European Journal of Pharmaceutical Sciences最新文献

{"title":"Elucidating the uptake and trafficking of nanostructured lipid carriers as delivery systems for miRNA","authors":"Ivana Ruseska ,&nbsp;Amina Tucak-Smajić ,&nbsp;Andreas Zimmer","doi":"10.1016/j.ejps.2024.106973","DOIUrl":"10.1016/j.ejps.2024.106973","url":null,"abstract":"<div><div>Cationic nanostructured lipid carriers (cNLCs) represent promising non-viral carriers for nucleic acids, such as miRNAs, forming stable self-assembled miRNA complexes due to electrostatic interactions. Prepared by high-pressure homogenization, cNLC formulations, both with and without Nile Red dye demonstrated stable particle sizes in the range of 100–120 nm and positive surface charges (&gt;30 mV), which are necessary for effective cellular uptake. The miRNA complexes formed at mass ratios of 1:2.5 and 1:5 showed similar stability and size, with positive zeta potentials, as well as high cell viability (&gt; 80 %) in 3T3-L1 and MCF-7 cell lines. The cellular uptake studies of miRNA:cNLC complexes in both cell lines revealed that uptake was time- and concentration-dependent, with rapid initial uptake in 30 min and a zig-zag pattern over 24 h. To elucidate the endocytosis mechanism of miRNA:cNLC complexes, 3T3-L1 and MCF-7 cells were incubated with different inhibitors (chlorpromazine, 5-[N-ethyl-N-isopropyl] amiloride, dynasore, nystatin, or sodium azide with 2-deoxy-d-glucose). Results showed significant inhibition of uptake at low temperatures and with ATP depletion, suggesting endocytosis, particularly macropinocytosis, as the main uptake mechanism in 3T3-L1 cells. In MCF-7 cells, the uptake was less inhibited by the substances, indicating the need for more specific methods to fully decipher the endocytic mechanisms involved. Confocal laser scanning microscopy images revealed that the complexes are internalized in vesicles, and are primarily localized in the juxtanuclear region, suggesting trafficking through the endolysosomal system. Colocalization study with LysoTracker™ Green DND-26 showed significant colocalization of miRNA:cNLC complexes with lysosomes in 3T3-L1 cells, indicating trafficking through the endolysosomal system. In MCF-7 cells, colocalization was lower, suggesting macropinocytosis as the primary uptake mechanism. Additional studies showed partial colocalization between labeled NLCs and miRNA, indicating that about 50 % of miRNA is released from NLCs within 30 min post-transfection.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106973"},"PeriodicalIF":4.3,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scaling up controlled nucleation in freeze drying: Translating vacuum-induced surface freezing from laboratory to GMP","authors":"Stefan C. Schneid,&nbsp;Michaela Cohrs ,&nbsp;Julian H. Lenger","doi":"10.1016/j.ejps.2024.106968","DOIUrl":"10.1016/j.ejps.2024.106968","url":null,"abstract":"<div><div>The freezing step often causes batch inhomogeneity and issues during freeze drying process transfer. The nucleation temperature at which the first ice is formed during freezing differs from vial to vial, and significantly between scales. To solve this issue, Controlled Ice Nucleation techniques can be applied to induce ice nucleation at a defined product temperature across the whole batch. This study describes the application of vacuum-induced surface freezing (VISF) for a therapeutic antibody formulation, including the process transfer from laboratory scale through pilot scale to a GMP line. The VISF method could be successfully implemented on all scales of freeze dryers without equipment adaptation. Some scale-dependent changes in pressure control and degassing were necessary to achieve nucleation in all vials and avoid defects. The resulting lyophilized products were characterized and further analyzed in a stability study. While most critical quality attributes were comparable for product manufactured with and without Controlled Nucleation, the appearance of cakes processed using VISF was much better, which could be linked to different product morphology due to freeze-concentration. The results of this study allow direct comparison of the application of controlled nucleation for an antibody formulation at different scales and confirm the applicability of the technology.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106968"},"PeriodicalIF":4.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in silico study of the synergistic anticancer effect of alpinumisoflavone with gemcitabine on pancreatic ductal adenocarcinoma through suppression of ribonucleotide reductase subunit-M1","authors":"Woonghee Lee ,&nbsp;Gwonhwa Song ,&nbsp;Hyocheol Bae","doi":"10.1016/j.ejps.2024.106969","DOIUrl":"10.1016/j.ejps.2024.106969","url":null,"abstract":"<div><div>A highly aggressive neoplastic disease, pancreatic ductal adenocarcinoma (PDAC) is documented as the third chief cause of cancer-associated mortality in both sexes combined in the United States. For decades, gemcitabine-based chemotherapy has been embraced as a cornerstone drug for the treatment of PDAC. However, there have been several unsolved problems, including cytotoxicity, and chemoresistance. Gemcitabine efficacy was attributed to the attenuation of ribonucleotide reductase subunit-M1 (RRM1). Overexpression of RRM1 in PDAC is highly correlated with gemcitabine resistance and reduced gemcitabine sensitivity, resulting in a poor survival rate even after gemcitabine treatment. Moreover, the status of TP53, a tumor suppressor gene, assumes a decisive role in the response of PDAC to gemcitabine. Therefore, targeting RRM1 and P53 might be a therapeutic strategy for strengthening gemcitabine efficacy and cytotoxicity against PDAC. Alpinumisoflavone (AIF) is a prenylated isoflavone originated in Cudrania tricuspidate with versatile bioactive properties, including anticancer activity. However, there was no report whether AIF can exert anticancer effect and exhibit synergistic effect with gemcitabine against PDAC. Therefore, the anticancer properties of AIF were assessed with PANC-1 and MIA PaCa-2. In addition, synergism between AIF and gemcitabine were analyzed. Moreover, the contribution of P53 and RRM1 expression to gemcitabine resistance was assessed by comparing their protein levels in PDAC cells and normal pancreatic cells. The interactions of AIF with RRM1 protein were confirmed by molecular docking and dynamics simulation. Therefore, AIF enhances gemcitabine efficacy against PDAC through the regulation of P53 and RRM1.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106969"},"PeriodicalIF":4.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetic analysis in children with different diseases treated with mycophenolate mofetil—Integrated analysis of clinical trials and real-world clinical data","authors":"Jumpei Saito ,&nbsp;Akimasa Yamatani ,&nbsp;Miki Akabane ,&nbsp;Mayumi Sako ,&nbsp;Kandai Nozu ,&nbsp;Kazumoto Iijima ,&nbsp;Hidefumi Nakamura","doi":"10.1016/j.ejps.2024.106970","DOIUrl":"10.1016/j.ejps.2024.106970","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aims to develop a population pharmacokinetic (PK) model of mycophenolic acid (MPA) in pediatric patients with different diseases.</div></div><div><h3>Methods</h3><div>To develop the PK model, electronic medical records (EMR) of pediatric patients with different diseases who received mycophenolic acid mofetil (MMF) at the National Center for Child Health and Development from February 2013 to May 2022 and the results of the MMF pharmacokinetic study of pediatric complicated frequently relapsing steroid-dependent nephrotic syndrome under the Advanced Medical Care B protocol (JSKDC09 study) from October 2015 to June 2019 were integrated and analyzed. Non-linear mixed-effects modeling was used to 1) develop a cross-disease population PK model and 2) estimate PK parameters (apparent clearance CL/F and Q/F; apparent volume of distribution Vc/F and Vp/F; absorption rate constant Ka) by post-hoc Bayesian methods. Patient backgrounds, concomitant medications, and laboratory data were included in the covariate analysis. Visual predictive checks with bootstrap and predictive correction were performed to evaluate the final model.</div></div><div><h3>Results</h3><div>A total of 249 patients with 1495 measurements were used in the analysis, including 68 with post-liver transplant, 65 with nephrotic syndrome, 28 with post-renal transplant, 31 with autoimmune diseases (17 with lupus nephritis and 14 with other collagen diseases), 13 with hematopoietic stem cell transplantation, and 5 with others from EMR and 39 with nephrotic syndrome from the JSKDC09 study. A two-compartment model with a first-order rate absorption process best explained the PK of MPA. A nonlinear relationship between dose and MPA exposure was observed and described by the power function of the model. The final population mean PK parameter estimates (95 % confidence interval) for non-renal transplant patients and average albumin levels were CL/F 15.2 (13.3, 18.0) L/h/70 kg, Vc/F 15.4 (14.4, 17.2) L, Vp/F 246.8 (159.1, 332.1) L, Q/F 7.0 (5.0, 9.0) L/h, and Ka (without proton pump inhibitor [PPI]) 4.4 (2.4, 4.9) h^–1. Weight, disease (post-renal transplant), and serum albumin level were significant covariates for CL/F, and serum albumin level for Vc/F. The use of PPIs also affected Ka.</div></div><div><h3>Conclusions</h3><div>An integrated population PK model of MPA was developed in children with the following conditions: post-solid organ transplantation, post-HSCTx, autoimmune disease, and nephrotic syndrome. Estimated parameters and parameter covariates were similar to those previously reported. This model is expected to provide useful information for using MPA in various diseases in the Japanese population.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106970"},"PeriodicalIF":4.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiphysics simulation of liposome release from hydrogels for cavity filling following patient-specific breast tumor surgery","authors":"Álvaro González-Garcinuño ,&nbsp;Antonio Tabernero ,&nbsp;Celia Nieto ,&nbsp;Eva Martín del Valle ,&nbsp;Sasa Kenjeres","doi":"10.1016/j.ejps.2024.106966","DOIUrl":"10.1016/j.ejps.2024.106966","url":null,"abstract":"<div><div>Several studies have recommended the use of hydrogels for localized targeted delivery of chemotherapeutic drugs following tumor removal surgery. This approach aims to both fill the cavity and prevent cancer recurrence. The use of Multiphysics-based simulation emerges as a valuable strategy for minimizing experimental work, providing detailed insights into how drug release occurs in the tissue, and enabling the optimization of the design.</div><div>In this study, we introduced a mathematical model, utilizing experimental data, to investigate the transport of liposomes carrying MZ1 from a thermosensitive hydrogel and their impact on the viability of breast cancer cells. The proposed comprehensive model considers not just the transport within the interstitial tissue, represented as a porous medium, but also the uptake by cells and its influence on cell viability, along with the potential lymphatic drainage.</div><div>The six real patient-specific tumor shapes extracted from MRI scans were used to investigate how the size and form of the tumor can modify the transport pattern. The computational results revealed that the concentration of liposomes in the tissue is significantly influenced by their release from the hydrogel, which proved to be the limiting step. Liposome concentrations of approximately 0.1 % weight were found to be sufficient in ensuring minimal cell survival in the vicinity of the tumor.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106966"},"PeriodicalIF":4.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated extrusion-based dispensing: Personalized dosing and quality control of clopidogrel tablets for pediatric care","authors":"Farnaz Shokraneh ,&nbsp;Anne M. Filppula ,&nbsp;Aleksi Tornio ,&nbsp;Jaan Aruväli ,&nbsp;Urve Paaver ,&nbsp;Niklas Sandler Topelius","doi":"10.1016/j.ejps.2024.106967","DOIUrl":"10.1016/j.ejps.2024.106967","url":null,"abstract":"<div><div>The exploration of three-dimensional (3D) printing inspired technologies in pharmaceutical compounding reveals a promising frontier in personalized medicine manufacture. This study focuses on the development of clopidogrel bisulphate tablets, with doses ranging from 2 mg to 20 mg per tablet, suitable for pediatric use. The study explored a semi-solid extrusion-based deposition technology already being used in compounding pharmacies across several European locations. The investigation explored various properties of two formulations of 1 % and 2 % clopidogrel gel tablets, with a specific focus on mass variation, drug content uniformity, <em>in vitro</em> drug release profiles, disintegration time, and stability.</div><div>The mean weights of the smallest printed 200 mg tablets with 1 % and 2 % clopidogrel concentrations were 199.1 ± 4.6 mg and 201.0 ± 3.2 mg, respectively. For the largest printed 500 mg tablets with 1 % and 2 % concentrations, the mean weights were 499.3 ± 7.7 mg and 501.7 ± 6.5 mg, respectively. The mean clopidogrel content uniformity for 1 % clopidogrel 200 mg and 500 mg tablets were 102.0 ± 1.8 %and 96.6 ± 2.6 %, respectively, and for 2 % clopidogrel 200 mg and 500 mg were 102.6 ± 3.9 % and 101.2 ± 1.6 %, respectively, well within the acceptable acceptance value (AV) range of 3 to 12. Both 1 % and 2 % formulations of clopidogrel tablets exhibited rapid drug release, meeting the USP pharmacopeial target of 85 % release in 15 min. All tablet sizes formulated at 1 % and 2 % concentrations met specified disintegration specifications. The stability assessment over three months revealed consistent pH values and assay results within target specifications for both clopidogrel formulations (93.5 % for 1 % formulation and 93.6 % for 2 % formulation). At three months, X-ray Diffraction (XRD) and Fourier Transform Infrared Spectroscopy (FTIR) results demonstrated stability in clopidogrel tablets.</div><div>In conclusion, a comprehensive evaluation of our developed clopidogrel tablets demonstrate their suitability for clinical use in an extemporaneous setting using the presented semi-solid extrusion-based automation technology.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106967"},"PeriodicalIF":4.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards optimization of dexamethasone therapy in the maintenance phase of pediatric acute lymphoblastic leukemia: A population pharmacokinetic and pharmacodynamic study of dexamethasone and metabolite","authors":"Letao Li ,&nbsp;Annelienke M. van Hulst ,&nbsp;Emma J. Verwaaijen ,&nbsp;M.(Marry) van den Heuvel-Eibrink ,&nbsp;E.L.T.(Erica) van den Akker ,&nbsp;W (Wim) J R Rietdijk ,&nbsp;B.C.P.(Birgit) Koch ,&nbsp;S.D.T.(Sebastiaan) Sassen","doi":"10.1016/j.ejps.2024.106964","DOIUrl":"10.1016/j.ejps.2024.106964","url":null,"abstract":"<div><div>Dexamethasone is crucial in pediatric acute lymphoblastic leukemia (ALL) treatment, however, studies regarding the pharmacokinetics of dexamethasone and its metabolites are scarce. Our study conducted a comprehensive pharmacokinetic-pharmacodynamic analysis of dexamethasone and metabolite, examining their association with dexamethasone-induced toxicity. Peak and trough concentrations were collected during the maintenance phase from pediatric ALL patients who received oral dexamethasone (6mg/m2/day). NONMEM was used to study the population pharmacokinetics including covariates. Pharmacokinetic (PK) and pharmacodynamic (PD) correlations between drug and its active metabolite exposure and adverse effects were examined. 382 samples (dexamethasone: <em>n</em> = 191; 6β-hydroxydexamethasone: <em>n</em> = 191) from 104 children (age range 3.0 -18.8 years) were collected. A one-compartment model described the data best. The estimated apparent dexamethasone total clearance was 26 L/h/70 kg with 18 % inter-individual variability, and an apparent volume of distribution of 123 L/70 kg, yielding a half-life of 3.3 h. Covariate analysis demonstrated that when asparaginase was co-administered, there was a 50 % reduction in both the clearance of dexamethasone and the extent to which dexamethasone was metabolized to 6β-hydroxydexamethasone. A statistically significant but weak positive correlation was observed between dexamethasone drug exposure and fasting hunger scores. Dexamethasone exposure significantly increased with asparaginase co-administration by inhibition of the CYP3A4 pathway. Our study found a statistically significant but weak positive correlation between dexamethasone exposure and increased hunger. These results support the need for more studies on how to personalize dexamethasone dosing in pediatric ALL treatment and adjust doses to limit side effects, especially in case of co-medication.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106964"},"PeriodicalIF":4.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disassembly and in vitro cell compatibility of α-lactalbumin particulates under physiologically relevant conditions","authors":"Mai Bay Stie ,&nbsp;Dirk Fennema Galparsoro ,&nbsp;Xin Zhou ,&nbsp;Vito Foderà","doi":"10.1016/j.ejps.2024.106962","DOIUrl":"10.1016/j.ejps.2024.106962","url":null,"abstract":"<div><div>Protein self-assemblies in the form of ordered supramolecular structures such as particulates hold great potential as new biomaterials. However, research in this field is rarely conducted under physiologically relevant conditions but such studies are crucially needed to unravel the potential use of particulates and other amyloid structures in health sciences. In this study, particulates of α-lactalbumin (ALA) were prepared at different stages of maturation by thermal incubation. Disassembly of particulates in isotonic buffer, neutral pH and at 37 °C was investigated by simultaneously measuring Thioflavin T fluorescence intensity and light scattering. Freshly formed particulates quickly disassembled and displayed complete release of soluble ALA within 1 h. Mature particulates displayed slower disassembly kinetics with incomplete release of ALA within 1 h. The biocompatibility of particulates at different maturation stages to epithelial lung and fibroblast cells was assessed <em>in vitro</em>. Good cell compatibility was observed in the presence of the particulates and their released species. Our findings display protein particulates as biodegradable and highly tunable particles, promoting them as good candidates for drug delivery purposes.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106962"},"PeriodicalIF":4.3,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of continuous spin-freeze-drying: The role of spin-freezing on quality attributes and drying efficiency of a model peptide formulation","authors":"Zarah Schaal ,&nbsp;Pieter-Jan Van Bockstal ,&nbsp;Joris Lammens ,&nbsp;Julian H. Lenger ,&nbsp;Adrian P. Funke ,&nbsp;Stefan C. Schneid ,&nbsp;Hristo L. Svilenov ,&nbsp;Thomas De Beer","doi":"10.1016/j.ejps.2024.106963","DOIUrl":"10.1016/j.ejps.2024.106963","url":null,"abstract":"<div><div>Continuous spin-freeze-drying is an innovative pharmaceutical manufacturing approach offering real-time monitoring and control at the individual vial level, unlike conventional batch lyophilization. A central feature of this technology is spin-freezing, which involves rapidly spinning liquid-filled vials under a precisely controlled cold gas flow, resulting in a thin, uniform frozen product layer. Using a model peptide formulation, we investigated the impact of different cooling and crystallization rates on quality attributes (QA) and primary drying duration. Key QAs included monomer content, peptide assay, moisture content, and pore structure. The monomer content, peptide content, and primary drying duration remained consistent across all spin-freezing conditions. However, scanning electron microscopy (SEM) and Karl Fischer titration revealed that freezing parameters significantly influenced pore structure and residual moisture content. Samples with smaller pores displayed lower residual moisture, as larger surface areas facilitate moisture desorption. Variations in freezing parameters also significantly impacted desorption kinetics during secondary drying. Slower crystallization rates led to more cracks and less shrinkage in the cake structure, while faster rates resulted in more uniform, stable cakes. Although specific to the product under study, these findings highlight the crucial role of spin-freezing in enhancing freeze-drying efficiency and product quality of biopharmaceuticals.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106963"},"PeriodicalIF":4.3,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biophysical insight into the interaction mechanism of 4-bromo-N-(thiazol-2-yl)benzenesulfonamide and human serum albumin using multi-spectroscopic and computational studies","authors":"Francis Ayimbila ,&nbsp;Kamonrat Phopin ,&nbsp;Waralee Ruankham ,&nbsp;Ratchanok Pingaew ,&nbsp;Supaluk Prachayasittikul ,&nbsp;Virapong Prachayasittikul ,&nbsp;Tanawut Tantimongcolwat","doi":"10.1016/j.ejps.2024.106961","DOIUrl":"10.1016/j.ejps.2024.106961","url":null,"abstract":"<div><div>4-Bromo-<em>N</em>-(thiazol-2-yl)benzenesulfonamide (<strong>1</strong>) is enriched with bioactive components and is highlighted for its pharmacological properties. However, its pharmacokinetic characteristics are yet to be reported. The interaction of compound <strong>1</strong> with carrier proteins in the bloodstream is an important factor that affects its potential therapeutic efficacy. This study aimed to elucidate the pharmacokinetic mechanisms of compound <strong>1</strong> in relation to human serum albumin (HSA) using multi-spectroscopic and computational techniques. Its predicted drug-like properties revealed no mutagenicity, although potential hepatotoxicity and interactions with certain cytochrome P450 enzymes were observed. Spectroscopic analyses extensively provided the interaction between HSA and <strong>1</strong> through a static fluorescence quenching mechanism with spontaneous hydrophobic interactions and hydrogen bonding. The binding constant of the HSA‒<strong>1</strong> complex was relatively moderate to strong at a level of 10⁶ M⁻¹. Various spectroscopic techniques including ultraviolet-visible, Fourier transform infrared, and circular dichroism spectroscopies indicated that its binding induced alteration in the α-helix content of HSA. Competitive binding and molecular docking studies designated the preferential binding of <strong>1</strong> to sub-structural domain IIA binding site I of HSA. Molecular dynamic simulations further illustrated the formation of a stable complex between <strong>1</strong> and HSA, accompanied by conformational changes in the protein. Importantly, esterase capacity of the HSA‒<strong>1</strong> complex increased compared to the free HSA. Therefore, elucidation of the HSA‒<strong>1</strong> binding mechanism provides valuable insights into the pharmacokinetics, suggesting potential benefits for the further development of <strong>1</strong> as a therapeutic agent.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"204 ","pages":"Article 106961"},"PeriodicalIF":4.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}