ± 0.23%. IPT@NLCs remained stable in SGF, while their cumulative in vitro release over 48 h reached 90.56 ± 3.12% in SIF. We established a Caco-2/HT29-MTX-E12 co-culture monolayer to examine mucus penetration, cellular uptake, and transcellular transport routes. In parallel, oxidative stress experiments using 3T3-L1 cells, along with in vivo pharmacokinetic and gastrointestinal safety evaluations, were conducted to provide complementary evidence. Our results indicate that NLC encapsulation significantly improves both the dissolution and intestinal uptake of IPT, primarily by shifting the absorption mechanism from passive diffusion to energy-dependent active transport. In addition, IPT@NLCs effectively reduce intracellular oxidative damage through modulation of endogenous antioxidant enzyme activities. Animal studies further reveal an approximately 9-fold increase in relative oral bioavailability, with no notable irritation to gastrointestinal tissues. Overall, GSO-based NLCs offer safe and efficient oral delivery, enhancing IPT bioavailability and antioxidant activity, providing a strategy for developing natural-product-based formulations. Full article

Poor adherence to prolonged antibiotic regimens remains a major challenge in the treatment and prevention of chronic infectious diseases such as tuberculosis. Transdermal drug delivery systems capable of sustained antibiotic release may improve therapeutic compliance while reducing the need for frequent oral administration. In this study, electrospun polymeric membranes based on poly(lactic acid) (PLA) and poly(ε-caprolactone) (PCL) were developed as transdermal rifampicin delivery platforms. Homogeneous nanofibrous membranes with average fiber diameters of approximately 250 nm were successfully fabricated and exhibited efficient drug incorporation while preserving the structural integrity of the polymeric matrix. The electrospun membranes retained sufficient tensile strength and dimensional stability after accelerated temperature–humidity aging, supporting their stability during storage, handling, and application. In vitro cytotoxicity and biocompatibility assays using primary human peripheral blood mononuclear cells (PBMCs) demonstrated that the developed systems did not induce significant cytotoxic or pro-inflammatory responses. Transdermal permeation studies using an in vitro mouse skin model demonstrated sustained rifampicin diffusion for at least 72 h. Importantly, the antibiotic recovered after skin permeation preserved antimycobacterial activity against Mycobacterium tuberculosis H37Ra and Mycobacterium bovis BCG, confirming that rifampicin maintained its biological functionality after electrospinning and transdermal migration. Overall, these findings demonstrate the potential of electrospun PLA/PCL membranes as stable and biocompatible transdermal antibiotic delivery systems capable of sustained release and preservation of antimicrobial activity. This proof-of-concept study supports the translational potential of electrospun polymeric platforms for controlled antibiotic delivery in long-term infectious disease therapies. Full article

Oral administration of narrow therapeutic index anticoagulants like phenprocoumon (PHP) necessitates careful control of the kinetic release of the drug to avoid dose dumping and severe haemorrhagic effects. This study was carried out to prepare and characterize novel PHP delivery systems based on κ-carrageenan hydrogels, exploring the importance of potassium ion (K⁺) stabilization in controlling the release process. FT-IR, TG/DTG, and in vitro release studies were employed in combination with a new validated RP-HPLC assay. FT-IR and thermal analysis results showed that PHP is physically encapsulated into the polysaccharide matrix, where there are no chemical incompatibilities between them. Furthermore, potassium ions increase the stability and heat resistance of the polymer network. However, when K⁺ was considered for modelling the kinetic release using the Korsmeyer–Peppas equation, it was observed that PHP is released from the K⁺ stabilized matrix in a relaxation dominated diffusion-controlled transport. Ionic cross-linking effectively reduces the initial burst effect, demonstrating that these matrices are promising vehicles for the sustained delivery of phenprocoumon. Full article

Background and Clinical Significance: Enfortumab vedotin combined with pembrolizumab has emerged as an effective first-line therapy for advanced urothelial carcinoma. While immune checkpoint inhibitors are associated with digestive tract toxicities, upper gastrointestinal involvement such as esophagitis remains rare, and its presentation in combination with enfortumab vedotin is not well characterized. Case Presentation: A 72-year-old man with metastatic urothelial carcinoma presented with generalized weakness, poor oral intake, odynophagia, dysphagia, anemia, and systemic symptoms following the second cycle of combination therapy of enfortumab vedotin and pembrolizumab. Endoscopic evaluation revealed diffuse circumferential ulcerative esophagitis involving the entire esophagus, with associated duodenitis. Infectious workup, including Clostridioides difficile, cytomegalovirus, and human immunodeficiency virus testing, was negative, and HSV-1 IgG was positive, consistent with prior exposure rather than active infection; however, tissue-based testing for active HSV infection was not performed. Lower gastrointestinal evaluation demonstrated nonspecific rectal inflammation. The patient was treated with high-dose intravenous corticosteroids (intravenous methylprednisolone 1 mg/kg/day) with rapid clinical improvement within 48–72 h, followed by a steroid taper and supportive care. Conclusions: This case represents a severe and diffuse manifestation of esophagitis associated with enfortumab vedotin and pembrolizumab therapy. While immune-mediated esophagitis is rare, the combination of antibody–drug conjugate therapy with immune checkpoint inhibition may contribute to synergistic mucosal injury. Early recognition and prompt initiation of immunosuppressive therapy are critical for favorable outcomes. Clinicians should be aware of severe esophagitis as a potential complication of enfortumab vedotin and pembrolizumab therapy. Timely diagnosis and management with corticosteroids can lead to rapid symptom resolution and may prevent serious complications. Full article

Background/Objectives: Breast cancer remains one of the most prevalent malignancies worldwide, highlighting the need for safer and more effective therapeutic strategies. Curcumin has shown considerable anticancer potential; however, its clinical application is limited by poor aqueous solubility and low skin permeability. Methods: Therefore, a curcumin-loaded microemulsion (CUR-ME) was developed and optimized using a Box–Behnken design, followed by incorporation into a Carbopol 934 gel for topical breast cancer therapy. Results: The optimized formulation exhibited a particle size of 177.4 nm, a polydispersity index of 0.1309, and a zeta potential of −4.45 mV, indicating favorable physicochemical characteristics. CUR-ME demonstrated superior dose-dependent cytotoxicity against MCF-7 breast cancer cells, with a lower IC₅₀ 8.89 µg/mL than free curcumin IC₅₀ 9.83 µg/mL. Furthermore, Hoechst 33342 staining and the DCFDA assay confirmed enhanced apoptosis and intracellular reactive oxygen species generation in CUR-ME-treated cells, indicating improved cellular uptake and anticancer activity. Rheological and texture profile analyses demonstrated suitable viscosity, firmness, and spreadability for topical application. In vitro drug release revealed sustained release from the CUR-ME gel, achieved through the polymeric gel matrix, which increased viscosity, entrapped microemulsion droplets, and acted as a diffusion barrier to prolong drug retention and release. Confocal laser scanning microscopy further confirmed enhanced skin penetration of CUR-ME. Conclusions: Collectively, these findings demonstrate that the developed CUR-ME gel is a promising topical drug delivery system with sustained release, improved skin retention, and enhanced therapeutic potential for breast cancer management. Full article