European Journal of Pharmaceutical Sciences最新文献

{"title":"Nitrite testing in excipients – Industry best practices","authors":"Sebastian Hickert ,&nbsp;Kevin Näf ,&nbsp;Jinjian Zheng ,&nbsp;Tamas Balogh ,&nbsp;Chris D. Smith ,&nbsp;Juan Manuel Pallicer ,&nbsp;Tom van Wijk ,&nbsp;Roy Akkermans ,&nbsp;Stéphanie Thonne ,&nbsp;Giorgio Blom ,&nbsp;James Sabatowski ,&nbsp;Emma Pata ,&nbsp;Grace Kocks ,&nbsp;Gemma Packer","doi":"10.1016/j.ejps.2025.107236","DOIUrl":"10.1016/j.ejps.2025.107236","url":null,"abstract":"<div><div><em>N<img></em>Nitrosamine risk assessment and control are essential components of pharmaceutical drug development and product evaluation. Nitrites present in excipients pose a risk to vulnerable amines that are present in APIs, API impurities or other process related amines, as they can be nitrosated to form <em>N</em>-nitrosamines. Detection and quantification of nitrite in excipients is an essential undertaking within the pharmaceutical industry to inform nitrosamine risk assessment and related risk mitigation strategies. An industry consortium and Lhasa Nitrites database was established to collaborate on this challenge, share knowledge, and reduce the testing burden. This article demonstrates the existing understanding of analytical techniques within this consortium for the quantification of nitrite in excipients incorporating IC with conductivity or UV detection, Griess derivatisation (with subsequent HPLC-UV or MS/MS detection or as PCD after IC), DAN derivatisation (with FL and MS detection) and cyclamate derivatisation (with GC-FID or GC–MS detection). We aim to highlight a variety of best practices as well as detailing their techniques principles, performance characteristics and sample preparation. Utilising the nitrite results in the database has highlighted a range in LOQs of nitrite that can be achieved, as well as knowledge of the advantages and disadvantages of using each analytical technique. This publication aims to facilitate the selection of an appropriate analytical method when considering nitrite in excipient determination.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107236"},"PeriodicalIF":4.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design and Synthesis of Potent and Selective Urea-linked Benzenesulfonamide Analogs as Carbonic Anhydrase II Inhibitors","authors":"Jisoo Kim ,&nbsp;Eun Lee ,&nbsp;Daniela Vullo ,&nbsp;Chandra Bhushan Mishra ,&nbsp;Claudiu T. Supuran ,&nbsp;Raok Jeon","doi":"10.1016/j.ejps.2025.107233","DOIUrl":"10.1016/j.ejps.2025.107233","url":null,"abstract":"<div><div>The development of isoform-selective carbonic anhydrase (CA) inhibitors is an essential strategy for enhancing therapeutic efficacy, reducing off-target interactions, and minimizing side effects. Non-selective CA inhibitors like acetazolamide target multiple isoforms found in various tissues, often causing side effects such as fatigue, GI disturbances, and renal dysfunction. In contrast, selective inhibition of hCA II—the predominant isoform in the ocular ciliary body—effectively lowers intraocular pressure with improved safety, making it a targeted strategy for glaucoma treatment. Herein, we report highly selective human CA II (hCA II) inhibitors with urea-linked benzenesulfonamide scaffolds that exhibit potent and selective inhibitory activities over other isoforms. Compound <strong>8c</strong> with 3-chlorophenyl tail group demonstrated the most potent inhibitory activity with a K_i value of 4.3 nM, whereas compound <strong>8f</strong> with 3-trifluoromethylphenyl tail group displayed high potency (K_i = 8.2 nM) and exceptional selectivity toward hCA II. This selectivity was achieved through strategic elongation of the tail moiety, as determined through detailed analysis of isoform-specific residues at the outer rim of the active site. Docking studies and molecular dynamics simulations further validated the stable binding and selective recognition of these compounds by hCA II. This approach provides valuable insight and a promising foundation for the development of selective hCA II inhibitors with potential clinical applications, particularly in anti-glaucoma therapies.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107233"},"PeriodicalIF":4.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144845036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PBPK-PD model for predicting pharmacokinetics, tumor growth inhibition, and toxicity risks of topoisomerase inhibitor ADCs in mice and humans","authors":"Zehua Wang ,&nbsp;Jinwei Zhu ,&nbsp;Lan Sang ,&nbsp;Linxiu Tang ,&nbsp;Sasa Zhang ,&nbsp;Yongmei Tan ,&nbsp;Yanlin Zhao ,&nbsp;Kun Hao","doi":"10.1016/j.ejps.2025.107234","DOIUrl":"10.1016/j.ejps.2025.107234","url":null,"abstract":"<div><h3>Background</h3><div>Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies conjugated to potent cytotoxic payloads via linkers for cancer treatment. However, the ADCs are also associated with the risk of drug-induced interstitial lung disease (ILD), primarily due to off-target payload distribution.</div></div><div><h3>Objectives and Methods</h3><div>This study aimed to develop a whole-body physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model to simultaneously predict the pharmacokinetics, therapeutic efficacy and associated risks of ILD using trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) as model drugs. The model was initially validated in corresponding tumor-bearing mice and subsequently scaled up to breast cancer patients. Plasma concentrations of ADCs and their released payloads as well as progression-free survival (PFS) following treatment with the ADCs were simulated in patients using the developed PBPK-PD model.</div></div><div><h3>Results</h3><div>The results showed that most of the observed plasma concentrations of ADCs and their payloads fell within the 5th–95th percentiles derived from simulations of 1000 virtual patients, with the predicted AUC_0-t and C_max were all within 0.5-fold to 2-fold of the observations. The predicted PFS values were also consistent with clinical observations. Data from Sobol’ global sensitivity analysis showed that tumor surface antigen expression levels and the internalization rate of the antigen-ADC complex are the primary factors influencing ADCs distribution. A relationship between payload concentration in lungs and the risk of ILD was also documented, showing that the risk increased with advancing patient age and elevated dosage.</div></div><div><h3>Conclusions</h3><div>All these results give a conclusion that the developed PBPK-PD model may be applied to predict the pharmacokinetics and therapeutical efficacy of T-DXd and SG as well as risk of ILD.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107234"},"PeriodicalIF":4.7,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144845037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel combined lipolysis-permeation screening approach in 96-well format: Method development using type I lipid-based formulations","authors":"Felix Paulus ,&nbsp;René Holm ,&nbsp;Jef Stappaerts ,&nbsp;Martin Brandl ,&nbsp;Ann-Christin Jacobsen ,&nbsp;Annette Bauer-Brandl","doi":"10.1016/j.ejps.2025.107232","DOIUrl":"10.1016/j.ejps.2025.107232","url":null,"abstract":"<div><div>For release testing of lipid-based formulations (LBFs), lipid digestion using the pH-stat approach is widely used despite the fact that it is a laborious exercise and predictivity towards <em>in vivo</em> performance could not be demonstrated. A probable reason is the lack of differentiation between readily absorbable (molecularly dissolved) and less absorbable (colloid associated) drug fractions. This work describes the development and testing of an alternative approach designed to address both issues of the pH-stat method, the labor-intensive nature and the limited ability to estimate <em>in vivo</em> behavior. The proposed solution involves combined lipolysis-permeation testing on 96-well microtiter sandwich plates.</div><div>In this new time-efficient and material-sparing approach, a highly buffered lipolysis medium was used in the donor chamber to avoid the need for pH stabilization by titration. Moreover, the method was optimized to minimize non-specific adsorption of cinnarizine to the plates and polytetrafluoroethylene (PTFE)-coated stirring bars.</div><div>The predictive power of the new high throughput screening (HTS) to estimate <em>in vivo</em> oral bioavailability of cinnarizine-loaded type I LBFs was evaluated against recent oral bioavailability data of the very same formulations in rats and compared to <em>in vitro</em> data generated by the pH-stat lipolysis approach. The following variables were studied: supersaturation, lipase inhibition, lipid chain length, and presence of an amphiphilic polymer (precipitation inhibitor).</div><div>While the HTS method correctly captured the <em>in vivo</em> impact of both supersaturation and lipase inhibition for all formulations, the pH-stat method revealed opposite trends for one out of four combinations in each formulation sets. <em>In vivo</em> there had been no effect observed for lipid chain length nor presence of the amphiphilic polymer. In contrast, both <em>in vitro</em> approaches wrongly predicted such effects in some cases. A better prediction for the long-chain systems was found with the HTS method as with the laborious pH-stat approach. The HTS lipolysis-permeation method can test multiple formulations in the 96-well plate format within hours and gave IVIVCs of up to 0.91 for grouped type I LBFs. In particular the <em>in vivo</em> performance of supersaturated formulations was correctly captured. This study demonstrates that this new method represents a promising alternative to existing tools for prediction of the <em>in vivo</em> performance of type I LBFs.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107232"},"PeriodicalIF":4.7,"publicationDate":"2025-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of formulation composition and flow conditions on the robustness of semisolid extrusion 3D printing: a case study on poorly water-soluble itraconazole for oral dosage form production","authors":"Atte Junnila ,&nbsp;Oskari Henriksson ,&nbsp;Ardaneh Fatemeh ,&nbsp;Eero Immonen ,&nbsp;Maha F. Emam ,&nbsp;Marianna Kemell ,&nbsp;Nikolaos Pahimanolis ,&nbsp;Kirsi Mikkonen ,&nbsp;Jouni Hirvonen ,&nbsp;Tapani Viitala ,&nbsp;Anssi-Pekka Karttunen ,&nbsp;Leena Peltonen","doi":"10.1016/j.ejps.2025.107230","DOIUrl":"10.1016/j.ejps.2025.107230","url":null,"abstract":"<div><div>Semisolid extrusion 3D printing is a manufacturing method that has shown promising results in precise production of patient specific dosage forms. Drug nanocrystals, where the particle size of the drug is in the nanometer range, is an attractive formulation strategy for improving the bioavailability of poorly water-soluble drugs. However, because nanocrystals remain suspended in the semisolid extrusion 3D printing formulation, dispensing of the material might be adversely affected by these particles. Currently, the effect of suspended drug nanocrystals on the semisolid extrusion dispensing precision is not well understood. In this study, dispensing precision was evaluated by analysing the weight variation during semisolid extrusion 3D printing. The formulation base, where itraconazole nanocrystals and nanofibrillated cellulose were added, consisted of polyethylene glycol, hydroxypropyl methylcellulose, and water. It was discovered that nanocrystals improved the dispensing precision compared to the nanocrystal free formulation base. Additionally, nanofibrillated cellulose could be combined with nanocrystals to improve the dispensing precision even further. The dispensing precision of the formulations was found to be linked with the viscosity at the high shear rate region. In conclusion, the data suggests that drug nanocrystal containing oral dosage forms can be precisely manufactured using semisolid extrusion 3D printing, without major indication of drug nanocrystals adversely affecting the dispensing process.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107230"},"PeriodicalIF":4.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preparation and characterization of a secnidazole-mandelic acid coamorphous system: enhanced dissolution profile, antibacterial properties, and theoretical druglikeness assessment","authors":"João G. de Oliveira Neto ,&nbsp;Ana B.N. Moreira ,&nbsp;Ayslla C. Moura ,&nbsp;Jailton R. Viana ,&nbsp;Mateus R. Lage ,&nbsp;Eliana B. Souto ,&nbsp;Rossano Lang ,&nbsp;Adenilson O. dos Santos","doi":"10.1016/j.ejps.2025.107231","DOIUrl":"10.1016/j.ejps.2025.107231","url":null,"abstract":"<div><div>This work describes the successful preparation of the first secnidazole (SNZ) coamorphous system using mandelic acid (MND) as a coformer via the slow solvent evaporation method, aiming to develop improved antimicrobial dosage forms. The coamorphous nature of the SNZ-MND system was confirmed by powder X-ray diffraction (PXRD), which revealed that the 1:1 ratio remained stable and amorphous for over 180 days. Its hygroscopicity and the structural, spectroscopic, and thermal properties were thoroughly investigated, supported by computational calculations, including Hirshfeld surface analysis, density functional theory (DFT), and <em>in silico</em> pharmacokinetic simulations. DFT calculations in the gas phase and ethanol provided insights into the thermodynamic, geometric, electronic, and vibrational parameters of the SNZ-MND heterodimer. The optimized geometry indicated that a hydrogen bond between the imidazole ring of SNZ and the carboxylic group of MND is a key stabilizing interaction. Thermodynamic data confirmed the spontaneity of this interaction, with an interaction energy of -2.02 kcal/mol in the gas phase. Vibrational modes were securely assigned by correlating experimental and calculated infrared spectra. Thermoanalytical analysis revealed a glass transition temperature of 106.5 °C, highlighting the system's thermostructural stability. Dissolution studies in phosphate buffer (pH 6.80) showed that the SNZ-MND coamorphous system exhibits a 1.22-fold higher dissolution rate than crystalline SNZ, a critical factor for bioavailability. The final plateau concentrations reflected the experimental setup under sink conditions. Similarly, apparent solubility measurements indicated a 22 % (39.5 ± 1.2 mg/mL) increase in dissolved concentration compared to the crystalline form of the drug. Importantly, the SNZ-MND (1:1) coamorphous system exhibited enhanced antibacterial activity against <em>Staphylococcus aureus, Klebsiella pneumoniae</em>, and <em>Pseudomonas aeruginosa</em> compared to the isolated compounds. These findings underscore the potential of the newly developed SNZ-MND coamorphous system as a promising antimicrobial binary composition with improved physicochemical and biological properties to be used in pharmaceutical dosage forms.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107231"},"PeriodicalIF":4.7,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144816143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of an oral versus intranasal delivered formulation of the phosphodiesterase type 5 inhibitor vardenafil in healthy men – a phase 1, randomized, open-label, single-dose, two-period, two-treatment, cross-over study","authors":"Eric Chung ,&nbsp;Christopher Argent ,&nbsp;Geoff Strange","doi":"10.1016/j.ejps.2025.107226","DOIUrl":"10.1016/j.ejps.2025.107226","url":null,"abstract":"<div><h3>Background</h3><div>Oral therapy with the PDE₅ inhibitor vardenafil is an effective, but imperfect treatment for erectile dysfunction (ED). We compared the pharmacokinetics of a new intranasal formulation of vardenafil with an oral tablet equivalent in healthy men.</div></div><div><h3>Methods &amp; Materials</h3><div>In this Phase 1, single-dose, randomized, open-label, 2-treatment, 2-period crossover study, 19 healthy men (mean age 30.2 ± 5.7 years) were randomized to receive SDS-089 nasal spray or an oral tablet of vardenafil (delivering 5 mg and 10 mg respectively). After 3-days washout, treatment was reversed. The primary outcome was the bioavailability of vardenafil. Standard pharmacokinetic parameters were computed from the individual plasma concentrations of 18 study participants (one withdrawal). Bioequivalence was accepted if the 90% CI for pharmacokinetic parameters were contained completely within the 80 to 125% range.</div></div><div><h3>Results</h3><div>Following administration, Tmax vardenafil reached peak levels between 0.150 h and 0.250 h post-dose for SDS-089 Nasal Spray and between 0.500 h and 2.500 h post-dose for Vardenafil Tablet. Exposure and maximum plasma concentration of vardenafil were higher for the oral (mean AUC0-t 42.17±25.79 h*ng/mL, mean C_max 16.74±14.50 ng/mL) versus intranasal formulation (mean AUC0-t 23.10±14.88 h*ng/mL, mean C_max 12.89±9.07 ng/mL). Mean dose normalized values for AUC0-t were 4.62±2.98 versus 4.22±2.58 h*ng/mL/mg and mean dose normalized values for C_max 2.58± 1.81 versus 1.67±1.45 ng/mL/mg for the nasal versus oral formulations, respectively. T_max was shorter (0.17 h, range 0.15–0.25 h) for the nasal versus oral (0.75 h, range 0.50–2.50) formulation. The mean t_½ of vardenafil was 4.15±1.67 versus 4.23±1.44 h for the nasal and oral formulations. Parametric analysis of AUC_0-t, AUC_0-t/D, AUC_0-∞, AUC_0-∞/D, C_max, and C_max/D showed that the investigational drugs did not satisfy the bioequivalence criteria. Overall, adverse events were similar for the two formulations, with more upper-respiratory irritation occurring following intranasal administration.</div></div><div><h3>Conclusions</h3><div>In healthy men, intranasally delivered vardenafil is associated with more rapid Tmax, but similar plasma concentrations without bioequivalence being statistically proven. This differential pharmacokinetic profile has potentially important clinical implications in treating men with ED.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107226"},"PeriodicalIF":4.7,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144811921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioinspired mycobacterial lipid coating of porous particles for enhanced antimicrobial efficacy","authors":"Jesús E. Campos Pacheco ,&nbsp;Camilla Davids ,&nbsp;Tetiana Yalovenko ,&nbsp;Elin Näsström ,&nbsp;Maria Ahnlund ,&nbsp;Gabriela Godaly ,&nbsp;Sabrina Valetti","doi":"10.1016/j.ejps.2025.107225","DOIUrl":"10.1016/j.ejps.2025.107225","url":null,"abstract":"<div><div>The study aimed to investigate the unique lipid composition of Mycobacterium bovis BCG and its potential to enhance antimicrobial efficacy of lipid-coated mesoporous silica particles (MSPs). The bacterial lipids (BL) were extracted with petroleum ether and analyzed via LC-MS, revealing a complex mixture of phospholipids, including cardiolipin, phosphatidylcholine, phosphatidylethanolamine, and triacylglycerols. Lipid coating (using bacterial lipids and lung surfactant DPPC as the main component) was performed on MSPs via vesicle fusion approach and confirmed with ATR-FTIR spectroscopy. MSPs were loaded with clofazimine (CLZ), as a drug model for tuberculosis. The obtained BL-DPPC-coated CLZ-MSPs were more effective in inhibiting mycobacterial growth and killing intracellular mycobacteria compared to uncoated and DPPC-coated CLZ-MSPs. The bacterial lipids showed a good safety profile on M1-like and M2-like human primary macrophages without inducing a strong immune response or formation of foam cells. These findings suggest that the obtained bacterial lipid coatings can improve antimicrobial efficacy in treating both extracellular and intracellular mycobacteria infections directly in the lungs.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107225"},"PeriodicalIF":4.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-L1 downregulation by carbonic anhydrase IX immunotherapy prompts immune checkpoint blockade in renal cell carcinoma","authors":"Renata Schmieder Pivetta ,&nbsp;Najla Santos Pacheco de Campos ,&nbsp;Gabriela Sarti Kinker ,&nbsp;Adriano de Oliveira Beserra ,&nbsp;Wayne Anthony Marasco ,&nbsp;Tiago da Silva Medina ,&nbsp;Tiago Góss dos Santos ,&nbsp;Tiago Rodrigues ,&nbsp;Eloah Rabello Suarez","doi":"10.1016/j.ejps.2025.107190","DOIUrl":"10.1016/j.ejps.2025.107190","url":null,"abstract":"<div><div>The carbonic anhydrase IX (CAIX) expression occurs in most cases of clear cell renal cell carcinoma (ccRCC). This tumor type is characterized by an immunosuppressive microenvironment, where approximately one-fourth of patients overexpress the programmed cell death ligand-1 (PD-L1), significantly increasing their risk of death. Herein, we present a secondary effect of CAIX inhibition using monoclonal antibodies (mAbs) and CAR T cells, leading to PD-L1 downregulation in ccRCC and in vivo immune checkpoint blockade<em>.</em> We identified a positive correlation between CAIX and PD-L1 expression in ccRCC cell lines using <em>in silico</em> RNA-seq data analysis, prompting us to perform fluorescence-activated cell sorting of SKRC52 ccRCC cell subpopulations based on their positive or negative expression of CAIX and PD-L1. After two weeks in culture, the cell population selected to be negative for CAIX and positive for PD-L1 became negative for CAIX and PD-L1. To explore the phenomenon, CAIX blockade was performed using two anti-CAIX monoclonal antibodies (mAbs) in multiple doses in two CAIX+ PD-L1+ clear cell renal cell carcinoma (ccRCC) cell lines. The expression of CAIX and PD-L1 decreased after treatment with the mAbs, and the PI3K/Akt signaling pathway is involved in this modulation. CAIX-targeted CAR T cells in vivo also reduced PD-L1 expression, resulting in superior CD3 infiltration and granzyme B expression, which decreased T cell exhaustion. Our findings demonstrate that CAIX-targeted immunotherapies can induce an indirect immune checkpoint blockade by PD-L1 downregulation.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107190"},"PeriodicalIF":4.7,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trehalose-stabilized micelle-in-microparticles of icariin targeting IL-4 pathway in chronic obstructive pulmonary disease","authors":"Chengwei Jiang,&nbsp;Satyanarayana Somavarapu","doi":"10.1016/j.ejps.2025.107223","DOIUrl":"10.1016/j.ejps.2025.107223","url":null,"abstract":"<div><div>Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory airway disorder with limited therapeutic strategies capable of addressing its underlying immunopathology. Icariin (ICA), a flavonoid with documented anti-inflammatory and antioxidant activity, exhibits mechanistic relevance to COPD pathology but is limited in clinical utility due to poor aqueous solubility and low systemic bioavailability. This study reports the development of a dry powder inhalation system comprising DSPE-PEG2000/DPPC micelle-in-microparticles stabilized with trehalose for targeted pulmonary delivery of ICA. Spray-drying produced respirable microparticles with a mass median aerodynamic diameter of 2.36 ± 0.3 µm, an emitted dose of 93 %, and a fine particle fraction of 44 %, consistent with efficient deposition in the lower respiratory tract. Physicochemical characterization confirmed ICA encapsulation in an amorphous state, with preservation of micellar structure upon rehydration, supporting formulation stability. <em>In vitro</em> studies demonstrated enhanced uptake of ICA-loaded micelles by RAW 264.7 macrophages and a 73 % reduction in IL-4-induced CD206 expression, indicative of inhibition of M2 macrophage polarization. These findings support the potential applicability of this inhalable system for modulating macrophage-mediated inflammation in COPD. <em>In vivo</em> studies are required to evaluate pharmacokinetic behaviour, pulmonary distribution, and therapeutic efficacy in validated models of chronic obstructive pulmonary disease.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"212 ","pages":"Article 107223"},"PeriodicalIF":4.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}