Search Results (2,277)

Background/Objectives: Curcumin (CUR) has shown promising potential as a wound-healing agent for diabetic wounds; however, its efficacy is hindered by poor aqueous solubility and limited skin permeability. To overcome these limitations, CUR was loaded into myrrh oil-based nanoemulsions (NEs). Methods: The NEs were optimized using a three-factor two-level D-optimal mixture design, and characterized for droplet size, polydispersity index, and zeta potential. The optimized NE was subjected to various stability testing and incorporated into a gel base containing insulin (INS) to form CUR-INS nanoemulgel (CUR-INS-NEG). The antibacterial efficacy of CUR-INS-NEG was tested against various bacterial strains, while its wound-healing effects were evaluated in a diabetic rat wound model. Results: The surfactant/co-surfactant concentration had a greater influence on the NE properties than the oil and aqueous phase concentrations. The optimal NE had a droplet size of 155.2 ± 0.8 nm, a polydispersity index of 0.28, and a zeta potential of −31.4 ± 0.8 mV. It demonstrated sustained drug release, with further release control upon incorporation into the gel base. CUR-INS-NEG demonstrated higher in vitro antibacterial efficacy compared with blank NEG, CUR gel, and INS gel. It also showed 2- and 4-fold reduction in the MIC against S. aureus and E. coli, respectively, compared with CUR gel. In a diabetic wound model, CUR-INS-NEG outperformed both CUR gel and INS gel by enhancing anti-inflammatory and antioxidant effects, as well as collagen deposition and endothelial cell proliferation. Conclusions: The CUR-INS-NEG emerges as an effective system for diabetic wound management, delivering complementary anti-inflammatory, antioxidant, and tissue-regenerative effects of myrrh oil, CUR, and INS. Full article

Background/Objectives: The widespread use of mupirocin and fusidic acid for the treatment and decolonization of Staphylococcus aureus (SA) skin infections has led to a rapid emergence of resistant strains, limiting the effectiveness of the few topical agents currently available for clinical use. Methods: In this study, we evaluate Fe(tropo)₃, a neutral and lipophilic iron(III)–tropolone complex, as a non-antibiotic topical antimicrobial candidate for the management of drug-resistant SA skin and soft tissue infections. Results: Fe(tropo)₃ exhibits potent in vitro activity against methicillin-susceptible SA, methicillin-resistant SA (MRSA), vancomycin-intermediate SA, and strains with high-level resistance to mupirocin and fusidate, with minimum inhibitory concentrations of 2 µg/mL across all tested isolates. The compound effectively penetrates bacterial cells, induces intracellular iron accumulation, and triggers dose-dependent reactive oxygen species generation, resulting in rapid bacterial killing and significant antibiofilm activity. Importantly, Fe(tropo)₃ shows a slower development of resistance compared with ciprofloxacin and displays synergistic activity with oxacillin against MRSA. When formulated as a 1% topical ointment, Fe(tropo)₃ significantly reduces bacterial burden in a murine excisional wound infection model, achieving a 98% ± 1% reduction in SA load without detectable hemolysis or skin irritation. Conclusions: These pilot study results support Fe(tropo)₃ as a clinically relevant, mechanism-distinct topical antimicrobial with potential utility in settings where resistance to existing topical antibiotics compromises standard care. Full article

Background/Objectives: Inclusion complexes among drugs and cyclodextrin-modified polymers are a topic of recent interest in pharmaceutical research and industry as they might expand the solubility, bioavailability, and stability of the guest molecules. Polyurethanes derived from cyclodextrins show some biomedical applications. In this study, two cross-linked polyurethane networks based on hydroxypropyl-β-cyclodextrin (HPβCD) and polyethylene glycols (PEG 2000 or PEG 6000) were synthesized with NCO/OH molar ratio 4.3 and 6.3 by the typical two-step polymerization method. Methods: Inclusion complexes of clotrimazole (CLOT) with two HPβCD-modified polyurethane networks and their corresponding physical mixtures were prepared using kneading methods and physical mixing in a 1:6 weight ratio of CLOT:HPβCD. Results: Obtained prepolymers, previously end-capped with isocyanate groups forming urethane links with HPβCD, which were confirmed by FTIR analysis. TGA results indicate a slight increase in thermal stability of the prepared complexes. The characteristic endothermic peak of the CLOT at around 145.90 °C did not appear in the DSC curve of the drug-loaded inclusion complexes. The XRD patterns of physical mixtures showed specific peaks corresponding to pure clotrimazole. SEM micrographs confirmed an elliptical/spherical- and plate-shaped particles without phase segregation, indirectly confirming that CLOT is not separately present due to inclusion into HPβCD and entrapment into polyurethane networks. Novel complexes PUR2/HPβCD-CLOT-IC and PUR3/HPβCD-CLOT-IC were applied as drug carriers, and diffusion-controlled kinetics of CLOT release were best described using Higuchi model. Conclusions: The obtained in vitro results showed surprisingly slow/prolonged clotrimazole release from modified polyurethane networks due to the significant influence of NCO/OH molar ratio and the chosen polyol soft segments chain length with potential in vivo applications. Full article

Purpose: Due to the lack of effective local therapeutic strategies for oral squamous cell carcinoma (OSCC), this study aimed to develop a novel gelatin/lignin hydrogel loaded with mesenchymal stem cell (MSC)-derived exosomes enriched in microRNA-185 (miR-185 EV) for intraoral delivery, followed by systematic evaluation of its therapeutic efficacy and underlying molecular mechanisms. Materials and Methods: The gelatin/lignin hydrogel was prepared and subsequently loaded with miR-185 EV. The physicochemical properties of the hydrogel, including microstructure, swelling behavior, chemical composition, and rheological characteristics, were systematically evaluated. Next, the stability, viscosity, biocompatibility, and exosome release kinetics of the hydrogel were further assessed. A 4-nitroquinoline-1-oxide (4NQO)-induced mouse tongue carcinogenesis model was established to assess the in vivo antitumor activity of the hydrogel via intraoral administration. Moreover, a proteomic analysis was conducted to investigate the molecular mechanisms of miR-185 EV on OSCC. Results: The miR-185 EV-loaded gelatin/lignin hydrogel exhibited favorable physicochemical properties, stability, and biocompatibility while prolonging the tissue retention time of miR-185 EV. In vivo antitumor efficacy experiments showed that the miR-185 EV-loaded hydrogel significantly inhibited tumor occurrence and alleviated epithelial dysplasia. Immunohistochemical analyses revealed significant suppression of tumor proliferation and epithelial–mesenchymal transition (EMT) of the hydrogel. Proteomic analysis indicated that miR-185 EV suppressed OSCC progression by downregulating interleukin-1β (IL-1β), consequently inhibiting the NF-κB signaling pathway. Conclusion: The findings demonstrate the successful development of the miR-185 EV-loaded gelatin/lignin hydrogel that represents an effective nanomedicine platform for intraoral drug delivery, providing a promising strategy for the clinical treatment of OSCC. Full article

Background/Objectives: The development of stimuli-responsive hydrogels for biomedical uses is an intense field of research. The use of dendritic crosslinkers can enhance the control over the structure and properties of the networks. This work presents a comparative study on the design and evaluation of Pluronic L35 thermogels, incorporating either hydrophobic carbosilane dendrimers (CBS, generations 1 to 3) or hydrophilic dendritic polyglycerols (dPG, 10 k) as crosslinkers. Methods: The thermogels were synthesized via UV-initiated thiol–ene click chemistry. Additionally, they were characterized through swelling studies, mechanical properties, degradation kinetics as well as loading and release studies of the antitumor drug doxorubicin as poorly soluble model cargo. Results: The incorporation of dendritic crosslinkers allowed higher control over the crosslinking process, while the amphiphilic polymer imparted temperature-responsive properties to the resulting networks. Remarkable differences were observed in swelling behavior, mechanical properties and degradation kinetics, depending on the nature of the dendritic crosslinker. Additionally, regarding doxorubicin loading and release in water, CBS hydrogels produced a sustained release over one week, led by network swelling, while dPG hydrogels exhibited a burst release in 4–24 h but were limited by the stronger interaction of DOX with the dPG scaffold. Conclusions: The study provided useful insight for the tailoring of dendritic thermogels for specific biomedical uses such as controlled drug delivery. Full article

Background/Objectives: The mycobacterial complex cell envelope serves as a formidable barrier against host immunity and antibiotics. Lipomannan (LM) and lipoarabinomannan (LAM) are key structural components of the mycobacterial envelope and potent immunomodulators. The mycobacterial lipoarabinomannan biosynthesis mannosyltransferase MptC modifies the multiple α-(1→2)-linked branched mannan residues of LAM in the mycobacteria. However, the role of MptC in mycobacterial infectivity, antibiotic susceptibility and host immune regulation remains poorly understood. Methods: An mptC (also named MSMEG_4247) knockout Mycobacterium smegmatis mc²-155 (M. smeg) strain (designated as M. smegΔmptC) was generated using CRISPR–Cas12a technology. The effects of MptC on bacterial physiology, cell wall permeability, drug sensitivity, immune cell function, and survival during infection are analyzed through glycogen staining, drug sensitivity tests, and cellular and mouse infection models. Results: MptC deficiency results in a loss of LM and increase in LAM synthesis. The M. smegΔmptC mutant strain exhibits enhanced cell wall permeability and reduces hydrophobicity. Functionally, the mptC knockout strain increases the intracellular cytokines (IFN-γ, TNF-a and IL-17) production of T cells in mice. Consequently, results based on both macrophage and mouse infection models demonstrate that the M. smegΔmptC strain has less bacterial loads and higher susceptibility to antibiotic rifampicin. Conclusions: Mannosyltransferase MptC plays an important role in maintaining cell wall integrity (via LM/LAM synthesis), regulating T cell responses, and influencing antibiotic susceptibility in mycobacteria. Full article

Background/Objectives: The limited targeting efficiency and systemic toxicity of conventional medicine present significant challenges in the treatment of skeletal disorders, such as bone tuberculosis. To address these limitations, we developed a bone-targeting nanomicelle delivery system functionalized with alendronate (ALN), designated ALN-PLGA-mPEG@RPT, to improve the targeted delivery and therapeutic efficacy of rifapentine (RPT) in bone tissue. Methods: The ALN-PLGA-mPEG blank micelles, prepared in accordance with our research group’s optimized protocol, were loaded with RPT and subjected to systematic formulation optimization. The resulting nanomicellar system was comprehensively characterized in terms of its physicochemical properties, including particle size and polydispersity index (PDI). Additionally, drug-loading capacity, encapsulation efficiency, and in vitro release curve were evaluated. Bone-targeting efficacy was assessed using in vivo imaging techniques, while biodistribution and safety profiles were determined through in vivo distribution studies and histopathological examination. Results: The optimized ALN-PLGA-mPEG@RPT nanomicelles exhibited a mean particle size of 101.90 ± 4.17 nm, and a PDI of 0.242 ± 0.021. The formulation achieved a drug loading of 16.74 ± 0.51% with an encapsulation efficiency of 50.27 ± 1.91%. In vitro release studies confirmed a sustained-release profile, with only 25% of RPT released within 12 h. In vivo imaging revealed significantly enhanced bone-targeting capability in the ALN-modified group, showing a 1.93-fold higher drug accumulation in bone tissue compared to blood. Histopathological analysis indicated no observable pathological alterations in major organs. Conclusions: The ALN-PLGA-mPEG@RPT nanomicelle system exhibits favorable bone-targeting efficiency, sustained-release properties, and biocompatibility, representing a promising strategy for the precise treatment of bone tuberculosis and other skeletal diseases. Full article

Objectives: Rhizoma Coptidis alkaloids (RCAs) have been proven highly promising in diabetes therapy. However, poor solubility, low bioavailability, and a lack of an effective delivery strategy are major hurdles to improving clinical outcomes. Herein, mPEG-PLGA nanoparticles were employed to deliver RCA orally to enhance anti-diabetic effects. Methods: The RCA-loaded nanoparticles (RCA NPs) were prepared using the emulsion solvent diffusion method. The physicochemical properties of RCA NPs were characterized by morphology, particle size, zeta potential, polydispersity index, drug loading, and drug release. Pharmacokinetic and tissue distribution were determined by UPLC-MS/MS. The hypoglycemic effect was evaluated in a type 2 diabetes mouse model. To illustrate potential mechanisms of action, the expression of PI3K/Akt signaling pathway-related genes and their proteins was detected by RT-PCR and Western blot, respectively. Results: The prepared RCA NPs were spherical in structure, with a particle size of approximately 145 nm and a sustained drug release profile (approximately 50% within 24 h). Compared with RCAs, RCA NP bioavailability increased approximately 2.2-fold, and the hypoglycemic, hypolipidemic, hepatoprotective, anti-inflammatory effects were significantly improved. The better outcome might be due to upregulation of expression and phosphorylation levels within the IRS1/PI3K/AKT/GLUT4 signal pathway in liver tissues. Conclusions: RCA NPs hold great potential for further clinical translation. Full article

Background/Objectives: Dementia remains one of the major global health challenges of the modern era. Researchers worldwide continue to seek effective therapeutic strategies to combat this neurodegenerative condition. Silymarin is a natural compound with strong neuroprotective and antioxidant properties that holds great potential for dementia management; however, its poor aqueous solubility and limited ability to cross the blood–brain barrier (BBB) have restricted its clinical application. This study focused on the formulation and evaluation of a heparin–pullulan silymarin liposomal (HPSL) nano-gel to enhance the neuroprotective efficacy of silymarin, with potential for improved brain targeting effects. Methods: The HPSL nano-gel was synthesized using the thin-film hydration technique and optimized based on entrapment efficiency, particle size distribution, zeta potential, and in vitro release kinetics. The neuroprotective efficacy of the HPSL nano-gel was evaluated in mice using behavioral evaluations, biochemical quantification of oxidative stress markers, evaluation of cholinergic enzyme activity and detailed histopathological examination of brain tissues. Results: Morphological characterization using scanning electron microscopy (SEM) confirmed a uniform nano-scale structure. The optimized formulation (HPSL-3) exhibited a particle size of 406.07 ± 19.33 nm, zeta potential of −23.72 ± 7.64 mV and an entrapment efficiency of 73.53 ± 12.05%, indicating good colloidal stability and efficient drug loading. The in vitro release profile followed non-Fickian diffusion kinetics, suggesting sustained drug release behavior. Behavioral studies in scopolamine-induced amnesic mice (elevated plus maze, hole board, and light/dark paradigms) demonstrated significant (p ≤ 0.001) improvements in learning and memory retention. Biochemical analyses showed increased levels of ChAT, SOD, CAT, and GSH, along with decreased AChE and MDA levels, supporting the neuroprotective potential of the formulation. Histopathological evaluation revealed marked attenuation of neuronal degeneration, inflammation, and edema (HAI = 4) compared to the scopolamine-treated group (HAI = 11). Conclusions: Overall, the HPSL-2 formulation effectively enhanced silymarin delivery across the BBB, demonstrating potent antioxidant, neuroprotective, and cholinergic modulatory effects. These findings suggest that HPSL-2 represents a promising nano-carrier system for the management of dementia and other oxidative-stress-related neurological disorders. Full article

Background/Objectives: Cannabidiol is a non-psychoactive substance that possesses properties suitable for the treatment of several disorders related to the central nervous system. However, successful administration of cannabidiol remains challenging due to low and variable bioavailability and potential adverse effects. Intranasal delivery of cannabidiol may help overcome these limitations, but the pharmacokinetics of such administration has not been fully established. Methods: Starch-based cannabidiol-loaded nanoparticles were used as carriers and were administered to rats via the intranasal route. Cannabidiol levels in plasma and the brain were examined at different time points and compared to cannabidiol levels in plasma and the brain following intravenous administration of cannabidiol solution for injection. Pharmacokinetic parameters were calculated for each delivery route, and a pharmacokinetic model was fitted for the intranasal administration. Results: Intranasal administration resulted in a bioavailability of 47.9%. Systemic absorption accounted for 44% of the absorbed drug, while 56% was absorbed by direct brain entry. Intranasal administration resulted in rapid brain penetration with a brain t_max of 10 min and demonstrated a brain bioavailability of 28.5% compared to bioavailability after intravenous bolus injection of cannabidiol solution. Conclusions: Intranasal administration of cannabidiol-loaded nanoparticles was found to be effective for the delivery of cannabidiol to the brain with significantly lower systemic exposure compared to intravenous administration. A proposed pharmacokinetic model was found to be appropriate in describing and predicting the disposition pathways following intranasal administration, especially when designing drug delivery systems for brain targeting. Full article

Lipid-based delivery systems (LDS), including lipid nanoparticles (LNPs) and liposomes, have become indispensable tools in modern biomedicine owing to their biocompatibility, capacity to encapsulate diverse therapeutic agents, and potential for targeted delivery. Despite their clinical success, conventional batch-based manufacturing methods are hindered by variability, limited scalability, and complex processing steps, slowing their broader translation. Microfluidic technologies offer a transformative solution by enabling precise fluid handling, rapid mixing, and reproducible production of LDS with tunable physicochemical attributes such as particle size, lamellarity, and drug-loading efficiency. This review highlights advances in microfluidic design strategies, including hydrodynamic flow focusing, staggered herringbone mixers, and toroidal micromixers, and evaluates how critical parameters such as flow rate, solvent composition, and lipid concentration influence LDS performance. Furthermore, we discuss the application of microfluidics in drug delivery, nucleic acid therapeutics, and vaccine platforms, underscoring its role in improving scalability, quality control, and clinical translation. Finally, we examine current challenges, including throughput limitations and solvent handling, while outlining future directions for integrating emerging materials and additive manufacturing to optimize LDS fabrication. Collectively, microfluidic platforms provide a promising pathway for next-generation lipid nanomedicines with enhanced precision, reproducibility, and therapeutic efficacy. Full article

Objective: The therapeutic efficacy of the classic antibiotic combination trimethoprim/sulfamethoxazole (TMP/SMZ) is often limited by the significant pharmacokinetic mismatch. In this study, a polyethylene glycol-polylactic-co-glycolic acid (PEG-PLGA) nanodelivery system was employed to improve the pharmacokinetic matching of TMP and SMZ. The investigation also evaluated the enhanced in vivo antibacterial efficacy of this formulation. Methods: Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS) was employed to systematically characterize the absorption, distribution, and excretion profiles of PEG-PLGA-loaded TMP nanoparticles (NPs) in rats. In vitro antibacterial activity was assessed against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In vivo efficacy and biosafety of the TMP NPs/SMZ regimen were evaluated using a murine E. coli infection model via survival monitoring, biochemical assays, and histopathology. Results: Pharmacokinetic analysis revealed that TMP NPs achieved a relative bioavailability of 193.05% and extended the elimination half-life by 3.37-fold compared to free TMP. Tissue distribution showed significantly increased drug accumulation in the liver, spleen, and kidneys, with renal clearance as the primary excretion pathway (73.89%). In vitro, the nano-formulation reduced the minimum inhibitory concentration (MIC) by 2-4-fold and shortened the bactericidal duration from 12 to 8 h. In vivo, the TMP NPs/SMZ combination significantly improved survival rates, accelerated recovery, and alleviated infection-induced organ damage without systemic toxicity. Conclusions: This nanotechnology-based strategy effectively aligns the pharmacokinetics of TMP and SMZ, prolongs their synergistic window, and enhances biosafety, offering a viable approach to revitalize classic antibiotic combinations. Full article

Background/Objectives: Current clinical evidence suggests that cannabidiol (CBD) demonstrates therapeutic potential in the management of chronic pain, particularly in conditions involving inflammation. However, its therapeutic potential is severely limited by poor oral bioavailability, extensive first-pass metabolism, and the need for frequent high-dose administration, which compromises patient adherence and tolerability. Long-acting injectable (LAI) delivery systems offer a strategy to overcome these limitations by providing sustained plasma concentrations and reducing dosing frequency. This study aimed to develop and optimise CBD-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres for LAI delivery and to evaluate poly(2-ethyl-2-oxazoline) (POx) as a functional and biocompatible alternative to the conventionally used poly (ethylene glycol) (PEG). Methods: CBD-loaded microspheres were prepared using emulsion–solvent evaporation technique. The formulations were optimised based on entrapment efficiency (EE), drug loading (DL), particle size distribution, surface morphology, thermal behaviour, in vitro release kinetics, and cytocompatibility using NIH 3T3 fibroblasts. Multiple in vitro release methodologies, including dialysis bag, shaking-flask, and USP Apparatus IV, were evaluated to identify the most discriminative and practical approach for long-term release assessment. Results: The optimised POx-based microspheres demonstrated superior control over particle size, yielding significantly smaller and more uniform particles compared with PEG-based microspheres (124 ± 1.47 µm vs. 218 ± 13.5 µm, respectively). Differential scanning calorimetry (DSC) confirmed molecular dispersion of CBD within the polymer matrix. In vitro release studies demonstrated sustained drug release over 20 days. Conclusions: POx represents a promising alternative to PEG for the formulation of CBD-loaded PLGA microspheres, offering enhanced physicochemical stability and biological compatibility. This platform supports the development of safe and effective long-acting injectable CBD therapies and consideration of POx as an alternative to PEG. Full article

Objectives: To examine the prescribing of non-vitamin K-dependent oral anticoagulants (DOACs) among multidose drug dispensing (MDD) users aged ≥65 years, and to describe associated drug–drug interactions (DDIs), concomitant use of fall-risk increasing drugs (FRIDs) and anticholinergic drugs (AC). Methods: Cross-sectional analysis of anonymized MDD medication lists from 87,519 patients in 2018. DDIs were identified using The Norwegian Medical Products Agency interaction tool, FRIDs were defined using the Swedish National Board of Health and Welfare list, and the CRIDECO Anticholinergic Load Scale assessed anticholinergic burden. Results: Among the 13,215 patients aged 65 and older the mean number of prescribed medications was 10.3. At least one DDI involving the prescribed DOACs was present in 26.8% of patients, whereas severe DDIs were rare (0.2%). Almost all (96.7%) used at least one FRID, and nearly half (46.8%) had an anticholinergic score ≥ 3. Conclusions: DOACs are frequently prescribed together with medications that increase the risk of falls and bleeding. These findings highlight the need for individualized risk–benefit evaluations and deprescribing or substituting high impact FRIDS and ACs when clinically appropriate. Full article

Background/Objectives: Poor aqueous solubility and limited nasal permeability remain key challenges in the intranasal delivery of carbamazepine. In this study, biocompatible bovine serum albumin nanoparticles functionalized with sulfobutyl-β-cyclodextrin (SβCD-BSA NPs), comprising individually cytocompatible components with confirmed physical interactions), were formulated for intranasal delivery of carbamazepine (CBZ). Methods: The ethanolic desolvation method was utilised for the preparation of the nanoparticles, with the functional moiety incorporated during nanoparticle preparation. The effects of different molar ratios of SβCD-BSA and different ethanol volume ratios were studied. For crosslinking, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), a non-toxic crosslinker, was utilised. To determine the role of the SβCD, two preparation samples were formulated, with and without SβCD. Results: The formulation without SβCD incorporation had a mean particle size of 125 ± 0.64 nm, polydispersity index (PDI) of 0.34, encapsulation efficiency (EE%) of 61.5 ± 1.40%, and drug-loading ratio (DL%) of 31.9 ± 1.50%. Conversely, the SβCD-functionalized formulation showed a mean particle size of 128 ± 2.12 nm, PDI of 0.21 ± 0.03, EE of 64.6 ± 0.35%, and DL of 34.28 ± 1.60%. Statistical analysis revealed that the incorporation of SβCD resulted in a statistically significant increase in both DL% and EE% (p < 0.05). Conversely, the observed differences in particle size and PDI were not statistically significant (p > 0.05). This addition provides precise context regarding the comparability of the formulations while highlighting SβCD’s functional benefits in solubility and permeation. The interaction between CBZ and SβCD-BSA was confirmed using Fourier-transform infrared spectroscopy. Lastly, the prepared formulations were characterised by their physicochemical attributes and in vitro biopharmaceutical studies. It was discovered that SβCD plays a dual role, enhancing the solubility of CBZ in one scenario while promoting its nasal permeation, suggesting its potential use in epilepsy treatment. Conclusions: These findings highlight the potential of SβCD-BSA NPs as a versatile pharmaceutics platform for the intranasal delivery of poorly soluble CNS drugs. Full article