Search Results (3,884)

Non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen, are widely used for the treatment of pain and inflammation; however, their therapeutic application is limited by poor aqueous solubility and low bioavailability. This study aimed to synthesize and characterize a novel amino acid-based naproxen derivative, L-phenylalanine menthol ester naproxenate ([PheOMent][NAP]), develop liposomal formulations containing the obtained compound, and evaluate their physicochemical properties and transdermal delivery potential. The derivative was synthesized via a three-step procedure and characterized using NMR, FT-IR, TG, DSC, and XRD analyses. Compared with naproxen, [PheOMent][NAP] exhibited lower lipophilicity (log P = 1.36 vs. 1.70). Liposomal formulations containing the modified derivative showed high encapsulation efficiency (89.6–90.7%), higher than that observed for naproxen-loaded liposomes (51.7–54.7%). The prepared systems exhibited bimodal particle size distributions, comprising both submicrometre and micrometre vesicle populations depending on the preparation method, as well as negative zeta potential values (−18.17 to −23.72 mV) and pH values ranging from 6.18 to 7.07, demonstrating physicochemical characteristics suitable for topical formulations. In vitro permeation studies using porcine skin demonstrated markedly enhanced transdermal delivery of [PheOMent][NAP]. After 24 h, cumulative permeation exceeded that of naproxen formulations by more than 1.5-fold (416.7 vs. 281.6 μg cm⁻²). These findings indicate that liposomal formulations containing amino acid-modified naproxen derivatives represent a promising strategy for improving transdermal NSAID delivery. Full article

Background/Objectives: Advanced prostate cancer remains difficult to treat because docetaxel, although clinically important, is limited by systemic toxicity, poor tumor selectivity, and acquired resistance. Camptothecin is a potent anticancer agent, but its clinical application is restricted by poor solubility and instability. This study investigated the synergy between docetaxel and camptothecin and developed transferrin-conjugated, camptothecin-bearing dendrimersomes entrapping docetaxel as a targeted nanocarrier for prostate cancer therapy. Methods: Drug synergy was evaluated in PC3-Luc cells using an MTT assay and combination index analysis. Transferrin-conjugated, disulfide-linked camptothecin-bearing PEGylated DAB dendrimers were synthesized and characterized by ¹H-NMR, critical aggregation concentration analysis, transmission electron microscopy, and entrapment efficiency measurements. pH- and redox-dependent drug release was assessed by dialysis. Cellular uptake and uptake mechanisms were investigated by confocal microscopy, flow cytometry, and inhibitor studies in PC3-Luc, DU145, and LNCaP cells. Anti-proliferative efficacy was determined by an MTT assay. Results: Docetaxel and camptothecin showed marked synergy in PC3-Luc cells, with a minimum combination index of 0.20 ± 0.01 and 88.10 ± 0.41% growth inhibition at low nanomolar concentrations. Transferrin-conjugated dendrimersomes self-assembled into spherical vesicles with a critical aggregation concentration of approximately 250 µg/mL. They had high docetaxel entrapment efficiency (89.10 ± 0.08%) and enhanced drug release under acidic and reductive conditions. They significantly increased cellular uptake of docetaxel relative to non-targeted dendrimersomes (by up to 3-fold) and free drugs (by up to 20-fold), mainly through transferrin receptor-mediated endocytosis, and improved anti-proliferative activity in all three cell lines. Tf-conjugated DPSSC produced the lowest IC₅₀ values among the tested formulations: 11.72 ± 1.02 nM in PC3-Luc, 9.88 ± 1.22 nM in DU145, and 7.88 ± 1.35 nM in LNCaP cells. Conclusions: Transferrin-conjugated camptothecin-based dendrimersomes entrapping docetaxel represent a promising multifunctional nanocarrier for prostate cancer that combines synergistic dual-drug therapy, active targeting, and stimulus-responsive release, supporting further evaluation as a selective delivery strategy in advanced prostate cancer using preclinical models and in vivo studies. Full article

Microneedle (MN) arrays offer a novel and minimally invasive platform for transdermal drug delivery. This study presents an approach for the design and fabrication of MN array models for biomedical applications using custom 3D-printed micro-molds. Material analysis of the polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP) matrix in a 3:1 weight ratio was conducted under varying geometric configurations, curcumin (CUR) dosages, and target penetration depths of 300 to 500 μm. Computational simulation using computer-aided design (CAD) and finite element analysis (FEA) on ANSYS (Canonsburg, PN, USA) measured for total deformation, stress distribution, insertion pressure, and factor of safety. Elimination criteria were applied, narrowing down to specific models that were experimentally validated through material formulation, micro-molding, and material characterization. The selected MN models were analyzed by insertion and penetration efficiency testing on porcine skin. The results showed that higher CUR concentrations reduced mechanical strength and Young’s modulus, while mid-range dosages (2–6 mg) combined with optimized geometric spacing produced MNs with maintained structural integrity and effective performance. Conical microneedles demonstrated the most favorable balance of mechanical stability, controlled swelling behavior, and high insertion efficiency. The study recommends this approach as a feasible and reproducible method for localized wound-healing applications. Full article

Oxidative stress in the tumor microenvironment, which is its own intrinsic property, is frequently utilized to deal with the drug-targeting issue in the nanoparticle drug delivery system. For this purpose, reactive oxygen species (ROS)-sensitive nanoparticles encapsulating doxorubicin (DOX) and chlorin e6 (Ce6) were synthesized for treatment of MDA-MB-231 breast cancer cells. Hyaluronic acid (HA) with a reductive end was conjugated with methoxy poly(ethylene glycol) (PEG) using thioketal diamine (ThdNH₂) linkage (HA-b-PEG copolymer). Then, Ce6 were conjugated to the carboxylic acid group of HA via ThdNH₂ (HA(Ce6)-b-PEG copolymer). DOX was physically incorporated to make DOX-incorporated HA(Ce6)-b-PEG copolymer nanoparticles (DOX-NP). HA(Ce6)-b-PEG copolymer nanoparticles (empty NP) and DOX-NP have a tiny particle size, less than 200 nm, with spherical morphology. They were responsively disintegrated according to the hydrogen peroxide (H₂O₂) concentration, then the release rate of Ce6 or DOX was accelerated, indicating that empty NP and DOX-NP have ROS sensitivity. DOX-resistant MDA-MB-231 cells were prepared by continuous treatment of DOX for three months. DOX-NP were efficiently internalized into the cells while intra-cellular delivery of DOX itself was inhibited. DOX-NP has higher anticancer activity against DOX-resistant MDA-MB-231 cells than that of DOX itself since cells were resistant to DOX itself. Under light irradiation, DOX-NP significantly decreased the viability of DOX-resistant MDA-MB-231 cells while DOX itself did not properly affect cell viability. Empty NP also efficiently inhibited cell viability rather than that of Ce6 itself while both of them did not affect the cell viability in the absence of light irradiation. Furthermore, empty NP showed higher ROS generation than that of Ce6 itself. DOX-NP more efficiently induced apoptosis/necrosis than DOX itself. In DOX-resistant MDA-MB-231 cell-bearing mice, DOX-NP was efficiently delivered to tumor tissue. DOX-NP greatly inhibited the growth of tumors under light irradiation, more than that of DOX itself or empty NP. In conclusion, DOX-NP showed promising antitumor activity against DOX-resistant MDA-MB-231 cells. Full article

The high recurrence rate of glioblastoma after surgical resection and conventional chemotherapy remains a major obstacle to effective treatment. Mitochondria-targeted long-acting local chemotherapy represents a promising therapeutic strategy to tackle this dilemma. In this study, a mitochondria-penetrating peptide (mito) was conjugated with lonidamine (LND), a mitochondrial hexokinase II inhibitor, to construct an amphiphilic peptide–drug conjugate (LND-mito) that could self-assemble into supramolecular hydrogels. This design achieves sustained localized release and mitochondria-targeted delivery, generating a tumor-selective oxidative phosphorylation inhibitor with 19-fold higher potency than LND. Our results demonstrated that LND-mito efficiently targeted tumor cell mitochondria, induced robust reactive oxygen species generation, decreased mitochondrial membrane potential, and activated mitochondrial apoptosis, ultimately markedly inhibiting glioma growth and prolonging postoperative survival in orthotopic glioma-bearing mice. Collectively, this study offers a promising therapeutic strategy for glioma management, while simultaneously informing the design of high-efficacy, low-toxicity local sustained-release delivery platforms for malignant tumors. Full article

Silybum marianum (SM) is a rich source of flavonolignans with promising antioxidant and antidiabetic properties; however, its therapeutic application is limited by poor stability and bioavailability. This study combined experimental and computational approaches to develop and evaluate SM-loaded chitosan nanoparticles (CS–SM nanoparticles). Microwave-assisted extraction followed by LC-MS/MS profiling identified eleven metabolites, including major flavonolignans characteristic of SM. Nanoparticles prepared by ionic gelation exhibited favorable physicochemical properties, including a particle size of 173–189 nm, a polydispersity index of 0.23, a zeta potential of +41.5 mV, an encapsulation efficiency of 98%, and a drug loading capacity of 50%, indicating the formation of a stable colloidal delivery system. CS–SM nanoparticles showed enhanced antioxidant, anti-inflammatory, and α-amylase inhibitory activities compared with crude extracts. The formulation exhibited an α-amylase IC₅₀ value of approximately 0.40 mg/mL and maintained low hemolytic activity, suggesting favorable preliminary biocompatibility. Molecular docking demonstrated favorable interactions of neosilyhermin A, silibinin, and silyhermin with α-amylase and α-glucosidase active sites. Short-timescale molecular dynamics simulations revealed ligand-dependent behavior within the chitosan–TPP matrix, indicating different release tendencies among the investigated flavonolignans. Overall, the results support CS–SM nanoparticles as a promising platform for the delivery of bioactive phytochemicals with antioxidant and antidiabetic potential. Full article

Castration-resistant prostate cancer (CRPC) is characterised by persistent androgen receptor (AR)-axis activity, therapy-driven resistance, and limited durability of available systemic treatments. Tumour-tropic mesenchymal stem/stromal cells (MSCs), including adipose-derived MSCs (ADSCs), have emerged as promising vehicles for targeted gene therapeutics. This review synthesises our three experimental studies examining stem cell-delivered gene-directed enzyme prodrug therapy (GDEPT) using cytosine deaminase (CD)/5-fluorocytosine (5-FC) and secreted TRAIL in CRPC xenograft models. We performed a comparative analysis of three studies in which hTERT-immortalised human ADSCs were engineered via lentiviral vectors to deliver CD alone, secreted TRAIL alone, or CD+TRAIL in combination, and were administered by intracardiac injection into male nude mice bearing PC3 xenografts. In vitro conversion efficiency, cell viability, apoptosis markers, and in vivo tumour volume endpoints were compared across studies. All three therapeutic platforms demonstrated measurable tumour growth inhibition relative to controls. The CD+TRAIL combination achieved the greatest in vivo efficacy (tumours approximately 26% of control at day 14), compared with CD alone (approximately 71%) or TRAIL paired with irinotecan. Enzymatic conversion of 5-FC to 5-FU exceeded 93% in conditioned medium. Primary translational risks include thrombotic events associated with systemic MSC dosing, tumourigenicity and genotoxicity of hTERT-immortalised, integrating-vector–engineered cells, immunogenicity of xenogeneic CD enzyme, and systemic 5-fluorouracil leakage from flucytosine metabolism. Stem cell-delivered CD/5-FC and TRAIL constitutes a biologically rational, modular strategy for local cytotoxicity and resistance circumvention in CRPC. Successful clinical translation will require resolution of delivery-route feasibility, thrombosis risk mitigation, and a rigorous investigational new drug (IND)-enabling safety package. Full article

Oral delivery of bioactive compounds in veterinary medicine offers important opportunities to improve animal health, productivity, and welfare, but its effectiveness is often limited by species-specific gastrointestinal physiology. This review aims to provide a comprehensive overview of microencapsulation strategies for oral veterinary delivery, focusing on species-specific gastrointestinal barriers and the formulation approaches developed to overcome them. Monogastric and ruminant animals present distinct gastrointestinal environments that compromise the stability, bioavailability, and therapeutic performance of orally administered compounds. In monogastrics, gastric acidity, digestive enzymes, gastrointestinal transit, and microbiota-mediated interactions represent major barriers, whereas in ruminants, ruminal fermentation, prolonged retention, and physicochemical conditions may cause premature degradation of bioactive compounds. These barriers significantly hinder the successful use of probiotics, enzymes, essential oils, nutrients, vaccines, and veterinary drugs. However, microencapsulation has emerged as a promising solution, providing a protective barrier that improves compound stability, enhances gastrointestinal survival, and enables controlled or site-specific release. By preserving bioactivity and modulating release kinetics, microencapsulation contributes to improved delivery efficiency and functional performance. A distinctive feature of this review is the integration of species-specific gastrointestinal physiology with microencapsulation technologies to provide a rational framework for designing oral delivery systems in veterinary medicine, rather than focusing solely on individual encapsulation technologies. Current challenges related to material selection, formulation optimisation, and industrial scalability are discussed. Overall, this review highlights that integrating gastrointestinal physiology with advanced microencapsulation technologies is essential for developing effective, targeted, and sustainable oral delivery systems, ultimately supporting improved animal health, productivity, and welfare. Full article

Background/Objectives: Shikonin (SKN) is a potential anti-psoriatic agent, yet its clinical application is hindered by poor water solubility and low stratum corneum permeability. This study aimed to develop a reactive oxygen species (ROS)-responsive hydrogel microneedle system encapsulating SKN-loaded polymeric micelles (SKN-M@MN) to enhance transdermal delivery and evaluate its therapeutic effects in psoriasis. Methods: Shikonin-loaded micelles (SKN-M) were optimised using a thin-film hydration method. SKN-M@MN was fabricated via a two-step casting method using phenylboronic acid-modified hyaluronic acid (HA-PBA) and polyvinylpyrrolidone K90 as the tip matrix. Skin penetration, ROS-responsive release, and anti-psoriatic efficacy were assessed in an imiquimod (IMQ)-induced mouse model. Mechanistic studies included RNA-seq, qPCR, and Western blotting. Results: SKN-M achieved an encapsulation efficiency of 93.45 ± 0.24%, a particle size of 62.49 ± 0.92 nm, and a zeta potential of −36.78 ± 1.12 mV. SKN-M@MN showed 100% skin penetration, sustained drug release, and accelerated degradation under high ROS conditions. In psoriatic mice, SKN-M@MN significantly alleviated skin lesions, reduced epidermal hyperplasia (Ki67), and downregulated IL-17A and TNF-α levels both locally and systemically. Mechanistically, it inhibited the PI3K/AKT and NF-κB signalling pathways. Conclusions: The SKN-M@MN microneedle platform integrates physical skin penetration, ROS-responsive drug release, and pathway inhibition, offering an effective strategy for transdermal delivery of poorly soluble drugs in psoriasis therapy. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor and remains difficult to treat due to its invasive nature, therapeutic resistance, and the presence of the blood–brain barrier (BBB), which represents a major obstacle to effective drug delivery. This study describes the development of biocompatible solid lipid nanoparticles (SLNs) based on a novel arginine stearate derivative for the encapsulation of idebenone, a synthetic antioxidant with potential biological activity. The objective of this work was to design and characterize a lipid-based nanoparticulate system for idebenone delivery and to evaluate its physicochemical properties and preliminary in vitro biological effects. The nanoparticles were characterized by Dynamic Light Scattering (DLS) and Differential Scanning Calorimetry (DSC), and in vitro release profiles were investigated under different pH conditions. Antioxidant activity and cell viability assays were also performed in glioblastoma and non-tumorigenic cell lines. The results indicate successful formulation of idebenone-loaded SLNs with good encapsulation efficiency, maintained antioxidant activity, and promising physical stability over time as monitored by size analysis. The rationale behind the development of arginine stearate-based SLNSs is to optimize the performance of pharmaceutical active ingredients, such as idebenone, versus non-tumorigenic cells. Overall, these findings support the potential of the developed SLNs as a promising delivery system for further in vitro and in vivo investigations. Full article

Metal oxide nanoparticles have been the subject of intense research interest because of their remarkable physicochemical properties, such as their high surface area, particle size tunability, outstanding chemical stability, optical activity, catalytic efficiency, and antimicrobial behavior. These properties make them very useful in environmental, biomedical, energy, sensing, agricultural and industrial applications. The chosen synthesis method is important in controlling the morphology, crystallinity, surface charge, band gap and overall performance of metal oxide nanoparticles. They have been prepared using various physical, chemical and biological means, such as sol–gel, co-precipitation, hydro/solvothermal, microwave-assisted, sonochemical, combustion and green synthesis. Of these, green synthesis is gaining more interest as it employs plant extracts, microorganisms, and other biological materials as reducing agents, stabilizing and capping agents that make the process more eco-friendly and cost-effective. Recent advancements in the synthesis and application of metal oxide nanoparticles are discussed. There is an emphasis on the major synthesis routes, the main factors that influence the formation of nanoparticles, the characterization techniques used, and the structure–property relationships uncovered. A special focus is given to the influence of synthesis parameters, such as the type of precursor and the pH, temperature, reaction time, solvents and capping agents, on the properties of nanoparticles. In addition, the uses of metal oxide nanoparticles in photocatalysis, wastewater treatment, antimicrobial activity, drug delivery, biosensing, energy storage, gas sensing, and agriculture are also included. Finally, present challenges, toxicity issues, the problems of large-scale production, and future research directions are discussed to support the practical and sustainable uses of metal oxide nanoparticles. 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

Plant-derived extracellular vesicles (PDEVs) have emerged as promising natural nanocarriers for biomedical applications owing to their distinctive ability to facilitate intercellular communication and transport bioactive molecules. In this review, we employ bibliometric analysis to identify research hotspots and trends, providing a comprehensive overview of these core themes. The bibliometric results reveal a sustained increase in annual publications in this field, with keyword analysis identifying drug delivery, cross-kingdom regulation, immunomodulation, engineering modification, and gut microbiota as five major research themes. The focus of research has evolved from early basic biological characteristics into engineered smart delivery platforms, with the application areas expanding from intestinal inflammation to neurological, metabolic, dermatological, and oncological diseases. This review systematically examines the core directions in this field. It compares the strengths and limitations of mainstream isolation methods and highlights the value of multi-omics integration, covering the molecular mechanisms of ferroptosis and gut microbiota regulation by PDEVs along with engineering strategies such as drug loading, surface modification, and membrane fusion. It also discusses the latest progress in frontier therapeutic applications of PDEVs, including cancer, inflammatory diseases, tissue regeneration and aesthetics, and neurological disorders. Finally, this review summarizes the key challenges confronting the field, including the lack of standardized protocols, production bottlenecks, and engineering obstacles. It also delineates future directions, including establishing international standardization definitions, advancing multi-omics and AI-driven mechanistic elucidation, developing scalable and efficient purification technologies, and executing systematic preclinical safety and pharmacokinetic evaluations to facilitate clinical translation. 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

Recurrent urinary tract infection (rUTI) continues to pose a formidable clinical challenge, largely owing to the rapid clearance of therapeutic agents from the bladder caused by short intravesical residence time and periodic urinary voiding. Although intravesical drug delivery has emerged as a promising local therapeutic strategy, conventional liquid instillations and physically crosslinked hydrogels frequently fail to sustain structural integrity and prolonged drug release within the dynamically changing bladder microenvironment. Herein, we develop a photocrosslinkable, pH-responsive intravesical floating drug delivery system (iFDDS) for sustained antimicrobial delivery. This system is fabricated using diacrylated Pluronic F127 (F127DA) as the core network-building component. The covalently crosslinked F127DA network confers superior mechanical stability while preserving amphiphilic micellar domains that enable efficient loading of hydrophobic drugs. A tertiary amine-based pH-responsive crosslinker (CLMA) is further integrated into the hydrogel matrix, endowing iFDDS with enhanced swelling capacity under the mildly acidic microenvironment. Additionally, lyophilization-induced porous architecture reduces the apparent density of the iFDDS below that of urine, achieving stable flotation for over 48 h and effectively mitigating the risk of urinary tract obstruction. The optimized iFDDS exhibits favorable catheter deliverability, shear-thinning rheological behavior adaptable to dynamic fluid conditions, and excellent biocompatibility with bladder epithelial cells. Upon loading with rifampicin, the iFDDS demonstrates potent and sustained antibacterial efficacy against Escherichia coli. This study establishes a robust, environment-adaptive platform for intravesical therapy, offering a viable strategy to address the short residence time limitation of conventional formulations and improve the therapeutic management of rUTI. Full article