Search Results (162)

Current primary liver cancer therapies, including sorafenib and transarterial chemoembolization, face significant limitations due to chemoresistance caused by impaired drug uptake, altered metabolism, and other genetic modulations. These challenges contribute to relapse rates of 50–80% within five years. The need for improved treatment strategies (adjuvant therapy, unsatisfactory enhanced permeability and retention (EPR) effect) has driven research into advanced drug delivery systems, including targeted nanoparticles, biomaterials, and combinatory approaches. Therefore, this review evaluates recent advancements in primary liver cancer pharmacotherapy, focusing on the potential of drug delivery systems for sorafenib and its derivatives. Approaches such as leveraging Kupffer cells for tumor migration or utilizing smaller NPs for inter-/intracellular delivery, address EPR limitations. Biomaterials and targeted therapies focusing on targeting have demonstrated effectiveness in increasing tumor-specific delivery, but clinical evidence remains limited. Combination therapies have emerged as an interesting solution to overcoming chemoresistance or to broadening therapeutic functionality. Biomimetic delivery systems, employing blood cells or exosomes, provide methods for targeting tumors, preventing metastasis, and strengthening immune responses. However, significant differences between preclinical models and human physiology remain a barrier to translating these findings into clinical success. Future research must focus on the development of adjuvant therapy and refining drug delivery systems to overcome the limitations of tumor heterogeneity and low drug accumulation. Full article

Chemotherapy resistance, particularly multidrug resistance (MDR), remains a significant barrier to effective cancer treatment, leading to high mortality rates. The development of novel therapeutic strategies targeting key molecular mechanisms to counteract drug resistance is thus an urgent clinical need. In this study, we evaluated the potential of the small molecule SCO-101 to restore chemotherapy sensitivity in drug-resistant cancer cells. Using in silico and in vitro models such as molecular docking, cell viability, colony formation, dye efflux, transporter assays and chemotherapy retention, we assessed the impact of SCO-101 on drug retention and response in several drug-resistant cancer cells. SCO-101 was found to inhibit the activity of breast cancer resistance protein (BCRP/ABCG2) and UDP Glucuronosyltransferase Family 1 Member A1 (UGT1A1), two key proteins involved in drug resistance by cellular drug excretion and drug metabolism. Our results demonstrate that inhibition of these proteins by SCO-101 leads to increased intracellular drug accumulation, enhancing the cytotoxic effects of chemotherapy agents. Additionally, we identified a strong correlation between high ABCG2 expression and MDR in non-drug-resistant models, where cells exhibiting elevated ABCG2 levels displayed chemotherapy resistance, which was effectively reversed by SCO-101 co-treatment. These findings highlight the therapeutic potential of SCO-101 in overcoming MDR by inhibiting drug efflux mechanisms and metabolism, thereby enhancing chemotherapy efficacy. SCO-101 is currently undergoing clinical trials as an orally administered drug and is considered a promising strategy for improving cancer treatment outcomes in patients with drug-resistant tumors. Full article

Nature-based solutions represent a decentralized wastewater treatment proposal, offering diverse mechanisms for effectively removing emerging contaminants, particularly acidic pharmaceuticals. This study evaluated the performance of acidic-drug (diclofenac, fenofibrate, ibuprofen, gemfibrozil, fenoprofen, naproxen, and indomethacin) removal from wastewater using a surface-flow constructed wetland with an organic bed (Eichhornia crassipes (Mart.) Solms, 18 ind/m²), and a horizontal subsurface-flow constructed wetland, divided into three sections. The process was complemented by two stabilization ponds and other horizontal subsurface-flow wetlands using papyrus (Cyperus papyrus L., 8–13 ind/m²) and tezontle as support media. The industrial-scale system (67.8 m²) was fed with wastewater at a rate of 1.33 m³/d with a hydraulic time retention of about 5.8 days. Drugs were quantified by gas chromatography. The results showed that gemfibrozil and indomethacin were completely removed (100%), while diclofenac (73%) and naproxen (94%) showed significant removals. Fenoprofen was not removed. Ibuprofen and fenofibrate showed increased concentrations, resulting in negative removals due to anoxic conditions (ibuprofen) and a slightly neutral pH (fenofibrate). These findings underscore the system’s ability to improve water quality by removing most acidic drugs, suggesting that the hybrid design is particularly effective in treating specific wastewater contaminants. Full article

The use of adenosine triphosphate (ATP) has shown promising effects in alleviating ischemic damage across various tissues. However, the penetration of ATP into kidney tubular cells presents a challenge due to their unique anatomical and physiological properties. In this study, we introduce a novel bioinspired drug delivery system utilizing extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) and engineered to carry ATP. ATP-loaded liposomes (ATP-LPs) and ATP-loaded EVs (ATP-EVs) were prepared using microfluidic technology, followed by characterization of their morphology (DLS, NTA, SEM, TEM), ATP content, and release rate at 37 °C (pH 7.4). Additionally, the delivery efficacy of ATP-LPs and ATP-EVs was evaluated in vitro on renal cells (HK2 cells) under chemically induced ischemia. The results indicated successful ATP enrichment in EVs, with ATP-EVs showing no significant changes in morphology or size compared to naïve EVs. Notably, ATP-EVs demonstrated superior ATP retention compared to ATP-LPs, protecting the ATP from degradation in the extracellular environment. In an ATP-depleted HK2 cell model, only ATP-EVs effectively restored ATP levels, preserving cell viability and reducing apoptotic gene expression (BCL2-BAX). This study is the first to successfully demonstrate the direct delivery of ATP into renal tubular cells in vitro using EVs as carriers. Full article

Background: Postoperative adhesions are a common complication following abdominal surgery, affecting over 90% of patients and leading to significant morbidity. Current anti-adhesion strategies, such as the use of physical and chemical barriers, have limitations such as short retention time, mechanical fragility, and inefficient drug delivery. This study developed a pectin-based emulsion gel loaded with celecoxib to prevent adhesions and provide localized pain relief. Methods: Formulations (F1–F4) with different pectin concentrations were evaluated for rheological properties, mucoadhesion, degradation rate, and celecoxib release. In vivo efficacy was evaluated in Sprague−Dawley rats via a standardized model of peritoneal abrasion, in which the formulations were compared to a commercially available anti-adhesion barrier. Results: The optimized emulsion gel (F4) exhibited improved mucoadhesion (9009 mPa·s), prolonged retention, and controlled celecoxib release over 14 days, reaching 80% release by day 9. In vivo, formulation F4 significantly reduced adhesions compared to a commercially available product. Pharmacokinetic analysis showed rapid absorption (T_max = 2 h) and sustained celecoxib plasma levels, confirming its effectiveness as a localized drug-delivery system. The celecoxib-loaded pectin-based gel successfully prevented postoperative adhesions and provided sustained pain relief. Conclusions: These findings suggest its potential clinical utility, though further preclinical and clinical evaluations are required. Full article

Background/Objectives: Triple-negative breast cancer (TNBC) is a major cause of cancer-related deaths among women. The Hedgehog (Hh) signaling pathway plays a critical role in tumor development, and targeting this pathway may provide new therapeutic opportunities for TNBC. TPB15 is a novel smoothened inhibitor of the Hh pathway, showing promising tumor reduction and low-toxicity properties in vivo/vitro. This study aims to evaluate TPB15’s protein binding rates, metabolic stability, and metabolism across different species, including mice, rats, dogs, monkeys, and humans. Methods: TPB15 was synthesized, and its pharmacokinetic profile was assessed. Plasma protein binding was determined using ultrafiltration across multiple species. Stability studies were conducted in plasma and liver microsomes from each species. Additionally, metabolic enzymes in human liver microsomes were characterized with selective CYP450 inhibitors, and high-resolution mass spectrometry was employed to identify metabolites. Results: Plasma protein binding of TPB15 was consistent across species, ranging from 81.5% to 82.4% in humans and rats. After 120 min, TPB15 remained stable in plasma, with retention rates of 97.2–98.3%. The elimination half-life (t_1/2) varied from 88 min in monkeys to 630 min in dogs. In human liver microsomes, metabolism was significantly inhibited by sulfaphenazole and ketoconazole, indicating the involvement of CYP3A4 and CYP2C9 enzymes. TPB15 underwent phase I metabolism, producing a major metabolite with a molecular weight of 468.9. Conclusions: TPB15 demonstrates stable pharmacokinetic properties across species, with consistent protein binding and significant variability in half-life. The observed differences in metabolism are primarily attributed to CYP2C9 and CYP3A4, offering valuable insights into its drug development potential. Full article

Interest in developing new, effective materials for emergency hemostasis and wound healing is steadily increasing, particularly for use in emergency, surgical, and military situations. Hydrogels, with their unique retention, swelling, and biocompatibility properties, have emerged as essential materials in emergency therapy. This review provides a comprehensive examination of recent hydrogel applications in acute medical scenarios, including hemostasis, wound management, drug delivery, soft tissue replacement, and tissue engineering. We discuss the physicochemical properties that make hydrogels suitable for rapid response situations, such as their tunable mechanical strength, adhesiveness, responsiveness to environmental stimuli, and ability to encapsulate and release therapeutic agents. Additionally, the article explores recent advancements in smart hydrogels with self-healing and antimicrobial properties, providing insights into their potential to revolutionize emergency care and increase survival rates in both civilian and military applications. Through a critical evaluation of current clinical trials and practical deployments, this review highlights both the successes and the challenges faced in integrating hydrogels into emergency medical protocols, providing a roadmap for future research and development in this dynamic field. Full article

Wound infections pose a significant challenge in healthcare settings due to prolonged healing times and the emergence of antibiotic-resistant bacteria. Traditional wound dressings often fail to provide sustained drug release, optimal moisture retention, and effective antibacterial protection, leading to suboptimal therapeutic outcomes. This study aimed to optimize and develop neomycin-integrated hydrogels crosslinked via tannic acid (TA) for the treatment of infectious wounds. The hydrogels were optimized using a central composite experimental design. The amounts of polyvinyl alcohol (PVA, 10–20% w/w) and polyvinylpyrrolidone (PVP, 5–20% w/w) were varied and mixed with a fixed concentration of TA (1% w/w) as a crosslinker. The water content (%), water absorption (%), erosion (%), water vapor transmission rate (WVTR), and the mechanical properties of the hydrogels were evaluated. Neomycin was integrated in the optimized hydrogel, and the antibacterial activity against Staphylococcus aureus was studied using a time-kill analysis method. The optimal hydrogel formula contained PVA and PVP at a ratio of 20:19.89 by weight. The resulting hydrogel possessed good physical and mechanical properties and had a water content of 71.86%, water absorption of 124.96%, minimal erosion of 33.08%, and optimal WVTR of 5567 g/m²/24 h. Furthermore, the hydrogel showed desirable elasticity, with a Young’s modulus of 474.81 Pa and a tensile strength that could resist breakage upon application. The neomycin-integrated hydrogels inhibited bacterial growth comparably to the neomycin solution (0.5% w/v). Therefore, TA was proven to be a promising natural crosslinker and the optimized hydrogel was demonstrated to be a propitious platform for neomycin cutaneous application, and which could be used to treat infected wounds in the future. Full article

In recent years, hydrogels have emerged as promising candidates for bone defect repair due to their excellent biocompatibility, high porosity, and water-retentive properties. However, conventional hydrogels face significant challenges in clinical translation, including brittleness, low mechanical strength, and poorly controlled drug degradation rates. To address these limitations, as a multifunctional polymer, polydopamine (PDA) has shown great potential in both bone regeneration and drug delivery systems. Its robust adhesive properties, biocompatibility, and responsiveness to photothermal stimulation make it an ideal candidate for enhancing hydrogel performance. Integrating PDA into conventional hydrogels not only improves their mechanical properties but also creates an environment conducive to cell adhesion, proliferation, and differentiation, thereby promoting bone defect repair. Moreover, PDA facilitates controlled drug release, offering a promising approach to optimizing treatment outcomes. This paper first explores the mechanisms through which PDA promotes bone regeneration, laying the foundation for its clinical translation. Additionally, it discusses the application of PDA-based nanocomposite hydrogels as advanced drug delivery systems for bone defect repair, providing valuable insights for both research and clinical translation. Full article

Background/Objectives: Orally or intravenously administered acetaminophen experiences considerable liver first-pass elimination and may cause liver/kidney damage. This work examined the pharmacological effects of acetaminophen-loaded poly(lactic-co-glycolic acid) nanoparticles (AAP PLGA NPs) intranasally administered to mice rapidly entering high altitudes. Methods: AAP PLGA NPs were prepared using ultrasonication-assisted emulsification and solvent evaporation and characterized in terms of drug encapsulation efficiency and loading, in vitro and in vivo release behaviors, and toxicity to hippocampal neurons. In vivo fluorescence imaging was used to monitor the concentrations of AAP PLGA NPs (labeled with indocyanine green) in the brain and blood of the mice after intranasal administration. The effects of these NPs on the pain threshold in mice rapidly entering high altitudes were evaluated through hot plate and tail flick experiments. Results: The AAP PLGA NPs were found to be noncytotoxic, highly biocompatible and stable, with a drug encapsulation efficiency and loading capacity of 42.53% and 3.87%, respectively. The in vitro release of acetaminophen lasted for up to 72 h, and the release rate was ~82%. After intranasal administration in vivo, the drug release occurred slowly, and the drug was mainly concentrated in the brain. Compared with nonencapsulated acetaminophen, the intranasal administration of AAP PLGA NPs resulted in higher brain levels of the drug and delayed its elimination, thus increasing the pain threshold in mice rapidly entering high altitudes. Conclusions: The proposed strategy addresses the common problems of intranasal drug administration (low retention time and bioavailability) and paves the way for effective pain management in high-altitude environments. Full article

(1) Background: This review study will delve into the potential of chitosan nanoparticles (NPs) as adaptable carriers for targeted drug delivery in different therapeutic areas. Chitosan is a biopolymer derived from chitin that has attracted interest in drug delivery applications because of its high biocompatibility and biodegradability. (2) Methods: A comprehensive literature review was conducted by following a careful systematized protocol for searching databases like PubMed, Google Scholar and ScienceDirect. (3) Results: Chitosan NPs are good drug delivery vehicles, notably for cancer. Studies reveal that doxorubicin-loaded chitosan NPs dramatically enhance toxicity to tumor cells compared to free medicines, yielding tumor suppression rates of up to 60%. Researchers found that chemotherapeutics had an 85% encapsulation efficiency (EE), lowering systemic toxicity. Magnetic and pH-responsive chitosan NPs boost drug accumulation by 63% and apoptosis by 54%. Chitosan also boosts medication retention in the lungs by 2.3×, per pulmonary delivery trials. Chitosan NPs also boost ocular medication bioavailability by 3× and improve nasal absorption by 30%, crossing the blood–brain barrier. For bone regeneration, chitosan scaffolds enhance bone mineral density by 46%, facilitating osteogenesis and healing. (4) Conclusions: NPs made of chitosan provide a solid foundation for improving drug delivery systems; yet there are still issues with material variability, scalability, and meeting regulatory requirements that need fixing. Research into combination treatments, ways to increase their specificity, and ways to optimize these NPs offers promising prospects for the creation of novel therapeutic approaches with the potential to improve patient outcomes. Full article

Background/Objectives: The pulmonary administration of antibiotics can be advantageous in treating pulmonary infections by promoting high intrapulmonary drug concentrations with reduced systemic exposure. However, limited benefits have been observed for pulmonary administration versus other administration routes due to its rapid clearance from the lung. Here, the effects of structural modifications on the epithelial permeability and antibacterial potency of a third-generation cephalosporin were investigated to improve the understanding of drug properties that promote intrapulmonary retention and how they may impact efficacy. Methods: Ceftazidime was modified by attaching 18 hydrophobic, hydrophilic, and mucus-binding motifs to the carboxylic acid distant from the beta-lactam by amidation. Epithelial permeability was investigated by drug transport assays using human bronchial epithelial air–liquid interface cultures. Antibacterial potency was determined by microtiter MIC assays with B. pseudomallei, P. aeruginosa, E. coli, and S. aureus. Results: A 40–50% reduction in the transepithelial transport rate was exhibited by two PEGylated ceftazidime analogs (mPEG8- and PEG5-pyrimidin-2-amine-ceftazidime) and n-butyl-ceftazidime. An increase in the transport rate was exhibited by four analogs bearing small and hydrophobic or negatively charged motifs (n-heptane-, phenyl ethyl-, glutamic acid-, and 4-propylthiophenyl boronic acid-ceftazidime). The antibacterial potency was reduced by ≥10-fold for most ceftazidime analogs against B. pseudomallei, P. aeruginosa, and E. coli but was retained by seven ceftazidime analogs primarily bearing hydrophobic motifs against S. aureus. Conclusions: The covalent conjugation of PEGs with MW > 300 Da reduced the epithelial permeability of ceftazidime, but these modifications severely reduced antibacterial activity. To improve the pulmonary retention of antibiotics with low membrane permeability, this work suggests future molecular engineering studies to explore high-molecular-weight prodrug strategies. Full article

Background: Silibinin (SLB), a flavonoid derived from milk thistle, exhibits promising therapeutic properties but faces significant clinical limitations due to poor solubility and bioavailability. Objectives: This study focuses on the development and characterization of SLB-loaded nanoemulsions designed for mucosal delivery. Methods: Nanoemulsions were prepared using the spontaneous emulsification method, guided by pseudoternary phase diagrams to determine selected component ratios. Comprehensive characterization included particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency, rheological properties, and surface tension. Mucoadhesive properties were evaluated using quartz crystal microbalance with dissipation (QCM-D) to quantify interactions with mucin layers. Results: The combination of Capryol 90, Tween 80, and Transcutol in selected proportions yielded nanoemulsions with excellent stability and solubilization capacity, enhancing the solubility of silibinin by 625 times compared to its intrinsic solubility in water. The ternary phase diagram indicated that achieving nanoemulsions with particle sizes between 100 and 300 nm required higher concentrations of surfactants (60%), relative to oil (20%) and water (20%), with formulations predominantly composed of Smix (surfactant and cosurfactant mixture in a 1:1 ratio). Rheological analysis revealed Newtonian behavior, characterized by constant viscosity across varying shear rates and a linear torque response, ensuring ease of application and mechanical stability. QCM-D analysis confirmed strong mucoadhesive interactions, with significant frequency and dissipation shifts, indicative of prolonged retention and enhanced mucosal drug delivery. Furthermore, contact angle measurements showed a marked reduction in surface tension upon interaction with mucin, with the SLB-loaded nanoemulsion demonstrating superior wettability and strong mucoadhesive potential. Conclusions: These findings underscore the suitability of SLB-loaded nanoemulsions as a robust platform for effective mucosal drug delivery, addressing solubility and bioavailability challenges while enabling prolonged retention and controlled therapeutic release. Full article

Yataprasen (YTPS) remedy ethanolic spray, one of the National Thai Traditional Medicine Formulary, is extensively employed in Thai traditional healthcare to manage musculoskeletal pain and inflammation. Despite its widespread use, the quality and stability of the YTPS formulation, critical to its efficacy, safety, and patient adherence, have not been comprehensively studied. This research developed and optimized a film-forming spray (FFS) formulation of YTPS ethanolic extract and conducted a 6-month stability evaluation. The FFS shares similarities with gel formulations, particularly in its ability to form a cohesive, semi-solid film upon application, enhancing localized drug delivery and prolonged contact time. Key physicochemical properties, including density (0.8450–0.9086 g/cm³), pH (4.72–4.95), spray angle (55.58–60.10°), evaporation time (1.04–1.27 min), and theoretical film thickness (7.72–13.97 µm), were analyzed across varying storage conditions. Active components β-amyrin and stigmasterol demonstrated retention rates of 96.78% and 68.22%, respectively, under refrigerated conditions, with degradation rates accelerating at higher temperatures. Significant variations in density, spray angle, film thickness, and stigmasterol concentration were observed. Additionally, the RP-HPLC method was validated for the accurate and precise quantification of the bioactive compounds such as β-amyrin and stigmasterol, demonstrating excellent linearity within a 10–100 µg/mL range for both compounds with excellent linearity R² > 0.999. The results confirmed that YTPS-FFS exhibits good stability and that the validated HPLC method is reliable for routine quality control. These findings supported the potential of YTPS-FFS formulation as a standardized and effective dosage form for managing musculoskeletal conditions, advancing its role in modernized traditional medicine. Full article

Exploring tazarotene, a third-generation retinoid for potential hand osteoarthritis treatment, this study presents the development and validation of an ultra-performance liquid chromatography with quadrupole detector mass spectrometry (UPLC-QDa) method for the simultaneous quantification of tazarotene and tazarotenic acid, its active metabolite, in porcine skin. Method development involved a design-of-experiments approach for chromatographic optimization of gradient steepness, organic solvent volume, column temperature, capillary voltage, flow rate, and cone voltage. Central composite orthogonal design was used to optimize peak area, peak width, retention time, and resolution. Validation was performed in accordance with U.S. Food and Drug Administration guidelines. The method was linear over the concentration range of 0.4–18,750 ng/mL for tazarotene and 13.3–12,500 ng/mL for tazarotenic acid, with r² values of ≥0.99. Chromatographic analysis demonstrated acceptable accuracy and precision (<15%), and stability tests confirmed the analytes’ stability under various conditions. This validated method offers a reliable and accurate approach for the simultaneous analysis of tazarotene and tazarotenic acid, facilitating further research into their therapeutic applications for hand osteoarthritis. Full article