Search Results (4,235)

Drug delivery systems based on nanoparticles have emerged as promising approaches for overcoming the blood–brain barrier (BBB), a major obstacle to treating disorders of the central nervous system (CNS). There are several reasons why conventional therapies fail, including poor brain penetration, rapid drug clearance, and nonspecific distribution. This review critically evaluates recent advances in nanoparticle-mediated BBB targeting, focusing particularly on in vivo findings. As part of this review, lipid-based, polymeric, metallic, dendrimeric, exosome-inspired, and magnetic nanoparticles are discussed in conjunction with their transport mechanisms. The review compares their therapeutic efficacy, biodistribution, targeting ability, and safety across a variety of neurological conditions. Additionally, emerging technologies are discussed, including biomimetic nanoparticles, stimuli-responsive systems, artificial intelligence, and personalized nanomedicine. Additionally, this review critically discusses the major barriers to clinical translation, including biosafety, manufacturing, and regulatory challenges. As a result, this review provides an updated perspective on current progress and future prospects for developing effective brain-targeted nanomedicine. Full article

Background: Hyperuricemia is a well-established risk factor for both chronic kidney disease and gout. Currently available urate-lowering drugs, however, are frequently compromised by hepatorenal toxicity and gastrointestinal adverse effects. Cinnamaldehyde, the principal bioactive constituent of the traditional Chinese medicine cinnamon, has documented renoprotective properties, yet its integrated effects on hyperuricemia-associated renal injury remain incompletely defined. Objectives: This study investigated the therapeutic effects of cinnamaldehyde on hyperuricemia and explored the molecular mechanisms involved. Materials and Methods: An in vivo hyperuricemia model was established in KM mice by co-administration of potassium oxonate and hypoxanthine for 14 consecutive days, and an in vitro injury model was generated by exposing HK-2 human renal tubular epithelial cells to uric acid. For the in vivo study, mice were divided into five groups (control, model, febuxostat, low-dose CA, and high-dose CA; n = 9 per group) and were treated by oral gavage. Serum biochemical indices, renal and intestinal histopathology, inflammatory cytokines, renal urate transporter proteins (OAT1, OCT2, ABCG2, and SLC2A9), and components related to AIF1 and CMPK2/NLRP3 inflammasome signaling (ASC, caspase-1, IL-18, and IL-1β) were examined. Western blotting, qPCR, immunofluorescence, apoptosis analysis, mitochondrial membrane potential assessment, transmission electron microscopy, siRNA-mediated knockdown, and 16S rRNA gene sequencing were used to characterize the relevant mechanisms. Results: CA reduced serum uric acid (p ≤ 0.001 vs. model), creatinine (p ≤ 0.01 vs. model), and blood urea nitrogen (p ≤ 0.01 vs. model), alleviated renal and intestinal histopathological injury, and decreased circulating and renal inflammatory cytokines. Cinnamaldehyde increased ABCG2, OAT1, and OCT2 protein expression and reduced SLC2A9 expression (all p ≤ 0.05 vs. model). In vivo and in vitro, cinnamaldehyde suppressed AIF1- and CMPK2/NLRP3-related inflammatory proteins, reduced uric acid-induced apoptosis, and preserved mitochondrial membrane potential and ultrastructure. Fecal 16S rRNA sequencing suggested changes in selected microbial taxa, although alpha-diversity and BrayCurtis-based PERMANOVA/ANOSIM analyses did not demonstrate significant global community separation. Conclusions: These findings suggest that CA alleviates hyperuricemia-associated renal injury by regulating renal urate transporters, attenuating AIF1- and CMPK2/NLRP3-related inflammatory signaling, accompanied by compositional shifts in selected gut microbial taxa that warrant further mechanistic investigation. The study provides experimental support for further evaluation of cinnamaldehyde as a multi-target candidate for hyperuricemia-related renal injury. Full article

Oleanolic acid is a naturally occurring pentacyclic triterpenoid with broad preclinical promise in inflammation, oxidative stress, liver injury, metabolic disorders, cancer-related models, skin disease, and wound repair. Its further development, however, is constrained by poor aqueous solubility, low and variable bioavailability, limited barrier transport, crystallinity, and strong dependence of biological response on the formulation used. These properties make oleanolic acid a useful example of a hydrophobic natural compound whose pharmacological performance is inseparable from delivery design. This review examines polymeric nanocarriers and polymer-assisted delivery platforms developed for oleanolic acid delivery. Polymeric nanocarriers discussed in the review include biodegradable PLA/PLGA nanoparticles, PEGylated polymeric nanoparticles, polymeric micelles, nanogels, hyaluronic-acid-based nanoprodrugs, and selected polymer-assisted hybrid nanostructures. Hydrogels, polymeric fiber membranes, local depots, and microneedle systems are included as route-enabling delivery platforms when the polymeric matrix directly contributes to OA incorporation, carrier stabilization, local retention, barrier bypass, or release control. Non-polymeric delivery systems are discussed only as comparators or when their performance depends on integration with a polymeric component. Rather than treating these carriers only as solubility enhancers, the review evaluates how polymer composition, carrier architecture, drug physical state, release behavior, and route of administration affect oleanolic acid exposure. Particular attention is given to controlled release, local retention, disease-oriented delivery, and critical quality attributes such as particle size, loading, encapsulation efficiency, solid-state form, stability, residual solvent, sterility, and batch-to-batch reproducibility. Representative quantitative data on carrier size, drug loading, encapsulation efficiency, release, stability, tissue exposure, and biological outcomes are compared to illustrate both formulation-specific performance and the substantial methodological heterogeneity of the available studies. The available evidence indicates that increased apparent solubility, increased biological exposure, and improved therapeutic response should be treated as related but distinct outcomes. The most realistic near-term opportunities may lie in local and tissue-targeted applications, including inflammatory skin disease, wound healing, dermal delivery, and osteoarthritis, where sustained target-site exposure may be more relevant than systemic bioavailability. Future progress will depend on demonstrating that each formulation provides reproducible, safe, and route-appropriate OA exposure, together with a measurable advantage over simpler delivery approaches. Full article

Biomimetic structures are now a major topic of research, as natural systems achieve high performance through hierarchical organization, multifunctional interfaces, and scale-bridging design principles. Nanofabrication provides a powerful approach to recapitulate biological architectures from the nanoscale to the macroscale, allowing accurate control of the surface chemistry, geometry, transport, mechanics and function. Recent work demonstrates that this approach is especially critical for bionic devices and systems, including biosensors, drug delivery platforms, tissue-engineered constructs, organ-on-chip systems, soft robots, and biohybrid devices. The aim of this review is to provide a systematic overview on how nanofabrication allows the construction of biomimetic structures, with emphasis on bio-templating and replication of natural structures, applications of nanofabrication in bionic devices and systems, and cross-scale biomimetics. Full article

The instability of ibrutinib in plasma at room temperature necessitates temperature-controlled sample transport, complicating therapeutic drug monitoring (TDM) and multicenter studies. Dried plasma spots (DPSs) offer a potential advantage by enabling sample storage and transport under ambient conditions. The aim of this study was to develop and validate an LC-MS/MS method for the simultaneous quantification of ibrutinib and ritonavir in plasma and DPSs. Following validation of an extended plasma calibration range, DPS method development included card selection and subsequent validation in accordance with ICH M10 and EMA guidelines. The analytical method demonstrated robust performance in plasma for both analytes. For DPS sampling, ritonavir fulfilled all validation criteria. In contrast, ibrutinib showed significant instability in DPS samples at room temperature after 48 h and did not meet the predefined acceptance criteria under these conditions. Refrigerated storage improved stability within the acceptance criteria for at least one week. The developed method is suitable for simultaneous quantification of ibrutinib and ritonavir in plasma and for ritonavir in DPSs. While DPS sampling may offer logistical advantages, its successful application is dependent on analyte stability. For ibrutinib, the requirement for refrigerated storage limits the anticipated benefits, and further research is needed to optimize dried sampling strategies. Full article

Hydrogel-forming microneedles (HFMNs) are minimally invasive interfaces that access interstitial fluid (ISF) through skin penetration, swelling-mediated uptake, analyte diffusion, and hydrated sensor integration. This review examines HFMN architectures, skin–device interfaces, ISF transport, molecular-recognition and signal-transduction strategies, analytical performance, benchmarking, wear-associated failure modes, therapeutic monitoring, and translational priorities. The field has expanded from glucose sensing to metabolites, ions, hormones, proteins, nucleic acids, microbial and wound biomarkers, and therapeutic drugs, enabled by advances in hydrogel chemistry, conductive networks, nanostructured electrodes, catalysis, affinity recognition, molecular imprinting, optical readouts, and multiplexed wearables. Performance remains context dependent and requires physiological range, calibration stability, biofouling resistance, reliable insertion, validated ISF-reference correlations, and interpretable thresholds. Evidence is strongest in artificial matrices, ex vivo tissue, and animals, while human validation remains limited. Translation will require standardized mechanics and transport reporting, longer wear studies, sterilization-compatible chemistries, scalable manufacturing, and clinical validation. HFMNs may complement rather than replace blood-based diagnostics. Full article

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

UDP-glucuronosyltransferases (UGTs) are a key family of phase II metabolic enzymes in humans that play a central role in maintenance of metabolic homeostasis and drug disposition by catalyzing glucuronidation of endogenous and exogenous substances. UGT-mediated metabolism of antitumor drugs plays a dual role in tumor drug resistance, emerging as a hotspot in cancer therapy. This review outlines the structural characteristics, classification system, tissue distribution, and multilevel regulation of UGTs, with a focus on their bidirectional roles in tumor drug resistance, i.e., promotion of resistance through metabolic clearance and inhibition of resistance through metabolic activation. This review also discusses strategies of multidimensional tumor resistance intervention based on UGTs, and we also discussed the challenges in the clinical translation of current UGT-targeting strategies. To date, most data on UGTs were derived from in vitro and preclinical models; clinical validation remains limited, and the dual roles of UGTs are highly context-dependent. This review article provides a perspective for comprehensive understanding of UGT-mediated tumor resistance and offers theoretical foundations and practical directions for development of novel antitumor strategies. 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

Crohn’s disease (CD) is a chronic inflammatory bowel disease with a rising incidence and prevalence worldwide. It is associated with Mycobacterium avium subspecies paratuberculosis (MAP). Current CD treatment strategies are based on anti-inflammatory therapies, including anti-TNF-α drugs. These treatment options provide short-term benefits and are associated with numerous side effects in CD patients. Manuka honey is distinguished from other honey by its high content of methylglyoxal (MGO). MGO, a reactive metabolite, is also generated endogenously in macrophages during infection through glycolysis; however, the amount is insufficient to neutralize the ongoing infection and subsequent tissue damage. This study examined whether exogenous, low-dose MGO can modulate MAP-driven inflammatory and glycolysis- and lactate-associated markers in infected macrophages. THP-1 macrophages were infected with the CD-associated MAP strain and then treated with MGO doses at defined time intervals. We measured markers of M1-/M2-like phenotype polarization, monocarboxylate transporters, lactate export, antioxidant responses, cytokines, and selected glycolysis- and lactate-associated markers at both the mRNA and protein levels. MGO reduced M1 signaling markers CXCL10 (p < 0.05), TNF-α (p < 0.0001), IL-1β (p < 0.01), and IL-6 (p < 0.0001). Simultaneously, MGO promoted M2 shift, elevating CD206 by 1.20-fold and IL-10 by 7-fold. Low-dose MGO administration was associated with increases in Nrf-2 (1.4-fold), HO-1 (1.4-fold), and IL-1Ra (1.5-fold), while the pro-inflammatory cytokines decreased. Metabolically, MGO downregulated MCT4 (p < 0.01) and reduced lactate export by 30%. These changes were coupled with higher PHD2 (1.4-fold) and decreases in GLUT1 (0.9-fold), PKD1 (0.8-fold), and IL-1β, consistent with attenuated glycolysis- and lactate-associated inflammatory signaling. These results suggest that hormetic concentration of MGO mitigates MAP-induced inflammatory activation while altering glycolysis- and lactate-related signaling markers in infected macrophages. Most importantly, we unraveled the predicted molecular mechanism by which MGO suppresses inflammation and modulates oxidative damage. Full article

Nanomedicine-based liposomal delivery systems are gaining increasing attention as advanced therapeutic platforms for managing ocular infections associated with antimicrobial resistance (AMR) and biofilm formation. The primary objective of this review is to critically evaluate the potential of liposomal drug delivery systems for improving the treatment of antimicrobial-resistant and biofilm-associated ocular infections by integrating current knowledge on antimicrobial resistance mechanisms, biofilm-targeted therapeutic strategies, and advances in liposomal formulations, while also identifying the major limitations, translational challenges, and knowledge gaps in this rapidly evolving field. Traditional ocular antimicrobial treatments are frequently limited by poor drug penetration, short precorneal residence time, low bioavailability, systemic side effects, and inadequate activity against resistant microorganisms and biofilm-embedded pathogens. This review provides a comprehensive overview of different liposomal systems, including conventional, cationic, polyethylene glycol (PEG)-modified, deformable, and stimulus-responsive liposomes, and discusses their advantages in ophthalmic drug delivery, such as enhanced corneal permeation, prolonged drug retention, controlled release, improved biocompatibility, and reduced ocular toxicity. The review further examines the mechanisms through which liposomes help overcome AMR, including improved epithelial transport, membrane disruption, intracellular drug delivery, efflux pump evasion, and enhanced antimicrobial efficacy. In addition, liposomal approaches targeting ocular biofilms are explored, focusing on improved biofilm penetration and the delivery of anti-biofilm agents such as antibiotics, enzymes, quorum-sensing inhibitors, and antimicrobial peptides. Current evidence from in vitro and in vivo ocular infection models is summarized together with disease-specific applications in keratitis, endophthalmitis, and contact lens-related infections. The article also compares liposomes with other ocular nanocarriers and addresses important considerations related to safety, stability, sterilization, large-scale production, and regulatory translation. In addition to highlighting recent advances, this review critically discusses the current limitations of liposomal formulations, the major barriers to clinical translation, and the key knowledge gaps that should be addressed to facilitate the future development and successful clinical application of these systems. Finally, emerging directions including ligand-targeted and stimulus-responsive liposomes, AI-driven formulation development, personalized nanotherapy, and gene therapy combinations are discussed as promising future strategies for combating resistant ocular infections. Full article

Background: Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML) and contributes to leukemogenesis, treatment response, and clinical heterogeneity. While genome-wide methylation studies have identified prognostic methylation signatures, the impact of DNA methylation within pharmacologic pathways and AML-relevant disease genes remains incompletely understood. We investigated the association of DNA methylation in genes of pharmacokinetic/pharmacodynamic (PK/PD) pathways of drugs used to treat AML and in myeloid leukemia-related genes with treatment outcomes in pediatric AML. Methods: DNA methylation profiles from 924 pediatric AML patients treated on Children’s Oncology Group trials (AAML1031, AAML0531, and AAML03P1—available publicly) were analyzed as a discovery cohort. A validation cohort included 159 patients treated on the AML02 trial. A total of 2296 variable CpG sites mapping to 65 PK/PD genes and 107 AML biology/leukemia stemness genes were evaluated. Associations between CpG methylation, gene expression, event-free survival (EFS), overall survival (OS), and measurable residual disease after induction I (MRD1) were assessed using Cox proportional hazards, logistic regression, and correlation analyses. Results: Twenty-three CpG sites in PK/PD genes and forty-two CpG sites in AML-related genes were significantly associated with at least one clinical endpoint after Bonferroni correction (p < 2.17 × 10⁻⁵). Hypermethylation of drug transporters ABCA3, ABCC1, and SLC22A1, as well as pharmacologically relevant genes MPO, NOS3, and CTPS1, was associated with inferior survival and/or increased MRD1 positivity. Among AML biology genes, methylation of ETV6, NOTCH1, RUNX1, KIT, MPL, DNMT3A, and DNMT3B demonstrated consistent associations with outcomes across discovery and validation cohorts. Several genes exhibited significant inverse correlations between DNA methylation and gene expression, including MPO, KIT, MPL, SPINK2, and DNMT3B, supporting functional epigenetic regulation. Notably, hypermethylation of ABCA3, MPO, and MPL was reproducibly associated with poor OS and EFS in both cohorts. Conclusions: DNA methylation of key pharmacologic and leukemia-related genes is associated with clinical outcomes in pediatric AML. These findings identify biologically and clinically relevant epigenetic biomarkers that may improve risk stratification and support the development of precision medicine approaches incorporating DNA methylation profiling and epigenetic therapies in pediatric AML. Full article

Resveratrol (RES) is a natural polyphenolic compound characterized by poor aqueous solubility and significant first-pass metabolism, resulting in extremely low oral bioavailability. Although resveratrol-loaded nanostructured lipid carriers (RES-NLCs) have shown potential in enhancing oral absorption, direct experimental evidence for their intestinal lymphatic transport mechanism remains limited, and existing explanations is largely based on indirect inference. RES-NLCs were prepared, and their pharmacokinetics and lymphatic transport characteristics were evaluated using a laboratory-established mesenteric lymph duct–jugular vein assisted reflux model in rats. Simultaneously, a 28-day repeated-dose toxicity study was conducted in ICR mice. Pharmacokinetic results showed that compared with RES-Sol, RES-NLCs increased Cmax by approximately 2.3-fold, improved relative bioavailability by 7-fold, and achieved an absolute bioavailability of 176%. The lymphatic transport model confirmed that RES-NLCs are absorbed via the intestinal lymphatic pathway. In the 28-day repeated-dose toxicity study, no mortality or obvious clinical symptoms were observed at a dose of 10 mg/kg. The RES-NLCs group exhibited increased liver coefficient and decreased spleen coefficient. Hematological analysis showed a mild increase in red blood cell count, along with decreases in mean corpuscular volume and red blood cell distribution width coefficient of variation. Serum biochemistry revealed significant elevations in aspartate aminotransferase and alanine aminotransferase (p = 9 × 10⁻⁵ and p = 4.02 × 10⁻⁷, respectively). However, no significant differences were observed in the organ coefficients of the heart, lungs, kidneys, or brain. Body composition and magnetic resonance imaging showed no abnormalities, and histopathological examination of major organs including the liver, stomach, and intestines revealed no structural damage. These findings provide direct evidence that RES-NLCs enhance the oral bioavailability by promoting intestinal lymphatic uptake, suggesting that this system may serve as an effective delivery platform for poorly soluble hydrophobic drugs. Full article

Background/Objectives: Phenotypic drug tolerance, distinct from genetic resistance, allows Mycobacterium tuberculosis (Mtb) to survive prolonged antibiotic exposure and contributes to treatment failure and relapse. The trehalose recycling pathway, mediated by the LpqY-SugABC transporter, has been implicated as a metabolic “escape” mechanism that sustains Mtb viability under antibiotic and nutrient-limiting stress, making it an attractive target for adjunctive, tolerance-breaking therapeutics. Methods and Results: Here, we conducted a high-throughput phenotypic screen of 50,000 compounds from chemically diverse libraries, using a carbon source-restricted assay that forces Mtb to rely on trehalose uptake for growth, to identify small-molecule inhibitors of this pathway. This approach yielded 23 confirmed hits in Mtb, spanning several chemical scaffolds, including thioureas, propanamides, benzamides, and carboxamides. Using an isogenic set of Mtb wild-type, LpqY-SugABC transposon knockout, and complemented strains, we confirmed that the genetic loss of transporter loss reproduces accelerated killing by isoniazid, rifampicin, and bedaquiline, but not moxifloxacin, and that loss of trehalose recycling sensitizes mycobacteria to oxidative stress. Using orthogonal functional assays, fluorescent trehalose probe (FITC-tre) uptake inhibition and H₂O₂ hypersensitization, thiourea-containing compounds emerged as the candidates most consistent with transporter-specific activity, phenocopying the effects of genetic LpqY-SugABC loss, while biochemical assays against recombinant trehalase (Rv2402) excluded downstream enzymatic inhibition as their mechanism of action. In addition, several hits potentiated rifampicin-mediated killing of intracellular Mtb in THP-1 macrophages, in some cases reducing bacterial burden below levels achieved by monotherapy. Conclusions: These findings indicate that the trehalose recycling pathway is functionally druggable by small molecules identified through unbiased phenotypic screening and nominate thiourea- and propanamide-based scaffolds as priority candidates for further mechanistic characterization, including direct target-engagement studies, and optimization as adjunctive anti-tuberculosis agents targeting drug-tolerant Mtb populations. Full article

Mammalian cells contain numerous membrane-bound organelles, of which endosomes serve as the initial destination for endocytosed molecules. Therapeutic agents are also internalized by cells and transported to endosomes or phagosomes and subsequently delivered to lysosomes for degradation. Therefore, these agents require drug delivery systems (DDSs) that enable their escape from endosomes into the cytosol before lysosomal degradation; however, endosomal escape is a major limitation of current DDSs. Studies of bacterial phagosomal escape have revealed mechanisms by which host cells detect damage to organelle membranes. These membrane damage-sensing molecules also recognize membrane damage caused by artificial DDSs or physical energy-based insults. In this review, we summarize the molecular mechanisms underlying the early stages of membrane damage in the plasma membrane, lysosomes and bacteria-containing vacuoles (BCVs) to better understand the early stages of endosomal membrane damage in the absence of pathogens. We summarize recent advances in galectins, endosomal sorting complexes required for transport (ESCRT) complexes, sphingomyelin, stress granules, and phosphatidylinositol 4-phosphate (PI4P) at membrane contact sites, as well as annexins. We also discuss the recruitment kinetics of these molecules to damaged membranes. Although the recruitment kinetics vary depending on cell type and experimental conditions, this information provides a timeframe for the events following membrane damage, including damage sensing, membrane repair, and degradation of damaged organelles. We also discuss a potential fourth event, fusion between the plasma membrane and endosomes or lysosomes for membrane repair in the annexin section. Finally, we summarize approaches for inducing “sterile” endosomal membrane damage. Future development of these approaches may facilitate the design of novel DDSs and physical energy-based strategies for manipulating specific organelles. Full article