Search Results (4,281)

Background: Ovarian cancer is frequently diagnosed at an advanced stage and remains one of the most lethal gynecologic malignancies. The development of multidrug resistance (MDR) during repeated chemotherapy is a major cause of treatment failure and is often associated with increased drug efflux mediated by transporters such as P-glycoprotein (P-gp). In this study, D-α-tocopheryl polyethylene glycol succinate (TPGS) and Soluplus^® (SOL) mixed micelles, abbreviated as TS, were developed to co-deliver apatinib (APA), a VEGFR-2 inhibitor, and etoposide (ETP), a topoisomerase II inhibitor, for MDR ovarian cancer models. The formulation was designed to improve the aqueous dispersion, cellular accumulation, and antitumor activity of APA and ETP. Methods: APA/ETP-loaded TS micelles (APA/ETP-mTS) were prepared and characterized in terms of particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), storage stability, and in vitro drug release. Anticancer efficacy was assessed using MTT assays, cellular uptake assays, and 3D tumor spheroid studies employing HeyA8-MDR cells, followed by in vivo toxicity and antitumor efficacy studies. Micellar formulations were denoted using the cargo–carrier format, where APA/ETP indicates co-loaded APA and ETP, C6 indicates coumarin-6 (C6) used as a fluorescent probe, mTS indicates TPGS/SOL mixed micelles, and mSOL indicates SOL-only micelles. Results: The selected APA/ETP-mTS formulation showed a particle size of 20.0 ± 5.1 nm, a PDI of 0.16 ± 0.05, near-neutral zeta potential, and encapsulation efficiencies exceeding 60% for both drugs. The micelles maintained colloidal stability at 4 °C for 4 weeks, although partial decreases in encapsulation efficiency were observed. Compared with APA/ETP solution, APA/ETP-mTS delayed the release of both drugs. C6-mTS showed higher intracellular fluorescence intensity than C6-mSOL, suggesting enhanced cellular accumulation associated with TPGS incorporation. APA/ETP-mTS showed greater cytotoxicity than free drugs in HeyA8-MDR monolayer cells and produced the strongest spheroid growth inhibition among the tested micellar formulations. In the HeyA8-MDR xenograft model, APA/ETP-mTS suppressed tumor growth and resulted in the lowest final tumor weight without apparent overt toxicity based on body weight and survival observations. Conclusions: These results suggest that APA/ETP-mTS is a promising micellar co-delivery platform for hydrophobic anticancer drugs in MDR ovarian cancer. Full article

Oxidative stress is a central and well-established driver of cardiovascular disease, contributing to mitochondrial dysfunction, endothelial injury, inflammatory activation, and progressive myocardial and vascular remodeling. Although the major endogenous sources of cardiovascular reactive oxygen species (ROS), including NADPH oxidases, mitochondrial electron transport chain leakage, and uncoupled nitric oxide synthase, are well characterized, an additional and underappreciated contributor has recently emerged: cytochrome P450 2D6 (CYP2D6), an enzyme classically regarded as a hepatic drug-metabolizing protein. Accumulating evidence indicates that CYP2D6 is expressed extrahepatically in cardiac, vascular, and neural tissue, where uncoupled catalytic cycling is proposed to generate ROS independently of its canonical xenobiotic-metabolizing role, although direct experimental evidence for this pathway in human cardiac and vascular tissue remains limited. CYP2D6-derived oxidative processes may interact with mitochondrial respiratory function, endothelial nitric oxide bioavailability, and redox-sensitive inflammatory pathways, potentially contributing to cardiovascular vulnerability under specific genetic or pathological conditions. Critically, the magnitude of this oxidative contribution is not fixed: it is dynamically shaped by inherited CYP2D6 genetic variation, with poor and ultra-rapid metabolizer phenotypes exhibiting divergent oxidative burden and pharmacokinetic vulnerability, and is further amplified by polypharmacy, multimorbidity, and inflammation-driven phenoconversion, whereby clinically expressed CYP2D6 activity diverges from inherited genotype in ways that intensify redox imbalance. These dynamics are particularly relevant in East Asian populations, where the decreased-function CYP2D6*10 allele is highly prevalent. In this narrative, hypothesis-generating review, we integrate evidence from pharmacogenomics, redox biology, and cardiovascular pharmacology to propose a conceptual framework that reframes CYP2D6 as a genetically and pharmacologically tunable node within cardiovascular redox biology. We further examine emerging redox biomarkers, multi-omics platforms, and AI-assisted modeling as translational strategies for capturing this dynamic oxidative risk in real time. This framework supports a shift from static genotype-guided prescribing toward oxidative-risk-informed, adaptive cardiovascular precision medicine. Importantly, our focus on CYP2D6 should not be interpreted as evidence that it is a major cardiovascular CYP isozyme or an established driver of cardiovascular pathology. Rather, CYP2D6 is examined here as a deliberately hypothesis-generating candidate whose unusually strong pharmacogenetic variability, clinically important cardiovascular drug substrates, dynamic susceptibility to phenoconversion, extrahepatic expression, and mechanistically plausible links to endogenous substrate metabolism and CYP-associated ROS generation provide a convergent rationale for focused investigation. The mechanistic framework proposed in this review has not yet been experimentally and prospectively validated and should not be applied directly to clinical decision-making without supporting clinical data. Full article

Objectives: Herpetrione (HPE) is a bioactive lignan recognized for its hepatoprotective properties; however, it exhibits limited oral bioavailability. This study aimed to classify HPE within the framework of the biopharmaceutics classification system (BCS) and to develop a nanoparticle formulation. Methods: To this end, a comprehensive investigation was conducted, encompassing computer prediction analysis, equilibrium solubility measurements across the gastrointestinal pH range, Caco-2 bidirectional transportation, in situ single-pass intestinal perfusion (SPIP), and molecular docking with P-glycoprotein (P-gp). Results: In silico analyses suggested that HPE possesses low solubility and low permeability characteristics. Experimental assays revealed pH-dependent solubility and inherently low aqueous dissolution. Unlike the computer prediction results, Caco-2 studies revealed moderate permeability but a high efflux ratio, suggestive of possible P-gp substrate activity for HPE, a finding further supported by molecular docking simulations. Conversely, SPIP studies demonstrated that the effective permeability (P_eff) of jejunal intestinal segments exceeded the high-permeability threshold, thereby classifying HPE as a high-permeability drug. Based on these findings, HPE was classified as a BCS class II compound. To overcome its solubility-limited absorption, a nanoparticle was developed, resulting in a marked enhancement of both solubility and dissolution rates. Conclusions: These findings underscore the importance of integrating experimental biopharmaceutical evaluations with computational tools when designing delivery systems for natural products. Full article

Sodium glucose cotransporter-2 inhibitors (SGLT2is) have rapidly evolved from glucose-lowering agents to multifaceted therapies with significant renoprotective and cardioprotective potential. Although originally developed to inhibit glucose reabsorption within the renal proximal tubule for the treatment of Type 2 diabetes mellitus (T2DM), growing evidence indicates that SGLT2is exert broad systemic actions extending beyond glycemic control. Among this drug class, dapagliflozin has emerged as a clinically important agent with pleiotropic effects involving renal hemodynamics, inflammatory signaling, mitochondrial function, fibrosis regulation, and cellular stress adaptation. This review outlines the historical progression from the discovery of phlorizin to the development of highly selective modern SGLT2 inhibitors while emphasizing mechanistic insights gained from experimental and clinical studies of dapagliflozin. In addition to the established effects on sodium–glucose transport, dapagliflozin modulates multiple epithelial transport proteins including NHE3, NaPi-2a, NCC, and NCX1, highlighting complex regulatory effects on sodium handling and tubular electrolyte transport. Emerging evidence further demonstrates that dapagliflozin suppresses inflammatory and profibrotic pathways involving YAP/TAZ, STAT1, TGF-β, NLRP3, and NF-KB signaling. Restoration of tubuloglomerular feedback, attenuation of oxidative stress, and preservation of mitochondrial function also appear to contribute substantially to the renoprotective actions of SGLT2 inhibition. Beyond the kidney, dapagliflozin and related SGLT2is exert cardioprotective effects through coordinated improvements in cardiac energetics, inflammatory regulation, and hemodynamic function. Emerging studies additionally suggest potential pulmonary benefits, including reductions in inflammatory signaling, pulmonary edema, and respiratory complications. Collectively, these findings support a shift in understanding SGLT2is from targeted metabolic therapies to broader regulators of cellular and organ function. Continued investigation into the glucose-independent mechanisms of dapagliflozin may reveal additional therapeutic applications across chronic metabolic, cardiovascular, and inflammatory diseases. Full article

Background/Objectives: Transdermal delivery of hydrophilic drugs remains limited by poor partitioning into the lipid-rich stratum corneum (SC). This study systematically investigated how ternary nanoemulsion composition and surfactant architecture jointly influence the transdermal delivery of salbutamol and whether the resulting composition–performance relationships are preserved across different skin models. Methods: Salbutamol-loaded nanoemulsions were prepared by the phase inversion temperature (PIT) method across a predefined ternary design space using two non-ionic surfactant systems: polyoxyl castor oil and polyoxyl hydroxystearate. Physicochemical characterization, ternary compositional mapping, in vitro permeation testing, generalized additive modeling (GAM), and attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy were combined to evaluate formulation-dependent transport across pig and mouse skin models, complemented by exploratory human-skin experiments. Results: Among the nanoemulsion formulations, pig skin showed the highest salbutamol permeation, with flux values reaching approximately 390 µg/cm²·h. Within the PHS-based system, mouse skin showed lower permeation and a stronger dependence on formulation composition than pig skin, while the simple aqueous vehicle also produced comparatively low permeation in the murine model. The aqueous-vehicle control produced substantially higher permeation than the nanoemulsions in pig skin but lower permeation in mouse skin, while receptor-phase salbutamol concentrations remained below the limit of quantification in human skin. Across both surfactant systems, the most favorable nanoemulsion-mediated permeation was generally associated with water-rich formulations containing comparatively low surfactant levels, whereas highly surfactant-rich regions showed reduced flux despite marked lipid- or protein-associated spectral changes in the descriptive ATR-FTIR analysis. Regression analyses suggested that droplet size and viscosity alone could not consistently explain permeation behavior, whereas compositional modeling revealed pronounced non-linear effects of the water–surfactant–oil balance. Conclusions: Overall, this study demonstrates that nanoemulsion-mediated delivery of hydrophilic drugs is governed primarily by ternary composition, with formulation effects varying across skin models. These findings highlight the importance of composition-based formulation design and appropriate skin-model selection during the development of transdermal systems for hydrophilic drugs. Full article

Cytoplasmic stress granules (SGs) form in response to diverse insults; they are dismantled when the stress subsides. SG clearance is facilitated by molecular chaperones, nuclear transport factors, and other components. The anti-parasitic drug ivermectin inhibits nuclear trafficking and has potential anti-cancer activities. However, the molecular pathways that promote ivermectin’s therapeutic actions are poorly understood. Our study defined the effects of ivermectin on stress recovery in human neuroblastoma and cervical carcinoma cells. We demonstrate that ivermectin interferes with SG disassembly in neuroblastoma cells. The delay of SG dissolution is accompanied by significant changes in the proteostasis network. Notably, ivermectin diminishes de novo protein synthesis in unstressed and stressed cells. During recovery, ivermectin reduces the abundance of hsp70 in neuroblastoma, but not in cervical carcinoma cells. Surprisingly, ivermectin has no effect on Hsf1 abundance and localization. Moreover, ivermectin does not diminish the levels of transcripts encoding hsp70. Bioorthogonal Non-Canonical Amino Acid Tagging revealed that ivermectin markedly reduces the stress-induced de novo synthesis of hsp70 in neuroblastoma cells. Taken together, ivermectin can derail stress responses by a unique mechanism that alters the translation of hsp70 mRNA and is determined by the cellular context. This information is directly relevant to ivermectin-based anti-cancer therapies. Full article

The growing accumulation of microplastics in marine ecosystems, coupled with the presence of emerging contaminants such as pharmaceuticals, represents an environmental problem that has received little attention to date. The present study evaluates the potential of microplastics to act as transport vectors for pharmaceuticals through their adsorption onto two plastic polymers widely used today: polyethylene terephthalate (PET) and medium-density polyethylene (MDPE) in seawater. As a control, the same experiments were conducted in ultrapure water (Milli-Q). Both plastics were exposed to a mixture of 29 pharmaceuticals belonging to different therapeutic classes over a 28-day period, with sampling conducted at various time intervals. The identification, quantification, and characterization of the compounds were performed using ultra-high-performance liquid chromatography coupled with mass spectrometry detection. Statistical analysis was performed using R-Studio software. Outcomes reveal that the type of polymer significantly influences adsorption, with MDPE being more efficient than PET. In contrast, the type of water and the therapeutic class of the drugs were not identified as determining factors. Furthermore, a positive, albeit moderate, correlation was observed between the hydrophobicity of the pharmaceutical and its adsorption efficiency on MDPE. These findings suggest that hydrophobic interactions play a key role in the adsorption of drugs onto microplastics, providing a solid foundation for future research, such as predictive models or mitigation strategies in aquatic ecosystems. Full article

Drug resistance in cancer remains a major barrier to durable therapeutic benefits and limits the effectiveness of chemotherapy, targeted therapy, and combination treatment in multiple malignancies. Increasing evidence indicates that specific kinesin superfamily proteins contribute to tumor adaptation and therapeutic response in a context-dependent manner through their roles in mitotic regulation, intracellular transport, and stress-response pathways. Aberrant expression of multiple kinesin family members has been documented across diverse cancers and is frequently associated with aggressive clinicopathological features, poor prognosis, and resistance to treatment. However, expression alterations alone do not establish functional dependency, and mechanistic validation is required to distinguish true resistance drivers from adaptive tumor states. In this review, we summarize the classification, biological functions, and abnormal expression patterns of kinesins in cancer; discuss the major mechanisms through which they contribute to drug resistance; and examine strategies for targeting kinesins, including natural-product-derived direct inhibitors, small-molecule inhibitor development, rational combination approaches, and structure-guided and computational optimization strategies. We also evaluate the biomarker potential of kinesin dysregulation and the value of advanced preclinical models for mechanistic and translational investigations. Finally, we highlight the major challenges that hinder clinical translation, including target specificity, compensatory resistance, insufficient biomarker validation, and tumor heterogeneity. Future progress will require integration of functional genomics, multiomics profiling, and mechanism-guided therapeutic strategies to determine when kinesin inhibition represents a clinically actionable approach for resistant malignancies. Full article

Methotrexate (MTX) remains central to the treatment of rheumatoid arthritis and several malignancies, yet its use is complicated by dose-dependent toxicity, variable oral exposure, photolability, and pH-dependent solubility. Cyclodextrins (CDs) can alter the molecular environment of MTX, but the literature often conflates true inclusion complexes with formulations in which CD merely forms part of a larger carrier. This review critically distinguishes direct MTX–CD complexes, dosage forms built from a preformed complex, CD-containing carriers without direct evidence of cavity occupancy, and covalent MTX–CD conjugates. Particular attention is given to binding stoichiometry, apparent association constants, guest orientation, preparation methods, and the evidence needed to establish inclusion. Both solution-state host–guest association and isolated solid products are considered; however, solid-state changes are treated as supportive evidence rather than as stand-alone proof of cyclodextrin cavity occupancy. Among the limited head-to-head comparisons of native cyclodextrins, β-CD generally showed more favorable MTX recognition than α- or γ-CD, although the magnitude of this difference is method- and condition-dependent. Complexation can improve dissolution, photostability, and oral or local delivery; however, greater solubilization does not necessarily enhance membrane transport. In carrageenan hydrogels, β-CD increased MTX loading and release while reducing membrane permeation, illustrating the importance of the equilibrium between complexed and freely permeating drug. The most promising systems remain preclinical. Progress toward translation will require clearer nomenclature, orthogonal structural characterization, mechanism-resolving controls, and standardized pharmacokinetic and safety studies. Full article

Nanomaterials are increasingly expected to do more than transport a payload, yet added complexity is useful only when it resolves a rate-limiting diagnostic, transport, release, or monitoring problem. This review develops a function-first framework for precision diagnostics and drug delivery in which formation and processing are linked to nanoscale structure, material properties, demonstrated function, route-specific evidence, and translational value. The scope includes AI-assisted plasmonic and terahertz biosensing; biopolymer nanoparticles and hydrogel depots; barrier-directed nose-to-brain and systemic delivery; graphene and carbon nanotube interfaces; lipid nanoparticles for nucleic acid packaging and endosomal escape; nanoporous, magnetic, and plasmonic carriers; and closed-loop theranostic systems. A platform is treated as genuinely multifunctional only when at least two deliberately engineered functions are experimentally supported and either act on distinct rate-limiting steps or close a sensing–intervention–monitoring loop. This review therefore distinguishes total loading from bioavailable payload, cellular uptake from productive delivery, imaging labels from intact carrier fate, and nominal stimulus responsiveness from controlled release in response to a physiologically realistic trigger. Recent independent studies are used to broaden comparisons across material classes and to separate proof-of-concept performance from translational evidence. Artificial intelligence is considered in three distinct roles—sensor interpretation, formulation/material optimization, and prediction of in vivo behavior—with external validation and, where a model is intended to guide decisions, prospective testing treated as essential. The resulting framework emphasizes biological identity, route-specific safety, carrier-versus-payload tracking, critical quality attributes, manufacturing reproducibility, and a minimum-evidence roadmap from concept to product. Full article

A central challenge in implantable local-delivery systems is to determine how internal device architecture shapes solute transport before drug-specific loading, release, and biological validation are available. This study examines the reservoir–channel architecture of the previously characterized KTD/KTM Ti-6Al-4V capsule platform and evaluates its effect on diffusion-dominated concentration redistribution in a preliminary finite-element model. Micro-computed tomography (micro-CT) was used for qualitative characterization of the as-fabricated internal architecture, whereas the representative computational geometry was defined from the capsule computer-aided design (CAD) concept and previously reported dimensions. Transport of a nominal, fully dissolved species was modeled in COMSOL Multiphysics 5.2 using Fickian diffusion with a prescribed effective diffusion coefficient (D_eff = 1 × 10⁻⁹ m²/s) and a nominal peak initial concentration scale of 1.0 mol/m³. Under the closed no-flux condition, the internal control-point concentration decreased to near zero within approximately 4 h, while the remote outer control point reached approximately 0.002–0.003 mol/m³ by 6 h. A one-sided Dirichlet sink produced a more directional concentration field, demonstrating the sensitivity of the simulated distribution to geometry and boundary conditions. These results describe an idealized, CAD-informed diffusion problem and do not represent experimentally validated drug-release kinetics, therapeutic concentrations, or biological performance. The model is therefore intended as a design-phase framework for guiding subsequent drug-specific transport and experimental validation studies. Full article

Gelatin hydrogels combine biological origin, biodegradability, abundant chemical functionality, and broad processability, but their native thermoreversible physical networks generally lack the stability required for sustained operation. Crosslinking overcomes this limitation while regulating hydration, mechanics, transport, degradation, and responsiveness. This review examines gelatin hydrogel crosslinking from a structure–property–function perspective, connecting molecular design with physicochemical characterization and functional performance. Temperature-induced gelation and ion-mediated physical interactions are compared with small-molecule- and coupling-agent-mediated, enzyme-catalyzed, and photoinduced covalent crosslinking strategies, highlighting their different balances among reversibility, stability, processability, and biocompatibility. Particular attention is given to the characterization methods required to relate junction chemistry and network organization to swelling, thermal behavior, mechanical response, degradation, and molecular or ionic transport. These relationships are evaluated across drug delivery and controlled release, tissue engineering and wound healing, food packaging, preservation and delivery, water remediation and environmental management, wearable sensing and bioelectronics, and energy storage. Across these fields, the central challenge is not to maximize crosslinking, but to balance network stability with the molecular mobility required for function. By integrating complementary crosslinking mechanisms with multiscale characterization, gelatin can be engineered as a programmable platform for advanced soft materials. Full article

Extracellular vesicles (EVs) are naturally occurring nanoscale carriers that have gained attention as next-generation platforms for diagnostics, site-specific drug delivery, and tissue engineering owing to their high biocompatibility, minimal immunogenicity, and capacity to transport diverse bioactive cargo across biological barriers. This review discusses the classification, biogenesis, molecular constituents, and therapeutic properties of the major EV subtypes such as exosomes, microvesicles, and apoptotic bodies. It also highlights recent advances in EV engineering for cancer treatment, emphasizing immune modulation and targeted therapeutic delivery. Particular attention is given to plant-derived EVs, which have shown promise as scalable, low-toxicity nanotherapeutics with inherent bioactivity and effective drug delivery potential. Selected preclinical studies, recent patents, and ongoing clinical trials are also summarized, providing an up-to-date perspective on the clinical translation of EV-based technologies. Current challenges in EV isolation, characterization, scalable manufacturing, cargo loading, standardization, and regulatory approval, along with future directions for clinical translation, are summarized. Collectively, this review summarizes the growing applicability of EVs as next-generation platforms for precision medicine, targeted drug delivery, and regenerative therapies while identifying the major obstacles that must be addressed to facilitate their successful clinical translation. Full article

Although oral peptide drug administration is the most desirable for both patients and healthcare systems, it is a major pharmaceutical challenge. Typically, less than 1% of orally administered peptide therapeutics reaches the systemic circulation. Modern research has focused on overcoming the physiological barriers responsible for the poor peptide drug bioavailability, while little attention has been given to understanding how measurable absorption occurs despite the barriers. This review aimed to explore the physiological factors that influence oral peptide absorption, such as enzymatic degradation and pH effects, motility, microbiota, transporters, tight junctions, and the effect of inflammation. The available data indicate that these factors function not only as barriers but may also create limited opportunities for peptide uptake. Enzymatic degradation and microbial metabolism reduce the availability of intact peptide drugs yet may generate biologically relevant fragments. Tight junctions are generally regarded as restrictive barriers but are shown to exhibit dynamic regulations that may permit transient paracellular transport. Similarly, gastrointestinal motility, microbiota, and inflammatory processes influence epithelial permeability and duration of peptide exposure both to absorptive surfaces and to degradative enzymes. In contrast, transporter-mediated uptake appears unlikely to account for the absorption of intact peptide drugs due to their substrate size limitations. Together, the findings suggest that measurable oral peptide absorption is unlikely to result from a single dominant pathway but rather from the cumulative contribution of the mechanisms. Improved understanding of these endogenous mechanisms may open opportunities to enhance oral peptide bioavailability and support the development of more effective therapeutics. Full article

Confined enzyme catalysis is a promising approach for pharmaceutical synthesis because it can combine high selectivity, catalytic efficiency and mild reaction conditions. This review examines recent advances in multiscale enzyme confinement for pharmaceutical applications, with emphasis on atomic-scale active-site regulation, molecular-scale immobilization and transport control and multi-enzyme cascade organization. We discuss how confined microenvironments modulate enzyme electronic states, conformational dynamics, substrate accessibility, local reaction conditions and intermediate transfer, thereby influencing catalytic activity, stability and stereoselectivity. Representative applications across major enzyme classes are discussed, with a focus on the synthesis of chiral drug intermediates and complex pharmaceutical molecules. The review also considers process-level sustainability, including process mass intensity (PMI) and the E-factor, together with limitations related to mass transfer, support preparation, long-term stability, scale-up and support material burdens. Overall, integrating multiscale confinement with spatially organized cascade catalysis offers a promising route toward more efficient and potentially more sustainable pharmaceutical manufacturing, although its net environmental benefit must be established through system-level assessment. Full article