Pub Date : 2026-01-07DOI: 10.1016/j.ejps.2026.107431
Zhuo Tao , Hongzhi Yu , Bin Xu , Xueming Wang , Junping Wu , Ying Wen , Tianjun Liu
Asthma, a common chronic inflammatory airway disease, affects 300 million people globally. Pathologically, it features Th2/Th17-driven airway inflammation and remodeling, which worsens disease and impairs lung function. Current therapies alleviate symptoms but cannot prevent irreversible airway structural changes, highlighting the need for targeted treatments. The TGF-β1/Smad axis is pivotal for epithelial‒mesenchymal transition (EMT) and airway fibrosis‒key features of asthmatic remodeling. This study aimed to explore the interaction between the TGF-β1/Smad pathway and EGR1 and evaluate the effect of LD4-based photodynamic therapy (LD4-PDT) as a potential anti-inflammatory agent on asthma by evaluating inflammatory cell infiltration, nitrosative and oxidative stress markers, and EMT-related substances in a rat model of asthma. Primarily, we evaluated the efficacy of LD4-PDT in ovalbumin (OVA)-induced asthmatic rats. Assessments included pulmonary function (FVC, MMF), airway histopathology, oxidative stress markers, and EMT-related proteins (TGF-β1, Smad, MMP-9). Transcriptomics identified key targets, molecular docking verified binding, and TGF-β1-stimulated BEAS-2B/16HBE cells validated mechanisms in vitro. LD4-PDT exerted dose-dependent effects: improved lung function (increased FVC/MMF), reduced inflammation (lower IgE/TNF-α), and attenuated remodeling (decreased collagen deposition and PAS+ cells). Mechanistically, it suppressed EMT by inhibiting EGR1-dependent TGF-β1/Smad signaling and modulating arachidonic acid metabolism. Transcriptomics confirmed EGR1 as a critical mediator, and molecular docking showed strong LD4-EGR1 binding—providing a molecular basis for LD4-PDT’s effects. LD4-PDT effectively targets EGR1-driven EMT, inflammation, and metabolic dysregulation, emerging as a novel therapeutic strategy for asthma.
{"title":"Novel porphyrin photosensitizer LD4-PDT alleviates asthma airway remodeling by inhibiting EGR1-dependent TGF-β1/Smad signaling","authors":"Zhuo Tao , Hongzhi Yu , Bin Xu , Xueming Wang , Junping Wu , Ying Wen , Tianjun Liu","doi":"10.1016/j.ejps.2026.107431","DOIUrl":"10.1016/j.ejps.2026.107431","url":null,"abstract":"<div><div>Asthma, a common chronic inflammatory airway disease, affects 300 million people globally. Pathologically, it features Th2/Th17-driven airway inflammation and remodeling, which worsens disease and impairs lung function. Current therapies alleviate symptoms but cannot prevent irreversible airway structural changes, highlighting the need for targeted treatments. The TGF-β1/Smad axis is pivotal for epithelial‒mesenchymal transition (EMT) and airway fibrosis‒key features of asthmatic remodeling. This study aimed to explore the interaction between the TGF-β1/Smad pathway and EGR1 and evaluate the effect of LD4-based photodynamic therapy (LD4-PDT) as a potential anti-inflammatory agent on asthma by evaluating inflammatory cell infiltration, nitrosative and oxidative stress markers, and EMT-related substances in a rat model of asthma. Primarily, we evaluated the efficacy of LD4-PDT in ovalbumin (OVA)-induced asthmatic rats. Assessments included pulmonary function (FVC, MMF), airway histopathology, oxidative stress markers, and EMT-related proteins (TGF-β1, Smad, MMP-9). Transcriptomics identified key targets, molecular docking verified binding, and TGF-β1-stimulated BEAS-2B/16HBE cells validated mechanisms in vitro. LD4-PDT exerted dose-dependent effects: improved lung function (increased FVC/MMF), reduced inflammation (lower IgE/TNF-α), and attenuated remodeling (decreased collagen deposition and PAS+ cells). Mechanistically, it suppressed EMT by inhibiting EGR1-dependent TGF-β1/Smad signaling and modulating arachidonic acid metabolism. Transcriptomics confirmed EGR1 as a critical mediator, and molecular docking showed strong LD4-EGR1 binding—providing a molecular basis for LD4-PDT’s effects. LD4-PDT effectively targets EGR1-driven EMT, inflammation, and metabolic dysregulation, emerging as a novel therapeutic strategy for asthma.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107431"},"PeriodicalIF":4.7,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941419","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 : 2026-01-06DOI: 10.1016/j.ejps.2026.107429
Meryem Kaplan , Fatma Betül Arslan , Süleyman Can Öztürk , Sıla Ulutürk , Çisel Aydın Meriçöz , Güneş Esendağlı , Sema Çalış , Kıvılcım Öztürk
Psoriasis is an inflammatory autoimmune skin disease that significantly impacts quality of life. The chronic and recurrent nature of the disease can last a lifetime. Current conventional treatment options have several drawbacks, including inadequate or short-lived efficacy, issues with tolerability and adherence, practical limitations associated with topical applications and phototherapy, and significant safety and cost concerns related to systemic treatments. Generally, symptomatic treatments are applied, but complete recovery is rarely achieved. Researchers are exploring alternative treatment approaches, such as biologically based therapies. These therapies specifically target the immune mechanisms involved in psoriasis and offer advantages such as more reliable disease control, noticeable improvements in patients’ quality of life, and a more favorable safety profile compared to conventional treatments. One innovative approach being investigated for the treatment of psoriasis is the use of microneedles as a transdermal drug delivery strategy, which has shown promising results in research. In this study, a biocompatible polymeric dissolving microneedle formulation composed of hyaluronic acid and sucrose was prepared using micro-molding. Microneedles were loaded with secukinumab (a human monoclonal antibody specific to IL-17A) and Stattic (a STAT3 inhibitor) for a combined treatment approach. It was expected that applying the microneedles directly to the psoriasis plaques would increase the localized drug concentration. Following in vitro characterization and cell culture studies, a psoriasis model was established in adult mice. The therapeutic effects of the microneedles containing secukinumab and Stattic (both individually and simultaneously loaded) were compared to control groups. Lesion progression was visually monitored and histologically examined following treatment. The results indicated that the secukinumab-loaded microneedles provided a more effective treatment at lower doses.
{"title":"Development and in vitro/in vivo evaluation of polymeric dissolving microneedle formulation for psoriasis treatment","authors":"Meryem Kaplan , Fatma Betül Arslan , Süleyman Can Öztürk , Sıla Ulutürk , Çisel Aydın Meriçöz , Güneş Esendağlı , Sema Çalış , Kıvılcım Öztürk","doi":"10.1016/j.ejps.2026.107429","DOIUrl":"10.1016/j.ejps.2026.107429","url":null,"abstract":"<div><div>Psoriasis is an inflammatory autoimmune skin disease that significantly impacts quality of life. The chronic and recurrent nature of the disease can last a lifetime. Current conventional treatment options have several drawbacks, including inadequate or short-lived efficacy, issues with tolerability and adherence, practical limitations associated with topical applications and phototherapy, and significant safety and cost concerns related to systemic treatments. Generally, symptomatic treatments are applied, but complete recovery is rarely achieved. Researchers are exploring alternative treatment approaches, such as biologically based therapies. These therapies specifically target the immune mechanisms involved in psoriasis and offer advantages such as more reliable disease control, noticeable improvements in patients’ quality of life, and a more favorable safety profile compared to conventional treatments. One innovative approach being investigated for the treatment of psoriasis is the use of microneedles as a transdermal drug delivery strategy, which has shown promising results in research. In this study, a biocompatible polymeric dissolving microneedle formulation composed of hyaluronic acid and sucrose was prepared using micro-molding. Microneedles were loaded with secukinumab (a human monoclonal antibody specific to IL-17A) and Stattic (a STAT3 inhibitor) for a combined treatment approach. It was expected that applying the microneedles directly to the psoriasis plaques would increase the localized drug concentration. Following <em>in vitro</em> characterization and cell culture studies, a psoriasis model was established in adult mice. The therapeutic effects of the microneedles containing secukinumab and Stattic (both individually and simultaneously loaded) were compared to control groups. Lesion progression was visually monitored and histologically examined following treatment. The results indicated that the secukinumab-loaded microneedles provided a more effective treatment at lower doses.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107429"},"PeriodicalIF":4.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932971","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 : 2026-01-06DOI: 10.1016/j.ejps.2026.107428
Simona Marzano , Maria Grazia Ferraro , Nicola Grasso , Rossella Buono , Valentina Arciuolo , Federica Iazzetti , Marialuisa Piccolo , Assunta Passarelli , Federica D’Aria , Francesco Merlino , Paolo Grieco , Antonio Randazzo , Bruno Pagano , Carlo Irace , Jussara Amato
AS1411 is a G-rich DNA aptamer that exhibits intrinsic antitumor activity through selective binding to nucleolin, a protein overexpressed in many cancers. Beyond its cytotoxic effects, AS1411 can also serve as an effective targeting ligand for the delivery of therapeutics with poor cellular uptake, including peptide-based drugs. One such candidate is the pro-apoptotic peptide KLA, which selectively disrupts mitochondrial membranes and induces apoptosis upon internalization. In this study, AS1411-KLA conjugates were designed and synthesized using strain-promoted azide-alkyne cycloaddition chemistry, incorporating protease-cleavable peptide linkers to enable intracellular release of both the aptamer and peptide as independent active units. Circular dichroism analysis showed that, in all constructs, the AS1411 domain preserved the characteristic G-quadruplex structural features, while surface plasmon resonance experiments revealed that all conjugates retained nucleolin binding. The biological activity of the conjugates was evaluated in MCF-7 breast cancer cells and in non-tumorigenic MCF-10A cells, and compared with that of the individual aptamer and peptide. One conjugate displayed an enhanced antiproliferative effect compared to the unconjugated components, underscoring the therapeutic potential of this modular design. Overall, this work demonstrates the potential of aptamer-peptide conjugates as a promising strategy for next-generation targeted cancer therapeutics, combining targeted delivery with synergistic therapeutic effects.
{"title":"Design and evaluation of dual-functional aptamer-peptide conjugates as a platform for targeted cancer therapy","authors":"Simona Marzano , Maria Grazia Ferraro , Nicola Grasso , Rossella Buono , Valentina Arciuolo , Federica Iazzetti , Marialuisa Piccolo , Assunta Passarelli , Federica D’Aria , Francesco Merlino , Paolo Grieco , Antonio Randazzo , Bruno Pagano , Carlo Irace , Jussara Amato","doi":"10.1016/j.ejps.2026.107428","DOIUrl":"10.1016/j.ejps.2026.107428","url":null,"abstract":"<div><div>AS1411 is a G-rich DNA aptamer that exhibits intrinsic antitumor activity through selective binding to nucleolin, a protein overexpressed in many cancers. Beyond its cytotoxic effects, AS1411 can also serve as an effective targeting ligand for the delivery of therapeutics with poor cellular uptake, including peptide-based drugs. One such candidate is the pro-apoptotic peptide KLA, which selectively disrupts mitochondrial membranes and induces apoptosis upon internalization. In this study, AS1411-KLA conjugates were designed and synthesized using strain-promoted azide-alkyne cycloaddition chemistry, incorporating protease-cleavable peptide linkers to enable intracellular release of both the aptamer and peptide as independent active units. Circular dichroism analysis showed that, in all constructs, the AS1411 domain preserved the characteristic G-quadruplex structural features, while surface plasmon resonance experiments revealed that all conjugates retained nucleolin binding. The biological activity of the conjugates was evaluated in MCF-7 breast cancer cells and in non-tumorigenic MCF-10A cells, and compared with that of the individual aptamer and peptide. One conjugate displayed an enhanced antiproliferative effect compared to the unconjugated components, underscoring the therapeutic potential of this modular design. Overall, this work demonstrates the potential of aptamer-peptide conjugates as a promising strategy for next-generation targeted cancer therapeutics, combining targeted delivery with synergistic therapeutic effects.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107428"},"PeriodicalIF":4.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932985","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 : 2026-01-02DOI: 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":"2026-01-02","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}
The purpose of this study was to evaluate how the dissolution-supersaturation-precipitation (DSP) behaviour of cocrystals translates into drug permeation, employing the biomimetic PermeaPad® barrier in a side-by-side cell set-up. Building on our previous work, which demonstrated that reducing an unnecessarily high cocrystal solubility advantage (SA = Scocrystal/Sdrug) through the generation of non-stoichiometric solution conditions can significantly extend the drug supersaturation, we now investigate this approach in the presence of an absorptive environment. Our findings with the 1:1 ketoconazole (KTZ) -p-aminobenzoic acid (PABA) cocrystal indicate the existence of an optimal SA value (7), where KTZ-PABA dissolution performance resulted in 8-fold AUC increase, translating to a 7-fold increase in cumulative KTZ permeation after 6 h. This enhancement was achieved by dissolving cocrystal (based on the drug therapeutic dose) with an additional coformer solid phase, rationally designed using a graphical approach grounded in the cocrystal thermodynamic (Ksp, Scocrystal, Sdrug) and kinetic parameters (σcrit). The strategy presented in this work can be readily applied during the pre-formulation stage of cocrystal development, enabling targeted selection of coformer concentrations for formulation development. Overall cocrystals offer unique flexibility as a formulation strategy for poorly water-soluble drugs, allowing for tailored DSP behaviour and drug transport over biological barriers based on mechanistic understanding, as demonstrated in this study.
{"title":"Impact of cocrystal dissolution-supersaturation-precipitation (DSP) behaviour on drug permeation across the PermeaPad® biomimetic barrier","authors":"Lucy May Newman , Matteo Guidetti , Annette Bauer-Brandl , Naír Rodríguez-Hornedo , Tatiane Cogo Machado","doi":"10.1016/j.ejps.2025.107426","DOIUrl":"10.1016/j.ejps.2025.107426","url":null,"abstract":"<div><div>The purpose of this study was to evaluate how the dissolution-supersaturation-precipitation (DSP) behaviour of cocrystals translates into drug permeation<strong>,</strong> employing the biomimetic PermeaPad® barrier in a side-by-side cell set-up. Building on our previous work, which demonstrated that reducing an unnecessarily high cocrystal solubility advantage (SA = S<sub>cocrystal</sub>/S<sub>drug</sub>) through the generation of non-stoichiometric solution conditions can significantly extend the drug supersaturation, we now investigate this approach in the presence of an absorptive environment. Our findings with the 1:1 ketoconazole (KTZ) -<em>p</em>-aminobenzoic acid (PABA) cocrystal indicate the existence of an optimal SA value (7), where KTZ-PABA dissolution performance resulted in 8-fold AUC increase, translating to a 7-fold increase in cumulative KTZ permeation after 6 h. This enhancement was achieved by dissolving cocrystal (based on the drug therapeutic dose) with an additional coformer solid phase, rationally designed using a graphical approach grounded in the cocrystal thermodynamic (K<sub>sp</sub>, S<sub>cocrystal</sub>, S<sub>drug</sub>) and kinetic parameters (σ<sub>crit</sub>). The strategy presented in this work can be readily applied during the pre-formulation stage of cocrystal development, enabling targeted selection of coformer concentrations for formulation development. Overall cocrystals offer unique flexibility as a formulation strategy for poorly water-soluble drugs, allowing for tailored DSP behaviour and drug transport over biological barriers based on mechanistic understanding<strong>,</strong> as demonstrated in this study.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107426"},"PeriodicalIF":4.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896350","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 : 2025-12-31DOI: 10.1016/j.ejps.2025.107425
Venkata Krishna Rao Balaga, Argyro Chatziadi, Luděk Ridvan, Miroslav Šoóš
Coamorphization is an attractive approach to modifying the physicochemical properties of drug molecules, especially the solubility, dissolution, and associated bioavailability. Although these formulations may be advantageous, they exhibit poor physical stability and undergo recrystallisation. To address this limitation, this study investigates the effect of positional isomerism on the coamorphous formation and associated physicochemical properties, to select an optimum solid form with improved stability. Enzalutamide (ENZ), a BCS class II drug, was used as a model compound. Four positional isomers including 2,3-, 2,4-, 2,5- and 2,6-dihydroxybenzoic acid (DHB) were used as coamorphous coformers. Coamorphous formulations were prepared by ball mill in a 2:1 molecular ratio (API:coformer). The solid-state properties of the prepared coamorphous forms were characterised using X-ray powder diffractometer (XRPD), modulated differential scanning calorimetry (mDSC), and Fourier transformed infrared spectrometry (FTIR). Additionally, intra isomer variability in the amorphization kinetics and dissolution enhancement of ENZ, along with physical stability, were evaluated. All coformers formed coamorphous systems, as confirmed by XRPD. mDSC data showed that the glass transition temperature (Tg) varied among the prepared coamorphous forms and was lower than that of pure ENZ. Although there was no significant difference in the dissolution behaviour, the physical stability data reveal a contrast trend. Among the prepared coamorphous forms, ENZ-24DHBCAM exhibited superior stability, while ENZ-26DHBCAM exhibited poor stability. This article summarises the similarities and differences between the physicochemical properties of coamorphous forms of Enz because of the change in coformer positional isomerism. Stability studies under different humidity conditions revealed significant differences: at 40% RH, all coamorphous forms remained stable for up to 8 weeks, with minor deviations for ENZ-23DHBCAM and ENZ-25DHBCAM. Under 75% RH, the stability varied markedly; ENZ-24DHBCAM maintained stability for at least 8 weeks, while ENZ-26DHBCAM became unstable within 1-2 weeks, and ENZ-AMP and ENZ-23DHBCAM lost stability by week 6. These results demonstrate the careful selection of coformer positional isomer can quantitatively enhance the stability of coamorphous forms, highlighting the importance of positional isomerism associated chemical design space in optimizing solid-state properties.
{"title":"Structurally Similar, Functionally Different: Impact of Coformer Positional Isomerism on Co-Amorphous Enzalutamide.","authors":"Venkata Krishna Rao Balaga, Argyro Chatziadi, Luděk Ridvan, Miroslav Šoóš","doi":"10.1016/j.ejps.2025.107425","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107425","url":null,"abstract":"<p><p>Coamorphization is an attractive approach to modifying the physicochemical properties of drug molecules, especially the solubility, dissolution, and associated bioavailability. Although these formulations may be advantageous, they exhibit poor physical stability and undergo recrystallisation. To address this limitation, this study investigates the effect of positional isomerism on the coamorphous formation and associated physicochemical properties, to select an optimum solid form with improved stability. Enzalutamide (ENZ), a BCS class II drug, was used as a model compound. Four positional isomers including 2,3-, 2,4-, 2,5- and 2,6-dihydroxybenzoic acid (DHB) were used as coamorphous coformers. Coamorphous formulations were prepared by ball mill in a 2:1 molecular ratio (API:coformer). The solid-state properties of the prepared coamorphous forms were characterised using X-ray powder diffractometer (XRPD), modulated differential scanning calorimetry (mDSC), and Fourier transformed infrared spectrometry (FTIR). Additionally, intra isomer variability in the amorphization kinetics and dissolution enhancement of ENZ, along with physical stability, were evaluated. All coformers formed coamorphous systems, as confirmed by XRPD. mDSC data showed that the glass transition temperature (Tg) varied among the prepared coamorphous forms and was lower than that of pure ENZ. Although there was no significant difference in the dissolution behaviour, the physical stability data reveal a contrast trend. Among the prepared coamorphous forms, ENZ-24DHB<sup>CAM</sup> exhibited superior stability, while ENZ-26DHB<sup>CAM</sup> exhibited poor stability. This article summarises the similarities and differences between the physicochemical properties of coamorphous forms of Enz because of the change in coformer positional isomerism. Stability studies under different humidity conditions revealed significant differences: at 40% RH, all coamorphous forms remained stable for up to 8 weeks, with minor deviations for ENZ-23DHB<sup>CAM</sup> and ENZ-25DHB<sup>CAM</sup>. Under 75% RH, the stability varied markedly; ENZ-24DHB<sup>CAM</sup> maintained stability for at least 8 weeks, while ENZ-26DHB<sup>CAM</sup> became unstable within 1-2 weeks, and ENZ-AMP and ENZ-23DHB<sup>CAM</sup> lost stability by week 6. These results demonstrate the careful selection of coformer positional isomer can quantitatively enhance the stability of coamorphous forms, highlighting the importance of positional isomerism associated chemical design space in optimizing solid-state properties.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107425"},"PeriodicalIF":4.7,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892224","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 : 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":"2025-12-28","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 : 2025-12-22DOI: 10.1016/j.ejps.2025.107423
Shengjie Cong , Yonggang Yang , Rasoul Akram
Bone tissue engineering (BTE) is an attempt to overcome the limitations of conventional grafting through the combination of bioactive scaffolds and regenerative signals. In this study, we prepared an extrusion-based 3D-printed composite scaffold composed of chitosan (CH) combined with dexamethasone (DEX)-loaded mesoporous silica nanoparticle (MSN), (MSN@DEX) in order to compensate for both mechanical insufficiency and temporary osteoinductive signal. MSNs were synthesized by a templated sol-gel method with high drug loading efficiency and biphasic release behavior. Inclusion of MSN@DEX in chitosan resulted in scaffolds with homogeneous and interconnected porosity (310–420 μm), high compressive strength, good swelling profile, and a degradation profile consistent with the time course of bone healing. In vitro experiments with mesenchymal stem cells (MSCs) resulted in a high hemocompatibility, a sustained cell proliferation and a significantly enhanced osteogenic differentiation given by alkaline phosphatase (ALP) activity, calcium deposits and stage-dependent upregulation of RUNX2, ALP, COL1A1 and OCN genes and protein. Together, the hierarchical scaffold architecture, nanostructured reinforcement, and local sustained DEX release provide a cost-effective, stable and clinically adaptable platform for robust osteogenesis with the possibility of enhanced osteogenic induction even with lower dexamethasone release. These findings underscore the potential of CH‑MSN@DEX scaffolds for bone regeneration applications. By combining structural reinforcement with sustained osteoinductive signaling within a single printable construct, this approach represents a clear advancement over previously reported chitosan‑based or DEX‑releasing scaffold systems.
{"title":"3-D printing of chitosan-MSN@dexamethasone scaffold with enhanced properties for bone tissue engineering","authors":"Shengjie Cong , Yonggang Yang , Rasoul Akram","doi":"10.1016/j.ejps.2025.107423","DOIUrl":"10.1016/j.ejps.2025.107423","url":null,"abstract":"<div><div>Bone tissue engineering (BTE) is an attempt to overcome the limitations of conventional grafting through the combination of bioactive scaffolds and regenerative signals. In this study, we prepared an extrusion-based 3D-printed composite scaffold composed of chitosan (CH) combined with dexamethasone (DEX)-loaded mesoporous silica nanoparticle (MSN), (MSN@DEX) in order to compensate for both mechanical insufficiency and temporary osteoinductive signal. MSNs were synthesized by a templated sol-gel method with high drug loading efficiency and biphasic release behavior. Inclusion of MSN@DEX in chitosan resulted in scaffolds with homogeneous and interconnected porosity (310–420 μm), high compressive strength, good swelling profile, and a degradation profile consistent with the time course of bone healing. In vitro experiments with mesenchymal stem cells (MSCs) resulted in a high hemocompatibility, a sustained cell proliferation and a significantly enhanced osteogenic differentiation given by alkaline phosphatase (ALP) activity, calcium deposits and stage-dependent upregulation of RUNX2, ALP, COL1A1 and OCN genes and protein. Together, the hierarchical scaffold architecture, nanostructured reinforcement, and local sustained DEX release provide a cost-effective, stable and clinically adaptable platform for robust osteogenesis with the possibility of enhanced osteogenic induction even with lower dexamethasone release. These findings underscore the potential of CH‑MSN@DEX scaffolds for bone regeneration applications. By combining structural reinforcement with sustained osteoinductive signaling within a single printable construct, this approach represents a clear advancement over previously reported chitosan‑based or DEX‑releasing scaffold systems.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107423"},"PeriodicalIF":4.7,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827119","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 : 2025-12-21DOI: 10.1016/j.ejps.2025.107422
Valerio Ciccone , Claudia Cecchin , Maria Frosini , Mario Saletti , Samuele Maramai , Germano Giuliani , Marco Paolino , Andrea Cappelli , Maurizio Anzini , Sandra Donnini , Lucia Morbidelli
Cyclooxygenase-2 (COX-2) is overexpressed in various cancers and has emerged as a promising target in oncological pharmacotherapy.
This study investigates the in vitro antitumor properties and mechanism of action of novel vicinal diaryl-substituted heterocyclic COX-2 inhibitors, with a focus on VA1213, in comparison to celecoxib, a widely marketed COX-2 inhibitor known for its off-target effects. We assessed cytotoxicity, apoptosis induction, cell-cycle distribution, antimetastatic activity, and alterations in key signaling pathways in HT-29 colorectal carcinoma and MDA-MB-231 breast carcinoma cell lines. Among the novel compounds, VA1213 exhibited the most potent growth-inhibitory activity, demonstrating time-dependent cytotoxicity with a lower IC50 after 48–72 h of treatment compared to VA692 and VA694, and consistent with that observed for celecoxib.
Unlike celecoxib, which produced rapid cytotoxic effects, VA1213 required prolonged exposure, suggesting a distinct mechanism of action. VA1213 induced G₀/G₁ phase cell cycle arrest and apoptosis via caspase-3 activation. Furthermore, it impaired EGFR downstream signaling by reducing ERK1/2 and AKT phosphorylation, without directly inhibiting EGFR itself. At sub-cytotoxic concentrations, VA1213 was more effective than celecoxib in inhibiting cell migration and demonstrated a comparable reduction in clonogenic potential. These findings highlight VA1213 as a COX-2 inhibitor with noteworthy in vitro antitumor efficacy, comparable to that of celecoxib. Its ability to interfere with multiple cancer-associated signaling pathways and reduce tumor cell aggressiveness underscores its potential as a promising therapeutic candidate. Further in vivo studies are warranted to confirm its efficacy and assess potential off-target effects.
{"title":"VA1213, a selective COX-2 inhibitor, exhibits antitumor activity by suppressing EGFR, AKT, and ERK1/2 phosphorylation","authors":"Valerio Ciccone , Claudia Cecchin , Maria Frosini , Mario Saletti , Samuele Maramai , Germano Giuliani , Marco Paolino , Andrea Cappelli , Maurizio Anzini , Sandra Donnini , Lucia Morbidelli","doi":"10.1016/j.ejps.2025.107422","DOIUrl":"10.1016/j.ejps.2025.107422","url":null,"abstract":"<div><div>Cyclooxygenase-2 (COX-2) is overexpressed in various cancers and has emerged as a promising target in oncological pharmacotherapy.</div><div>This study investigates the in vitro antitumor properties and mechanism of action of novel vicinal diaryl-substituted heterocyclic COX-2 inhibitors, with a focus on <strong>VA1213</strong>, in comparison to celecoxib, a widely marketed COX-2 inhibitor known for its off-target effects. We assessed cytotoxicity, apoptosis induction, cell-cycle distribution, antimetastatic activity, and alterations in key signaling pathways in HT-29 colorectal carcinoma and MDA-MB-231 breast carcinoma cell lines. Among the novel compounds, <strong>VA1213</strong> exhibited the most potent growth-inhibitory activity, demonstrating time-dependent cytotoxicity with a lower IC<sub>50</sub> after 48–72 h of treatment compared to <strong>VA692</strong> and <strong>VA694</strong>, and consistent with that observed for celecoxib.</div><div>Unlike celecoxib, which produced rapid cytotoxic effects, <strong>VA1213</strong> required prolonged exposure, suggesting a distinct mechanism of action. <strong>VA1213</strong> induced G₀/G₁ phase cell cycle arrest and apoptosis via caspase-3 activation. Furthermore, it impaired EGFR downstream signaling by reducing ERK1/2 and AKT phosphorylation, without directly inhibiting EGFR itself. At sub-cytotoxic concentrations, <strong>VA1213</strong> was more effective than celecoxib in inhibiting cell migration and demonstrated a comparable reduction in clonogenic potential. These findings highlight <strong>VA1213</strong> as a COX-2 inhibitor with noteworthy in vitro antitumor efficacy, comparable to that of celecoxib. Its ability to interfere with multiple cancer-associated signaling pathways and reduce tumor cell aggressiveness underscores its potential as a promising therapeutic candidate. Further in vivo studies are warranted to confirm its efficacy and assess potential off-target effects.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107422"},"PeriodicalIF":4.7,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818640","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 : 2025-12-18DOI: 10.1016/j.ejps.2025.107412
Conglu Zhao , Liyuan Ji , Xiaoting Wang , Jia Zhang , Xiang Xu , Xiaoting Zhang , Yanjie Ding , Keran Li , Chaoyue Zheng , Kaijun Qiu , Jing Yan , Songtao Gu , Honggang Zhou , Cheng Yang , Hongli Li , Xiaoting Gu , Xiaoyu Ai
{"title":"Erratum to “Intratracheal instillation of chitosan-coated formononetin-loaded porous microspheres prolongs lung retention and improves the treatment” [European Journal of Pharmaceutical Sciences. 2025 Dec 1;215:107347]","authors":"Conglu Zhao , Liyuan Ji , Xiaoting Wang , Jia Zhang , Xiang Xu , Xiaoting Zhang , Yanjie Ding , Keran Li , Chaoyue Zheng , Kaijun Qiu , Jing Yan , Songtao Gu , Honggang Zhou , Cheng Yang , Hongli Li , Xiaoting Gu , Xiaoyu Ai","doi":"10.1016/j.ejps.2025.107412","DOIUrl":"10.1016/j.ejps.2025.107412","url":null,"abstract":"","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107412"},"PeriodicalIF":4.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793541","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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