Pub Date : 2026-03-01Epub Date: 2026-01-25DOI: 10.1016/j.ejps.2026.107452
Hong Shao , Wen Li , Zhuohan Li , Peng Shi , Zheng Li , Yuxiang Wang , Chao Pi , Lingmao Zhao , Wenwu Zheng , Yumeng Wei , Ling Zhao
Tegafur (FT) is widely used in the treatment of breast cancer. However, it has poor efficacy and significant toxic side effects. In this study, we first modified FT with aspirin to obtain a new FT derivative, named TAK5399. Then, TAK5399 in situ thermosensitive gel (TAK5399-TSG) was prepared using poloxamer F68 and F127 as carriers, and evaluated in vitro and in vivo. Among the five tested tumor cell lines, TAK5399 exhibited the highest sensitivity toward human breast cancer cells (MCF-7), with an inhibition rate 8.41 times higher than that of FT. Its potential anti-breast cancer mechanism may be related to inhibiting the PI3K/AKT signaling pathway to induce apoptosis and blocking the S phase of the cell cycle. The optimal formulation process for TAK5399-TSG is F127: 24.0%, F68: 6.5%, TAK5399 content of 1.25 mg/mL, and curing time of 24 hours. The maximum drug solubility, gelation temperature, and dissolution time were 1.25 mg/mL, 31 ± 0.21°C, and 6.5 ± 0.25 h, respectively. The Cmax of TAK5399-TSG administered via in situ injection was 15.5% and 23.8% of that of oral and in situ injection of TAK5399, respectively. In tumor-bearing mice, the tumor inhibition rates of oral TAK5399 and in situ injection of TAK5399-TSG were 1.28-fold and 1.82-fold higher than those of oral FT, respectively, with good biocompatibility. In conclusion, TAK5399-TSG is an in situ gel delivery system with potential for the treatment of breast cancer.
{"title":"Construction of in situ temperature-sensitive gel of Tegafur derivative TAK5399 and its evaluation against breast cancer","authors":"Hong Shao , Wen Li , Zhuohan Li , Peng Shi , Zheng Li , Yuxiang Wang , Chao Pi , Lingmao Zhao , Wenwu Zheng , Yumeng Wei , Ling Zhao","doi":"10.1016/j.ejps.2026.107452","DOIUrl":"10.1016/j.ejps.2026.107452","url":null,"abstract":"<div><div>Tegafur (FT) is widely used in the treatment of breast cancer. However, it has poor efficacy and significant toxic side effects. In this study, we first modified FT with aspirin to obtain a new FT derivative, named TAK5399. Then, TAK5399 in situ thermosensitive gel (TAK5399-TSG) was prepared using poloxamer F68 and F127 as carriers, and evaluated in vitro and in vivo. Among the five tested tumor cell lines, TAK5399 exhibited the highest sensitivity toward human breast cancer cells (MCF-7), with an inhibition rate 8.41 times higher than that of FT. Its potential anti-breast cancer mechanism may be related to inhibiting the PI3K/AKT signaling pathway to induce apoptosis and blocking the S phase of the cell cycle. The optimal formulation process for TAK5399-TSG is F127: 24.0%, F68: 6.5%, TAK5399 content of 1.25 mg/mL, and curing time of 24 hours. The maximum drug solubility, gelation temperature, and dissolution time were 1.25 mg/mL, 31 ± 0.21°C, and 6.5 ± 0.25 h, respectively. The Cmax of TAK5399-TSG administered via in situ injection was 15.5% and 23.8% of that of oral and in situ injection of TAK5399, respectively. In tumor-bearing mice, the tumor inhibition rates of oral TAK5399 and in situ injection of TAK5399-TSG were 1.28-fold and 1.82-fold higher than those of oral FT, respectively, with good biocompatibility. In conclusion, TAK5399-TSG is an in situ gel delivery system with potential for the treatment of breast cancer.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107452"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146061204","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}
Pub Date : 2026-03-01Epub Date: 2025-12-28DOI: 10.1016/j.ejps.2025.107424
Praveen Kumar Singh , Matej Zore , Paola San-Martin-Galindo , Moritz M. Kornmayer , Inés Reigada , Leena Hanski , Kirsi Savijoki , Jari Yli-Kauhaluoma , Jayendra Z. Patel
Febuxostat, a marketed anti-gout drug, has been reported to inhibit quorum sensing (QS), biofilm formation, and virulence in Gram-negative bacteria Pseudomonas aeruginosa PAO1 and Chromobacterium violaceum CV026. However, no structure-activity relationship (SAR) studies have been reported to date. To address this gap, we synthesized 27 novel febuxostat analogs and evaluated their QS inhibitory activity using wild-type C. violaceum and the mutant strain CV026. This dual-strain assay enabled differentiation between quorum sensing inhibition and quorum quenching mechanisms, allowing determination of whether QS interference occurred at the level of signal synthesis or signal reception.
Here, we demonstrated that febuxostat acts as a quorum quencher at concentrations lower than previously reported, strongly inhibiting violacein production in CV026 without affecting bacterial viability. At 400 µM, several analogs showed comparable or stronger activity than febuxostat in one or both strains. At 40 µM, trifluoromethoxyphenyl analog 49 emerged as the most effective QS inhibitor in the wild-type strain, whereas cyclopentyl analog 24 was most active in CV026, with a few other derivatives also retaining notable activity. We also assessed whether febuxostat and its analogs exhibit antibacterial activity. While febuxostat showed no antibacterial activity, seven analogs (26–30, 33, and 49) exhibited minimum inhibitory concentrations (MICs) ranging from 2.5 to 40 µM against Gram-positive bacteria Staphylococcus aureus, S. epidermidis, Enterococcus faecalis, and E. faecium. On the other hand, no activity was observed against Gram-negative bacteria. In follow-up studies, the two most potent antibacterial compounds 29 (MIC = 5 µM) and 30 (MIC = 10 µM), showed no cytotoxicity against the mammalian cell line A549, while they were less tolerated by THP-1 cells. In summary, our results provide SAR insights into febuxostat analogs and highlight their potential as novel anti-QS and antibacterial agents against multidrug-resistant bacteria.
{"title":"Febuxostat analogs as anti-quorum sensing and antibacterial agents","authors":"Praveen Kumar Singh , Matej Zore , Paola San-Martin-Galindo , Moritz M. Kornmayer , Inés Reigada , Leena Hanski , Kirsi Savijoki , Jari Yli-Kauhaluoma , Jayendra Z. Patel","doi":"10.1016/j.ejps.2025.107424","DOIUrl":"10.1016/j.ejps.2025.107424","url":null,"abstract":"<div><div>Febuxostat, a marketed anti-gout drug, has been reported to inhibit quorum sensing (QS), biofilm formation, and virulence in Gram-negative bacteria <em>Pseudomonas aeruginos</em>a PAO1 and <em>Chromobacterium violaceum</em> CV026. However, no structure-activity relationship (SAR) studies have been reported to date. To address this gap, we synthesized 27 novel febuxostat analogs and evaluated their QS inhibitory activity using wild-type <em>C. violaceum</em> and the mutant strain CV026. This dual-strain assay enabled differentiation between quorum sensing inhibition and quorum quenching mechanisms, allowing determination of whether QS interference occurred at the level of signal synthesis or signal reception.</div><div>Here, we demonstrated that febuxostat acts as a quorum quencher at concentrations lower than previously reported, strongly inhibiting violacein production in CV026 without affecting bacterial viability. At 400 µM, several analogs showed comparable or stronger activity than febuxostat in one or both strains. At 40 µM, trifluoromethoxyphenyl analog <strong>49</strong> emerged as the most effective QS inhibitor in the wild-type strain, whereas cyclopentyl analog <strong>24</strong> was most active in CV026, with a few other derivatives also retaining notable activity. We also assessed whether febuxostat and its analogs exhibit antibacterial activity. While febuxostat showed no antibacterial activity, seven analogs (<strong>26</strong>–<strong>30, 33</strong>, and <strong>49</strong>) exhibited minimum inhibitory concentrations (MICs) ranging from 2.5 to 40 µM against Gram-positive bacteria <em>Staphylococcus aureus, S. epidermidis, Enterococcus faecalis</em>, and <em>E. faecium</em>. On the other hand, no activity was observed against Gram-negative bacteria. In follow-up studies, the two most potent antibacterial compounds <strong>29</strong> (MIC = 5 µM) and <strong>30</strong> (MIC = 10 µM), showed no cytotoxicity against the mammalian cell line A549, while they were less tolerated by THP-1 cells. In summary, our results provide SAR insights into febuxostat analogs and highlight their potential as novel anti-QS and antibacterial agents against multidrug-resistant bacteria.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107424"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862528","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}
Pub Date : 2026-03-01Epub Date: 2026-01-17DOI: 10.1016/j.ejps.2026.107447
Jihad Mahmoud Alsofany , Soha Osama Hassanin , Ahmad S. Kodous , Mohammed Aufy , Maha O. Mahmoud , Islam M. Adel , Mohamed A. El-Nabarawi , Eman Abdelhakeem
Griseofulvin, a potent antifungal drug, has recently demonstrated potential anticancer activity in mammalian cancer cells. This study aims to comprehensively investigate the anti-cancer potential of griseofulvin encapsulated into nanospanlastics, focusing on enhanced cellular uptake, selectivity, and robust activation of multiple apoptotic pathways. Griseofulvin nanospanlastics were fabricated using a 23 full factorial experimental design with Span 60 as the non-ionic surfactant and Tween 80 as the edge activator. Nanospanlastics were characterized for vesicle size, size distribution, zeta potential, and entrapment efficiency. The statistically optimized formulation was selected for further physical characterization and investigation of its anticancer potential via cytotoxicity, selectivity assays, and analysis of molecular pathways (p53, Bax/Bcl-2, caspase 3, pAKT, VEGFR2, ROS). The optimized formulation exhibited circular morphology without any aggregation, 143.5±15.56 nm vesicle size, 0.739±0.021 size distribution, -30±0.99 mV zeta potential, 89.07±0.11 % entrapment efficiency, and 30.2±0.14 g deformability index. In vitro drug release showed an improved drug dissolution rate, critical for cellular uptake. The optimized formulation attained exceptional therapeutic activity with a 2.29-fold improvement in cytotoxicity and an 8.1-fold enhancement in cancer cell selectivity compared to the free drug solution, while simultaneously modulating critical molecular pathways including p53 activation, Bax/Bcl-2, caspase 3, phosphorylated AKT (pAKT) inhibition, and VEGFR2. Most surprisingly, the study revealed an unexpected reduction in reactive oxygen species (ROS) levels, challenging conventional therapeutic paradigms and highlighting novel "redox paradox" mechanisms in cancer treatment. This comprehensive investigation highlights the remarkable apoptotic potential of nanosized griseofulvin, driven by enhanced cellular uptake, superior selectivity, and robust activation of multiple apoptotic pathways.
{"title":"From fungistatic to cytotoxic: Nano-engineered griseofulvin triggers redox-mediated apoptosis in colon cancer","authors":"Jihad Mahmoud Alsofany , Soha Osama Hassanin , Ahmad S. Kodous , Mohammed Aufy , Maha O. Mahmoud , Islam M. Adel , Mohamed A. El-Nabarawi , Eman Abdelhakeem","doi":"10.1016/j.ejps.2026.107447","DOIUrl":"10.1016/j.ejps.2026.107447","url":null,"abstract":"<div><div>Griseofulvin, a potent antifungal drug, has recently demonstrated potential anticancer activity in mammalian cancer cells. This study aims to comprehensively investigate the anti-cancer potential of griseofulvin encapsulated into nanospanlastics, focusing on enhanced cellular uptake, selectivity, and robust activation of multiple apoptotic pathways. Griseofulvin nanospanlastics were fabricated using a 2<sup>3</sup> full factorial experimental design with Span 60 as the non-ionic surfactant and Tween 80 as the edge activator. Nanospanlastics were characterized for vesicle size, size distribution, zeta potential, and entrapment efficiency. The statistically optimized formulation was selected for further physical characterization and investigation of its anticancer potential via cytotoxicity, selectivity assays, and analysis of molecular pathways (p53, Bax/Bcl-2, caspase 3, pAKT, VEGFR2, ROS). The optimized formulation exhibited circular morphology without any aggregation, 143.5±15.56 nm vesicle size, 0.739±0.021 size distribution, -30±0.99 mV zeta potential, 89.07±0.11 % entrapment efficiency, and 30.2±0.14 g deformability index. In vitro drug release showed an improved drug dissolution rate, critical for cellular uptake. The optimized formulation attained exceptional therapeutic activity with a 2.29-fold improvement in cytotoxicity and an 8.1-fold enhancement in cancer cell selectivity compared to the free drug solution, while simultaneously modulating critical molecular pathways including p53 activation, Bax/Bcl-2, caspase 3, phosphorylated AKT (pAKT) inhibition, and VEGFR2. Most surprisingly, the study revealed an unexpected reduction in reactive oxygen species (ROS) levels, challenging conventional therapeutic paradigms and highlighting novel \"redox paradox\" mechanisms in cancer treatment. This comprehensive investigation highlights the remarkable apoptotic potential of nanosized griseofulvin, driven by enhanced cellular uptake, superior selectivity, and robust activation of multiple apoptotic pathways.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107447"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003385","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}
Pub Date : 2026-03-01Epub Date: 2026-01-08DOI: 10.1016/j.ejps.2026.107434
Ming-Yao Chen , Shiue-Wei Lai , Yi-Chiao Cheng , Vijesh Kumar Yadav , Iat-Hang Fong , Kuang-Tai Kuo , Kuen-Haur Lee , Yih-Giun Cherng
Background
Lenvatinib is a first-line therapy for advanced hepatocellular carcinoma (HCC), yet the emergence of lenvatinib-tolerant persister cells (LTPCs) contributes to therapeutic failure and tumor relapse. The molecular programs that sustain this tolerant state remain insufficiently defined. Here, we investigated the role of the PPP1R15B–ATF4 stress-response axis in mediating lenvatinib tolerance and ferroptosis resistance.
Methods
LTPCs were generated from multiple HCC cell lines through continuous lenvatinib exposure and confirmed by phenotypic and molecular profiling. Transcriptomic analysis (RNA-seq) was performed to identify pathways enriched in LTPCs. Functional relevance of the PPP1R15B–ATF4–GPX4 axis was evaluated using genetic perturbation (siRNA/CRISPR) and pharmacologic inhibition. Redox homeostasis, lipid peroxidation, and ferroptosis susceptibility were assessed through biochemical and imaging assays. An LTPC xenograft mouse model was used to evaluate in vivo therapeutic efficacy.
Results
RNA-seq revealed that LTPCs exhibit robust activation of the PPP1R15B–ATF4–GPX4 signaling axis, accompanied by enhanced redox buffering and suppression of ferroptotic vulnerability. Mechanistic studies demonstrated that PPP1R15B stabilizes ATF4, which in turn transcriptionally upregulates GPX4, thereby sustaining the drug-tolerant persister phenotype. Genetic or pharmacological inhibition of PPP1R15B disrupted ATF4–GPX4 signaling, impaired redox homeostasis, increased lipid peroxidation, and effectively re-sensitised LTPCs to ferroptosis and lenvatinib. In vivo, PPP1R15B inhibition significantly reduced LTPC survival and restored lenvatinib responsiveness in xenograft models.
Conclusion
The PPP1R15B–ATF4–GPX4 axis is a key determinant of lenvatinib tolerance in HCC by orchestrating redox adaptation and ferroptosis resistance. Targeting PPP1R15B represents a promising therapeutic strategy to eliminate lenvatinib-tolerant persister cells and overcome acquired resistance in HCC.
{"title":"Targeting PPP1R15B and ATF4 axis in hepatocellular carcinoma: A novel strategy for overcoming lenvatinib-tolerant persister cells through GPX4-mediated ferroptosis induction","authors":"Ming-Yao Chen , Shiue-Wei Lai , Yi-Chiao Cheng , Vijesh Kumar Yadav , Iat-Hang Fong , Kuang-Tai Kuo , Kuen-Haur Lee , Yih-Giun Cherng","doi":"10.1016/j.ejps.2026.107434","DOIUrl":"10.1016/j.ejps.2026.107434","url":null,"abstract":"<div><h3>Background</h3><div>Lenvatinib is a first-line therapy for advanced hepatocellular carcinoma (HCC), yet the emergence of lenvatinib-tolerant persister cells (LTPCs) contributes to therapeutic failure and tumor relapse. The molecular programs that sustain this tolerant state remain insufficiently defined. Here, we investigated the role of the PPP1R15B–ATF4 stress-response axis in mediating lenvatinib tolerance and ferroptosis resistance.</div></div><div><h3>Methods</h3><div>LTPCs were generated from multiple HCC cell lines through continuous lenvatinib exposure and confirmed by phenotypic and molecular profiling. Transcriptomic analysis (RNA-seq) was performed to identify pathways enriched in LTPCs. Functional relevance of the PPP1R15B–ATF4–GPX4 axis was evaluated using genetic perturbation (siRNA/CRISPR) and pharmacologic inhibition. Redox homeostasis, lipid peroxidation, and ferroptosis susceptibility were assessed through biochemical and imaging assays. An LTPC xenograft mouse model was used to evaluate in vivo therapeutic efficacy.</div></div><div><h3>Results</h3><div>RNA-seq revealed that LTPCs exhibit robust activation of the PPP1R15B–ATF4–GPX4 signaling axis, accompanied by enhanced redox buffering and suppression of ferroptotic vulnerability. Mechanistic studies demonstrated that PPP1R15B stabilizes ATF4, which in turn transcriptionally upregulates GPX4, thereby sustaining the drug-tolerant persister phenotype. Genetic or pharmacological inhibition of PPP1R15B disrupted ATF4–GPX4 signaling, impaired redox homeostasis, increased lipid peroxidation, and effectively re-sensitised LTPCs to ferroptosis and lenvatinib. <em>In vivo</em>, PPP1R15B inhibition significantly reduced LTPC survival and restored lenvatinib responsiveness in xenograft models.</div></div><div><h3>Conclusion</h3><div>The PPP1R15B–ATF4–GPX4 axis is a key determinant of lenvatinib tolerance in HCC by orchestrating redox adaptation and ferroptosis resistance. Targeting PPP1R15B represents a promising therapeutic strategy to eliminate lenvatinib-tolerant persister cells and overcome acquired resistance in HCC.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107434"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145943037","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}
FMS-like tyrosine receptor kinase 3 (FLT3) mutations have been recognized as ideal drug discovery targets for the treatment of acute myeloid leukemia (AML). Starting from the reported inhibitor 13v, we rationally designed and synthesized ZZP-2, a pyridine–pyridazine hybrid that displayed single-digit nanomolar IC₅₀ values against FLT3-ITD-positive AML cell lines (MOLM-13 and MV4–11). ZZP-2 suppressed FLT3 autophosphorylation and downstream STAT5, ERK, and AKT signaling in a concentration-dependent manner, exerting antiproliferative effects through multiple mechanisms, including apoptosis induction and cell cycle arrest. However, ZZP-2′s aqueous solubility is < 0.5 μg/mL, a very low value which may affect the rate and extent of drug absorption from suspension formulations throughout the gastrointestinal tract. To overcome this limitation, we developed an optimized nano-self-emulsifying drug-delivery system (SEDDS) that reproducibly formed fine droplets (23.77 ± 0.20 nm) upon dilution and achieved > 95 % drug loading efficiency. After oral administration, the SEDDS formulation increased the ZZP-2 plasma area under the curve (AUC0-∞) by 3.7-fold relative to a suspension formulation in Sprague-Dawley (SD) rats and significantly prolonged survival in MOLM-13-luciferase-bearing NSG mice compared to positive controls sunitinib and gilteritinib, without noticeable toxicity. Our study presents a novel FLT3-ITD inhibitor with high potency and in vivo stability.
{"title":"Design, synthesis, formulation, and bioevaluation of ZZP-2, a FLT3-ITD inhibitor for the treatment of acute myeloid leukemia","authors":"Wentao Zhu , Junhao Qiao , Xiaoyong Rao , Xiuwa Huang , Peiyu Peng , Weike Liao , Xiaojian Luo , Wei Liu","doi":"10.1016/j.ejps.2026.107440","DOIUrl":"10.1016/j.ejps.2026.107440","url":null,"abstract":"<div><div>FMS-like tyrosine receptor kinase 3 (FLT3) mutations have been recognized as ideal drug discovery targets for the treatment of acute myeloid leukemia (AML). Starting from the reported inhibitor 13v, we rationally designed and synthesized ZZP-2, a pyridine–pyridazine hybrid that displayed single-digit nanomolar IC₅₀ values against FLT3-ITD-positive AML cell lines (MOLM-13 and MV4–11). ZZP-2 suppressed FLT3 autophosphorylation and downstream STAT5, ERK, and AKT signaling in a concentration-dependent manner, exerting antiproliferative effects through multiple mechanisms, including apoptosis induction and cell cycle arrest. However, ZZP-2′s aqueous solubility is < 0.5 μg/mL, a very low value which may affect the rate and extent of drug absorption from suspension formulations throughout the gastrointestinal tract. To overcome this limitation, we developed an optimized nano-self-emulsifying drug-delivery system (SEDDS) that reproducibly formed fine droplets (23.77 ± 0.20 nm) upon dilution and achieved > 95 % drug loading efficiency. After oral administration, the SEDDS formulation increased the ZZP-2 plasma area under the curve (AUC<sub>0-∞</sub>) by 3.7-fold relative to a suspension formulation in Sprague-Dawley (SD) rats and significantly prolonged survival in MOLM-13-luciferase-bearing NSG mice compared to positive controls sunitinib and gilteritinib, without noticeable toxicity. Our study presents a novel FLT3-ITD inhibitor with high potency and <em>in vivo</em> stability.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107440"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951393","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}
Pub Date : 2026-03-01Epub Date: 2026-01-14DOI: 10.1016/j.ejps.2026.107441
Matthias Jackwerth , Severin Mairinger , Marcus Hacker , Nicolas Tournier , Markus Zeitlinger , Oliver Langer
Organic anion-transporting polypeptide 2B1 (OATP2B1/SLCO2B1) is an uptake transporter expressed in the liver and in several extrahepatic tissues, including skeletal muscle. Muscular OATP2B1 is thought to facilitate intracellular accumulation of statins, potentially contributing to statin-induced myotoxicity. To investigate functional OATP2B1 activity in vivo in human skeletal muscle, we performed positron emission tomography (PET) with the radiolabelled OATP2B1 substrate [11C]erlotinib. Nine healthy male volunteers (age: 31 ± 9 years) underwent two dynamic 60-min PET scans of the head with concurrent arterial blood sampling following intravenous injection of a microdose of [11C]erlotinib (< 10 µg). The first scan was performed without any pharmacological pre-treatment (baseline scan), whereas the second scan was performed after pre-treatment with a single oral dose of unlabelled erlotinib (650 mg), administered 3.0 ± 0.1 h before the start of the PET scan. Volumes of interest (VOIs) were manually delineated for the right and left temporal muscle surrounding the skull on co-registered PET/magnetic resonance imaging (MRI) data and averaged to generate a global temporal muscle VOI. Time-activity curves for temporal muscle and arterial plasma were analysed using a 1-tissue-2-rate constant (1T2K) compartment model and Logan graphical analysis to estimate the total volume of distribution (VT) of [11C]erlotinib (reflecting the steady-state muscle-to-plasma concentration ratio), as well as the rate constants for transfer of [11C]erlotinib from plasma to muscle (K1) and from muscle to plasma (k2). Both Logan analysis and the 1T2K model demonstrated a significant reduction in VT after erlotinib pre-treatment compared with baseline (VT Logan: baseline: 0.85 ± 0.11 mL/cm3, erlotinib: 0.70 ± 0.08 mL/cm3, −18 ± 8%, p = 0.00047; VT 1T2K: baseline: 0.83 ± 0.11 mL/cm3, erlotinib: 0.67 ± 0.07 mL/cm3, −18 ± 7%, p = 0.00033). K1 showed a trend toward reduction after erlotinib pre-treatment without reaching statistical significance, whereas k2 remained unchanged. Our findings demonstrate saturable distribution of [¹¹C]erlotinib to human skeletal muscle, consistent with functional OATP2B1 activity. These results support a mechanistic role for muscular OATP2B1 in statin-induced myotoxicity and highlight its potential broader relevance for the safety and pharmacology of other OATP2B1 substrate drugs.
{"title":"In vivo evidence of functional OATP2B1 activity in human skeletal muscle using [11C]erlotinib PET","authors":"Matthias Jackwerth , Severin Mairinger , Marcus Hacker , Nicolas Tournier , Markus Zeitlinger , Oliver Langer","doi":"10.1016/j.ejps.2026.107441","DOIUrl":"10.1016/j.ejps.2026.107441","url":null,"abstract":"<div><div>Organic anion-transporting polypeptide 2B1 (OATP2B1/SLCO2B1) is an uptake transporter expressed in the liver and in several extrahepatic tissues, including skeletal muscle. Muscular OATP2B1 is thought to facilitate intracellular accumulation of statins, potentially contributing to statin-induced myotoxicity. To investigate functional OATP2B1 activity <em>in vivo</em> in human skeletal muscle, we performed positron emission tomography (PET) with the radiolabelled OATP2B1 substrate [<sup>11</sup>C]erlotinib. Nine healthy male volunteers (age: 31 ± 9 years) underwent two dynamic 60-min PET scans of the head with concurrent arterial blood sampling following intravenous injection of a microdose of [<sup>11</sup>C]erlotinib (< 10 µg). The first scan was performed without any pharmacological pre-treatment (baseline scan), whereas the second scan was performed after pre-treatment with a single oral dose of unlabelled erlotinib (650 mg), administered 3.0 ± 0.1 h before the start of the PET scan. Volumes of interest (VOIs) were manually delineated for the right and left temporal muscle surrounding the skull on co-registered PET/magnetic resonance imaging (MRI) data and averaged to generate a global temporal muscle VOI. Time-activity curves for temporal muscle and arterial plasma were analysed using a 1-tissue-2-rate constant (1T2K) compartment model and Logan graphical analysis to estimate the total volume of distribution (<em>V</em><sub>T</sub>) of [<sup>11</sup>C]erlotinib (reflecting the steady-state muscle-to-plasma concentration ratio), as well as the rate constants for transfer of [<sup>11</sup>C]erlotinib from plasma to muscle (<em>K</em><sub>1</sub>) and from muscle to plasma (<em>k</em><sub>2</sub>). Both Logan analysis and the 1T2K model demonstrated a significant reduction in <em>V</em><sub>T</sub> after erlotinib pre-treatment compared with baseline (<em>V</em><sub>T Logan</sub>: baseline: 0.85 ± 0.11 mL/cm<sup>3</sup>, erlotinib: 0.70 ± 0.08 mL/cm<sup>3</sup>, −18 ± 8%, <em>p</em> = 0.00047; <em>V</em><sub>T 1T2K</sub>: baseline: 0.83 ± 0.11 mL/cm<sup>3</sup>, erlotinib: 0.67 ± 0.07 mL/cm<sup>3</sup>, −18 ± 7%, <em>p</em> = 0.00033). <em>K</em><sub>1</sub> showed a trend toward reduction after erlotinib pre-treatment without reaching statistical significance, whereas <em>k</em><sub>2</sub> remained unchanged. Our findings demonstrate saturable distribution of [¹¹C]erlotinib to human skeletal muscle, consistent with functional OATP2B1 activity. These results support a mechanistic role for muscular OATP2B1 in statin-induced myotoxicity and highlight its potential broader relevance for the safety and pharmacology of other OATP2B1 substrate drugs.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107441"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988848","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}
Pub Date : 2026-03-01Epub Date: 2026-01-02DOI: 10.1016/j.ejps.2026.107427
Sofie Heylen , Johan Nicolaï , Stijn Van Asten , Katie De Wagter , Andrea Treyer , Jan Snoeys , Raymond Evers , Stephanie Kourula , Pieter Annaert
In vitro to in vivo extrapolation (IVIVE) methods for hepatic clearance (CLH) prediction often underpredict, partly due to reliance on mathematical liver disposition models such as the well-stirred model (WSM) or parallel tube model (PTM). The ex vivo isolated perfused rat liver (IPRL) model bridges in vitro and in vivo data, providing mechanistic insights into the predictive accuracy of IVIVE models. This study evaluates the IPRL model across a diverse selection of 16 compounds, and benchmarks results against in vitro and in vivo data to verify the predictive performance of the WSM and PTM. Results demonstrate that both the IPRL and in vivo clearance conflict with assumptions of the WSM (AAFE = 2.85) or PTM (AAFE = 1.74), which consider the liver outlet concentration as a driver for the hepatic elimination rate. However, except for terfenadine, IPRL clearance predictions were within two-fold (AAFE = 1.59) of in vivo clearance when the liver inlet concentration was utilized to calculate the CLH. When employing the WSM or PTM for in vitro to ex vivo extrapolation, underpredictions were observed for compounds with high plasma protein binding and subject to sinusoidal hepatic uptake, reflecting model oversimplification compared to in vivo dynamics. Our findings experimentally challenge the theoretical assumptions underlying the use of the WSM and PTM in IVIVE methods. Unique insights from the IPRL model point to the next steps needed to advance IVIVE: refining current liver disposition models through enhanced and next-generation in vitro assays, capturing dynamic in vivo disposition mechanisms, and exploring complementary models.
{"title":"Deconvoluting the in vitro to in vivo drug clearance gap: Questioning the predictive performance of traditional hepatic clearance models","authors":"Sofie Heylen , Johan Nicolaï , Stijn Van Asten , Katie De Wagter , Andrea Treyer , Jan Snoeys , Raymond Evers , Stephanie Kourula , Pieter Annaert","doi":"10.1016/j.ejps.2026.107427","DOIUrl":"10.1016/j.ejps.2026.107427","url":null,"abstract":"<div><div><em>In vitro</em> to <em>in vivo</em> extrapolation (IVIVE) methods for hepatic clearance (CL<sub>H</sub>) prediction often underpredict, partly due to reliance on mathematical liver disposition models such as the well-stirred model (WSM) or parallel tube model (PTM). The <em>ex vivo</em> isolated perfused rat liver (IPRL) model bridges <em>in vitro</em> and <em>in vivo</em> data, providing mechanistic insights into the predictive accuracy of IVIVE models. This study evaluates the IPRL model across a diverse selection of 16 compounds, and benchmarks results against <em>in vitro</em> and <em>in vivo</em> data to verify the predictive performance of the WSM and PTM. Results demonstrate that both the IPRL and <em>in vivo</em> clearance conflict with assumptions of the WSM (AAFE = 2.85) or PTM (AAFE = 1.74), which consider the liver outlet concentration as a driver for the hepatic elimination rate. However, except for terfenadine, IPRL clearance predictions were within two-fold (AAFE = 1.59) of <em>in vivo</em> clearance when the liver inlet concentration was utilized to calculate the CL<sub>H</sub>. When employing the WSM or PTM for <em>in vitro</em> to <em>ex vivo</em> extrapolation, underpredictions were observed for compounds with high plasma protein binding and subject to sinusoidal hepatic uptake, reflecting model oversimplification compared to <em>in vivo</em> dynamics. Our findings experimentally challenge the theoretical assumptions underlying the use of the WSM and PTM in IVIVE methods. Unique insights from the IPRL model point to the next steps needed to advance IVIVE: refining current liver disposition models through enhanced and next-generation <em>in vitro</em> assays, capturing dynamic <em>in vivo</em> disposition mechanisms, and exploring complementary models.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107427"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899620","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}
Pub Date : 2026-03-01Epub Date: 2026-01-15DOI: 10.1016/j.ejps.2026.107445
Maria Rautamo , Hanna M. Tolonen , Viivi Peltoniemi , Mia Sivén
Advances in three-dimensional (3D) printing technologies have created new possibilities for pharmaceutical manufacturing in hospital setting. One of the key attributes of various 3D printing methods is their capacity for customisation, which benefit patients who require individualised doses and dosage forms. However, the regulatory landscape in Europe regarding 3D printing of pharmaceuticals remains unclear.
This study aimed to (1) survey the perceptions of European medicines authorities regarding the implementation of 3D printing technology in hospital setting, (2) assess the manufacturing process and quality considerations that influence the adoption of the new technology from regulatory standpoint and (3) examine practical collaboration models between hospital pharmacies acting as dosage form manufacturers and pharmaceutical companies acting as suppliers of equipment, material, intermediate and/or product and process development.
A subset of European medicines authorities (n = 5/27) participated in semi-structured interviews, which were guided by three predefined scenarios describing potential approaches to implementing 3D printing in hospital settings. The collected data were analysed using qualitative content analysis.
3D printing was seen as a transformative advancement in pharmaceutical manufacturing. The potential in the production of personalised medicine was identified as a valuable opportunity, whereas the primary concerns pertained the safety and quality of 3D printed pharmaceuticals. Despite the challenges in recruiting the participants, this research highlights the need for more explicit regulatory guidelines and measures to establish robust quality control that ensure the safety and efficacy of the finished products.
{"title":"Implementing printing technology in hospital pharmacy preparation – An interview study on opportunities and challenges from medicines authorities’ perspective","authors":"Maria Rautamo , Hanna M. Tolonen , Viivi Peltoniemi , Mia Sivén","doi":"10.1016/j.ejps.2026.107445","DOIUrl":"10.1016/j.ejps.2026.107445","url":null,"abstract":"<div><div>Advances in three-dimensional (3D) printing technologies have created new possibilities for pharmaceutical manufacturing in hospital setting. One of the key attributes of various 3D printing methods is their capacity for customisation, which benefit patients who require individualised doses and dosage forms. However, the regulatory landscape in Europe regarding 3D printing of pharmaceuticals remains unclear.</div><div>This study aimed to (1) survey the perceptions of European medicines authorities regarding the implementation of 3D printing technology in hospital setting, (2) assess the manufacturing process and quality considerations that influence the adoption of the new technology from regulatory standpoint and (3) examine practical collaboration models between hospital pharmacies acting as dosage form manufacturers and pharmaceutical companies acting as suppliers of equipment, material, intermediate and/or product and process development.</div><div>A subset of European medicines authorities (<em>n</em> = 5/27) participated in semi-structured interviews, which were guided by three predefined scenarios describing potential approaches to implementing 3D printing in hospital settings. The collected data were analysed using qualitative content analysis.</div><div>3D printing was seen as a transformative advancement in pharmaceutical manufacturing. The potential in the production of personalised medicine was identified as a valuable opportunity, whereas the primary concerns pertained the safety and quality of 3D printed pharmaceuticals. Despite the challenges in recruiting the participants, this research highlights the need for more explicit regulatory guidelines and measures to establish robust quality control that ensure the safety and efficacy of the finished products.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107445"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994340","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}
Pub Date : 2026-03-01Epub Date: 2026-01-22DOI: 10.1016/j.ejps.2026.107450
Claudia Giannachi , Evin Allen , Sonja Vucen , Abina Crean
The glass stability of lyophilized amorphous peptide formulations, intended for incorporation into solid oral dosage forms, require stabilisation against the challenges of manufacturing, storage and handling temperature and humidity. High glass transition temperature (Tg) polymers, polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-vinyl acetate (PVPVA), were added to insulin-sucrose formulations to enhance glass stability when exposed to temperature and humidity. Tg and onset glass transition humidity (RHg) parameters were experimentally determined as indicators of formulation glass stability with respect to temperature and humidity, respectively. A mixture design of experiment approach was employed to determine the influence of insulin, sucrose and polymer composition on formulation Tg and RHg. Statistical regression models were established to evaluate the relationship between formulation composition and the corresponding glass transition parameters, Tg and RHg. Phase separation noted for PVPVA-containing formulations, undermined regression model goodness of fit. Insulin content was shown to have a negative effect on both formulation Tg and RHg. Formulation Tg appeared to be influenced by insulin’s dynamical temperature rather than a previously reported insulin Tg value. Insulin-sucrose and insulin-polymer interactive effects resulted in increased Tg and RHg values, indicating enhanced formulation glass stability. Formulation optimization for maximized Tg and RHg identified a formulation composed of 26 % w/w insulin, 40 % w/w sucrose, and 34 % w/w PVP, with a predicted Tg of 82 °C and RHg of 60 % RH. The enhanced glass stability of the ternary insulin-sucrose-polymer formulations offers potential advantages for the manufacture, storage and handling of peptide containing oral dosage forms.
{"title":"Design of co-lyophilised ternary insulin-sucrose-polymer systems with enhanced amorphous glass stability","authors":"Claudia Giannachi , Evin Allen , Sonja Vucen , Abina Crean","doi":"10.1016/j.ejps.2026.107450","DOIUrl":"10.1016/j.ejps.2026.107450","url":null,"abstract":"<div><div>The glass stability of lyophilized amorphous peptide formulations, intended for incorporation into solid oral dosage forms, require stabilisation against the challenges of manufacturing, storage and handling temperature and humidity. High glass transition temperature (Tg) polymers, polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-vinyl acetate (PVPVA), were added to insulin-sucrose formulations to enhance glass stability when exposed to temperature and humidity. Tg and onset glass transition humidity (RHg) parameters were experimentally determined as indicators of formulation glass stability with respect to temperature and humidity, respectively. A mixture design of experiment approach was employed to determine the influence of insulin, sucrose and polymer composition on formulation Tg and RHg. Statistical regression models were established to evaluate the relationship between formulation composition and the corresponding glass transition parameters, Tg and RHg. Phase separation noted for PVPVA-containing formulations, undermined regression model goodness of fit. Insulin content was shown to have a negative effect on both formulation Tg and RHg. Formulation Tg appeared to be influenced by insulin’s dynamical temperature rather than a previously reported insulin Tg value. Insulin-sucrose and insulin-polymer interactive effects resulted in increased Tg and RHg values, indicating enhanced formulation glass stability. Formulation optimization for maximized Tg and RHg identified a formulation composed of 26 % w/w insulin, 40 % w/w sucrose, and 34 % w/w PVP, with a predicted Tg of 82 °C and RHg of 60 % RH. The enhanced glass stability of the ternary insulin-sucrose-polymer formulations offers potential advantages for the manufacture, storage and handling of peptide containing oral dosage forms.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107450"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044009","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}
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