Pub Date : 2026-03-01Epub Date: 2026-01-13DOI: 10.1016/j.ejps.2026.107444
Zeming Wang , Jiaxiang Ding , Yuanyuan Xu , Wang Hu , Tonghao Zhang , Huiwen Wang , Lu-Ning Sun , Huan Zhou
Objectives
To explore the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of ADC189 in vivo.
Methods
In this study, which used a single-center, open, nonrandomized, single-dose trial design.
Results
[14C] ADC189 is rapidly absorbed in humans and undergoes O-dealkylation to form [14C] ADC189-I07 (M485b). The metabolite M485b has been reported to exhibit Tmax was 3.51 h, Cmax was 57.5 ng/mL, and AUC0-∞ was 2647 h·ng/mL. In plasma and blood, the mean Cmax values for radioactivity were 152 and 119 ng eq./mL, respectively, the mean AUC0-∞ values were 7373 and 1011 ng eq./mL·h, respectively, the mean Tmax values were 3373 and 1011 ng eq./mL·h, respectively, the mean Tmax values were 3.03 and 3.15 h, and the mean t1/2 values were 40.4 and 11.6 h, respectively. Based on the results of the metabolite profile, and metabolite structure analyses of the urine and fecal samples, it was hypothesized that the main clearance pathways of ADC189 in the human body after a single dose of the drug are as follows: the prodrug ADC189 is metabolized and excreted via several pathways: it can be O-dealkylated to form M485b (excreted in feces and urine), glucuronidated to form M661 (excreted in urine), oxidized to form M501a/b (excreted in feces and urine), or deoxygenated to form M457 (excreted in feces).
Conclusion
The results of this study collectively indicate that [14C]ADC189 does not significantly bind to blood cells, and its primary excretion route is fecal excretion, while urinary excretion is a secondary route.
{"title":"Pharmacokinetics, mass balance and metabolism of [14C] ADC189, a novel inhibitor of the polymerase acidic protein, in humans","authors":"Zeming Wang , Jiaxiang Ding , Yuanyuan Xu , Wang Hu , Tonghao Zhang , Huiwen Wang , Lu-Ning Sun , Huan Zhou","doi":"10.1016/j.ejps.2026.107444","DOIUrl":"10.1016/j.ejps.2026.107444","url":null,"abstract":"<div><h3>Objectives</h3><div>To explore the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of ADC189 in vivo.</div></div><div><h3>Methods</h3><div>In this study, which used a single-center, open, nonrandomized, single-dose trial design.</div></div><div><h3>Results</h3><div>[<sup>14</sup>C] ADC189 is rapidly absorbed in humans and undergoes O-dealkylation to form [<sup>14</sup>C] ADC189-I07 (M485b). The metabolite M485b has been reported to exhibit T<sub>max</sub> was 3.51 h, C<sub>max</sub> was 57.5 ng/mL, and AUC<sub>0-∞</sub> was 2647 h·ng/mL. In plasma and blood, the mean C<sub>max</sub> values for radioactivity were 152 and 119 ng eq./mL, respectively, the mean AUC<sub>0-∞</sub> values were 7373 and 1011 ng eq./mL·h, respectively, the mean T<sub>max</sub> values were 3373 and 1011 ng eq./mL·h, respectively, the mean T<sub>max</sub> values were 3.03 and 3.15 h, and the mean t<sub>1/2</sub> values were 40.4 and 11.6 h, respectively. Based on the results of the metabolite profile, and metabolite structure analyses of the urine and fecal samples, it was hypothesized that the main clearance pathways of ADC189 in the human body after a single dose of the drug are as follows: the prodrug ADC189 is metabolized and excreted via several pathways: it can be O-dealkylated to form M485b (excreted in feces and urine), glucuronidated to form M661 (excreted in urine), oxidized to form M501a/b (excreted in feces and urine), or deoxygenated to form M457 (excreted in feces).</div></div><div><h3>Conclusion</h3><div>The results of this study collectively indicate that [<sup>14</sup>C]ADC189 does not significantly bind to blood cells, and its primary excretion route is fecal excretion, while urinary excretion is a secondary route.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107444"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145975269","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: 2026-01-07DOI: 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":"2026-03-01","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 : 2026-03-01Epub Date: 2026-01-08DOI: 10.1016/j.ejps.2026.107439
Raghad Alsheikh , Dániel Nemes , Pálma Fehér , Zoltán Ujhelyi , Ádám Haimhoffer , Ádám Papp , Ildikó Bácskay
Ocular drug delivery presents significant challenges due to the unique anatomical and physiological barriers of the human eye, with the rapid precorneal elimination, limiting the bioavailability of conventional eye drops. Thermosensitive in situ gels have emerged as a promising delivery system to overcome these limitations by undergoing a reversible sol-to-gel transition upon contact with ocular surface temperature, which facilitates ease of administration as a liquid and subsequent transformation into a gel, thereby enhancing precorneal residence time, prolonging the drug release, and improving therapeutic efficacy. This review provides a comprehensive overview of thermos-responsive polymer-based ocular delivery systems, with a specific focus on poloxamers, poly(N-isopropylacrylamide), and cellulose derivatives. Particular attention is given to the physicochemical mechanisms of thermogelation, such as poloxamer micellization and micelle packing, as well as the role of auxiliary polymers in enhancing mucoadhesion, mechanical strength, and gel retention. Additionally, the review synthesizes findings from multiple experimental studies to highlight the critical formulation parameters essential for developing effective in situ gels, including sol–gel transition temperature and time, clarity, rheological behavior, gelling capacity, isotonicity, and ocular biocompatibility. By selecting an optimized thermosensitive in situ gel formulation with suitable characteristics, it becomes possible to develop effective delivery systems targeting both the anterior and posterior segments of the eye.
{"title":"Thermosensitive in situ gels for ocular drug delivery: Advances in polymer-based formulations","authors":"Raghad Alsheikh , Dániel Nemes , Pálma Fehér , Zoltán Ujhelyi , Ádám Haimhoffer , Ádám Papp , Ildikó Bácskay","doi":"10.1016/j.ejps.2026.107439","DOIUrl":"10.1016/j.ejps.2026.107439","url":null,"abstract":"<div><div>Ocular drug delivery presents significant challenges due to the unique anatomical and physiological barriers of the human eye, with the rapid precorneal elimination, limiting the bioavailability of conventional eye drops. Thermosensitive in situ gels have emerged as a promising delivery system to overcome these limitations by undergoing a reversible sol-to-gel transition upon contact with ocular surface temperature, which facilitates ease of administration as a liquid and subsequent transformation into a gel, thereby enhancing precorneal residence time, prolonging the drug release, and improving therapeutic efficacy. This review provides a comprehensive overview of thermos-responsive polymer-based ocular delivery systems, with a specific focus on poloxamers, poly(N-isopropylacrylamide), and cellulose derivatives. Particular attention is given to the physicochemical mechanisms of thermogelation, such as poloxamer micellization and micelle packing, as well as the role of auxiliary polymers in enhancing mucoadhesion, mechanical strength, and gel retention. Additionally, the review synthesizes findings from multiple experimental studies to highlight the critical formulation parameters essential for developing effective in situ gels, including sol–gel transition temperature and time, clarity, rheological behavior, gelling capacity, isotonicity, and ocular biocompatibility. By selecting an optimized thermosensitive in situ gel formulation with suitable characteristics, it becomes possible to develop effective delivery systems targeting both the anterior and posterior segments of the eye.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107439"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948428","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.2026.107432
Rui Ding , Fan Huang , Ziyan Ding , Yanting Li , Qun Gu , Fang Men , Chongyou Lee , Jiaojiao Zhang , Wenyan Zhao , Qian Wang , Yian Liu , Shuang Li , Qingshan Zheng , Haifeng Song , Liming Chen , Wei Wang , Suping Niu , Yi Fang
Background
GR2002 is a novel bispecific antibody targeting dual epitopes on thymic stromal lymphopoietin (TSLP). We aimed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of GR2002 in healthy Chinese adults.
Methods
In this randomized, double-blind, placebo-controlled, dose-escalation, phase 1 trial of GR2002, healthy adults were enrolled and assigned to one of five dose cohorts. Within each cohort, participants were randomized (4:1) to receive a single subcutaneous dose of GR2002 (35, 70, 140, 280, or 420 mg) or placebo and were followed for 85 days. The primary endpoints included safety and tolerability. Secondary endpoints comprised PK, PD, and immunogenicity.
Results
Fifty eligible subjects were enrolled and randomized to receive either GR2002 (n = 40) or placebo (n = 10). A total of 92 treatment-emergent adverse events (TEAEs) were reported, with comparable incidence between the GR2002 and placebo groups. TEAEs were generally mild to moderate in severity and did not exhibit dose dependency. The most common treatment-related adverse event was upper respiratory tract infection, occurring in 7/40 (17.5%) participants in the GR2002 group and 2/10 (20%) in the placebo group. GR2002 displayed linear PK across the dose range tested, with a mean half-life ranging from 26.0 to 58.9 days. Dose-dependent reductions in serum TSLP levels from baseline were observed in the 140–420 mg dose groups. Anti-drug antibodies were detected in six subjects (15%) following GR2002 administration.
Conclusions
Single-dose subcutaneous administration of GR2002 demonstrated favorable safety and tolerability, linear PK, and low immunogenicity. These findings warrant the subsequent clinical development of GR2002.
{"title":"Safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of a novel anti-TSLP bispecific antibody (GR2002) in healthy Chinese adults: A randomized, placebo-controlled phase 1 trial","authors":"Rui Ding , Fan Huang , Ziyan Ding , Yanting Li , Qun Gu , Fang Men , Chongyou Lee , Jiaojiao Zhang , Wenyan Zhao , Qian Wang , Yian Liu , Shuang Li , Qingshan Zheng , Haifeng Song , Liming Chen , Wei Wang , Suping Niu , Yi Fang","doi":"10.1016/j.ejps.2026.107432","DOIUrl":"10.1016/j.ejps.2026.107432","url":null,"abstract":"<div><h3>Background</h3><div>GR2002 is a novel bispecific antibody targeting dual epitopes on thymic stromal lymphopoietin (TSLP). We aimed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of GR2002 in healthy Chinese adults.</div></div><div><h3>Methods</h3><div>In this randomized, double-blind, placebo-controlled, dose-escalation, phase 1 trial of GR2002, healthy adults were enrolled and assigned to one of five dose cohorts. Within each cohort, participants were randomized (4:1) to receive a single subcutaneous dose of GR2002 (35, 70, 140, 280, or 420 mg) or placebo and were followed for 85 days. The primary endpoints included safety and tolerability. Secondary endpoints comprised PK, PD, and immunogenicity.</div></div><div><h3>Results</h3><div>Fifty eligible subjects were enrolled and randomized to receive either GR2002 (<em>n</em> = 40) or placebo (<em>n</em> = 10). A total of 92 treatment-emergent adverse events (TEAEs) were reported, with comparable incidence between the GR2002 and placebo groups. TEAEs were generally mild to moderate in severity and did not exhibit dose dependency. The most common treatment-related adverse event was upper respiratory tract infection, occurring in 7/40 (17.5%) participants in the GR2002 group and 2/10 (20%) in the placebo group. GR2002 displayed linear PK across the dose range tested, with a mean half-life ranging from 26.0 to 58.9 days. Dose-dependent reductions in serum TSLP levels from baseline were observed in the 140–420 mg dose groups. Anti-drug antibodies were detected in six subjects (15%) following GR2002 administration.</div></div><div><h3>Conclusions</h3><div>Single-dose subcutaneous administration of GR2002 demonstrated favorable safety and tolerability, linear PK, and low immunogenicity. These findings warrant the subsequent clinical development of GR2002.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107432"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948433","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: 2026-01-06DOI: 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":"2026-03-01","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 : 2026-03-01Epub Date: 2026-01-26DOI: 10.1016/j.ejps.2026.107451
Sevda Akcesme , Stefanie Schmager , Yassir Al-Tikriti , Lars Gedda , Magnus Bergström , Katarina Edwards , Heiko Heerklotz , Ulrich Massing
Previous research shows that thermosensitive small multilamellar lipid nanoparticles (tSMLPs) offer promising features for temperature-triggered cytostatic drug delivery, remaining completely stable at body temperature (37°C) and releasing their payload under mild hyperthermia conditions (42°C). A distinguishing characteristic of tSMLPs is their unique particle morphology - multiple tightly packed bilayers with progressively decreasing intermembrane spacing toward the particle core. In this study, we shift the focus from their thermosensitivity to an in-depth exploration of the particle’s morphology. Using in-vial homogenization by dual centrifugation (DC) at very high lipid concentrations (60%), we prepare SMLPs composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG2). A systematic screening of DPPC/DPPG2 100-x/x (mol/mol) from x = 0 to 100 enabled the formation of SMLPs with sizes below 200 nm, narrow size distribution and well-distinguishable morphologies. These lipid nanoparticles also demonstrated the capacity to entrap hydrophilic compounds, despite their multilamellar structure and thus limited interlamellar aqueous space. We propose that specific headgroup interactions between DPPC and DPPG2 underlie the observed water influx upon dilution of the initially formed vesicular phospholipid gels (VPGs) during in-vial homogenization by DC. With a combination of biophysical techniques (DLS, Time-resolved fluorescence, SAXS and WAXS) and morphological analysis (cryo-EM), we present a hypothesis to explain the evolving SMLP morphology as a function of increasing DPPG2 content in the phospholipid blend.
{"title":"Revealing the Morphology of Small Multilamellar Lipid Nanoparticles (SMLPs) made by In-Vial Homogenization","authors":"Sevda Akcesme , Stefanie Schmager , Yassir Al-Tikriti , Lars Gedda , Magnus Bergström , Katarina Edwards , Heiko Heerklotz , Ulrich Massing","doi":"10.1016/j.ejps.2026.107451","DOIUrl":"10.1016/j.ejps.2026.107451","url":null,"abstract":"<div><div>Previous research shows that thermosensitive small multilamellar lipid nanoparticles (tSMLPs) offer promising features for temperature-triggered cytostatic drug delivery, remaining completely stable at body temperature (37°C) and releasing their payload under mild hyperthermia conditions (42°C). A distinguishing characteristic of tSMLPs is their unique particle morphology - multiple tightly packed bilayers with progressively decreasing intermembrane spacing toward the particle core. In this study, we shift the focus from their thermosensitivity to an in-depth exploration of the particle’s morphology. Using in-vial homogenization by dual centrifugation (DC) at very high lipid concentrations (60%), we prepare SMLPs composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG<sub>2</sub>). A systematic screening of DPPC/DPPG<sub>2</sub> 100-x/x (mol/mol) from x = 0 to 100 enabled the formation of SMLPs with sizes below 200 nm, narrow size distribution and well-distinguishable morphologies. These lipid nanoparticles also demonstrated the capacity to entrap hydrophilic compounds, despite their multilamellar structure and thus limited interlamellar aqueous space. We propose that specific headgroup interactions between DPPC and DPPG<sub>2</sub> underlie the observed water influx upon dilution of the initially formed vesicular phospholipid gels (VPGs) during in-vial homogenization by DC. With a combination of biophysical techniques (DLS, Time-resolved fluorescence, SAXS and WAXS) and morphological analysis (cryo-EM), we present a hypothesis to explain the evolving SMLP morphology as a function of increasing DPPG<sub>2</sub> content in the phospholipid blend.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107451"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090562","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 : 2026-02-01Epub 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":"2026-02-01","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}
Pub Date : 2026-02-01Epub Date: 2025-12-08DOI: 10.1016/j.ejps.2025.107405
Sergi Coll , Claudia Bressan , Núria Monfort , Ana Aldea-Perona , Marcel·lí Carbó , Rosa Ventura
Dexamethasone (DEX) is prohibited in sports competitions when administered by all injectable, oral or rectal routes, and is permitted at all times when administered by all other routes. The present work aimed to assess the urinary excretion profile of DEX after single and multiple oral administrations to verify the suitability of the new minimum reporting level (MRL) of 60 ng/mL established by the World Anti-Doping Agency to distinguish allowed and prohibited administrations. Moreover, the minimum washout period of three days established for out-of-competition treatments with oral glucocorticoids will be evaluated.
DEX was administered to healthy volunteers using two different oral treatments: single administration (4 mg, n = 8 male volunteers) and multiple administrations (2 mg/12 h for 5 days, n = 8 male volunteers). Urine and plasma samples collected before and after administration were analysed using liquid chromatography-tandem mass spectrometry. DEX and 6β‑hydroxy-DEX, were the predominant compounds detected in urine, with peak urinary excretion observed within the first 4 h post-dose. DEX concentrations exceeded the new MRL mainly within 12 h after a single dose, with one volunteer showing levels above this threshold up to 24–36 h. In the multiple-dose study, most of the DEX concentrations remained above 60 ng/mL after the second dose and throughout the dosing period and declined quickly after the final dose. Plasma DEX kinetics was defined by an open bicompartmental model with a first order oral absorption. DEX was detectable up to 48 h post-administration. In the multiple dose study, the steady-state concentrations were reached soon after the first dose, and DEX showed no evidence of accumulation. CORT levels decreased rapidly after both single and multiple administrations due to suppression of the hypothalamic-pituitary-adrenal axis. Recovery times varied among volunteers.
The MRL of 60 ng/mL proved appropriate for distinguishing permitted from prohibited use with a 3-day washout, though further studies on non-systemic routes are recommended to refine sensitivity.
{"title":"Pharmacokinetic profile of dexamethasone in urine and plasma after single and multiple oral administration: Relevance to doping controls","authors":"Sergi Coll , Claudia Bressan , Núria Monfort , Ana Aldea-Perona , Marcel·lí Carbó , Rosa Ventura","doi":"10.1016/j.ejps.2025.107405","DOIUrl":"10.1016/j.ejps.2025.107405","url":null,"abstract":"<div><div>Dexamethasone (DEX) is prohibited in sports competitions when administered by all injectable, oral or rectal routes, and is permitted at all times when administered by all other routes. The present work aimed to assess the urinary excretion profile of DEX after single and multiple oral administrations to verify the suitability of the new minimum reporting level (MRL) of 60 ng/mL established by the World Anti-Doping Agency to distinguish allowed and prohibited administrations. Moreover, the minimum washout period of three days established for out-of-competition treatments with oral glucocorticoids will be evaluated.</div><div>DEX was administered to healthy volunteers using two different oral treatments: single administration (4 mg, <em>n</em> = 8 male volunteers) and multiple administrations (2 mg/12 h for 5 days, <em>n</em> = 8 male volunteers). Urine and plasma samples collected before and after administration were analysed using liquid chromatography-tandem mass spectrometry. DEX and 6β‑hydroxy-DEX, were the predominant compounds detected in urine, with peak urinary excretion observed within the first 4 h post-dose. DEX concentrations exceeded the new MRL mainly within 12 h after a single dose, with one volunteer showing levels above this threshold up to 24–36 h. In the multiple-dose study, most of the DEX concentrations remained above 60 ng/mL after the second dose and throughout the dosing period and declined quickly after the final dose. Plasma DEX kinetics was defined by an open bicompartmental model with a first order oral absorption. DEX was detectable up to 48 h post-administration. In the multiple dose study, the steady-state concentrations were reached soon after the first dose, and DEX showed no evidence of accumulation. CORT levels decreased rapidly after both single and multiple administrations due to suppression of the hypothalamic-pituitary-adrenal axis. Recovery times varied among volunteers.</div><div>The MRL of 60 ng/mL proved appropriate for distinguishing permitted from prohibited use with a 3-day washout, though further studies on non-systemic routes are recommended to refine sensitivity.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107405"},"PeriodicalIF":4.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721647","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 : 2026-02-01Epub Date: 2025-12-08DOI: 10.1016/j.ejps.2025.107403
Luca Morici , Ines Nikolic
Osteoarthritis is the most common degenerative joint disease affecting millions of people in the world and leading to disability. Currently, the only available treatments on the market are symptomatic therapies for pain and inflammation. There are no intra-articular drugs that can restore the cartilage matrix, also known as disease-modifying osteoarthritis drugs (DMOADs). This review focuses on all clinical trials of pro-anabolic DMOADs, which stimulate the regeneration of the cartilage matrix by inducing the differentiation of mesenchymal progenitors into chondrocytes, a process known as chondrogenesis. This review also discussed some pathways of chondrocytes, which boost the transcription of genes involved in the production of extracellular matrix components. Finally, the review also covers some implants in the commercial and clinical phases for cartilage repair.
{"title":"Update on clinical trials of intra-articular disease-modifying osteoarthritis drugs inducing cartilage regeneration","authors":"Luca Morici , Ines Nikolic","doi":"10.1016/j.ejps.2025.107403","DOIUrl":"10.1016/j.ejps.2025.107403","url":null,"abstract":"<div><div>Osteoarthritis is the most common degenerative joint disease affecting millions of people in the world and leading to disability. Currently, the only available treatments on the market are symptomatic therapies for pain and inflammation. There are no intra-articular drugs that can restore the cartilage matrix, also known as disease-modifying osteoarthritis drugs (DMOADs). This review focuses on all clinical trials of pro-anabolic DMOADs, which stimulate the regeneration of the cartilage matrix by inducing the differentiation of mesenchymal progenitors into chondrocytes, a process known as chondrogenesis. This review also discussed some pathways of chondrocytes, which boost the transcription of genes involved in the production of extracellular matrix components. Finally, the review also covers some implants in the commercial and clinical phases for cartilage repair.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107403"},"PeriodicalIF":4.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721731","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 : 2026-02-01Epub Date: 2025-12-10DOI: 10.1016/j.ejps.2025.107408
Mandeep Kaur Marwah , Lissette Sanchez-Aranguren , Hala Shokr , Mohamad Anas Al Tahan , Keqing Wang , Shakil Ahmad
Hydrogen sulphide (H2S), is a well described essential physiological molecule that is finely balanced to maintain cellular functions. Considering its important biological roles, H2S has promising therapeutic potential resulting in the development of many H2S donors. Such donors have proved to have therapeutic benefit in cognitive pathways, inflammation, reproduction, and the regulation of blood pressure. However, controlled delivery and targeted administration of this reactive and hazardous gas are necessary yet challenging due to its rapid diffusivity, and toxicity at high doses. Drug delivery systems are vital for the effective administration of many active pharmaceutical excipients, and H2S donors stands to benefit significantly from the tuneable physical, chemical, and pharmacokinetic properties of various formulation systems. To date, few studies have focused on the formulation and delivery aspects of H2S and its donors. Instead, H2S usually is administered either by inhalation or via site-specific injections of donor solution. Whilst therapeutic benefit has been observed following such administration, these are not patient friendly solutions. This review focuses on highlighting the advances in H2S donor formulations and their ability in sustaining the release of H2S as well as improving drug targeting.
{"title":"Advancing therapeutics with targeted formulations of hydrogen sulphide donors","authors":"Mandeep Kaur Marwah , Lissette Sanchez-Aranguren , Hala Shokr , Mohamad Anas Al Tahan , Keqing Wang , Shakil Ahmad","doi":"10.1016/j.ejps.2025.107408","DOIUrl":"10.1016/j.ejps.2025.107408","url":null,"abstract":"<div><div>Hydrogen sulphide (H<sub>2</sub>S), is a well described essential physiological molecule that is finely balanced to maintain cellular functions. Considering its important biological roles, H<sub>2</sub>S has promising therapeutic potential resulting in the development of many H<sub>2</sub>S donors. Such donors have proved to have therapeutic benefit in cognitive pathways, inflammation, reproduction, and the regulation of blood pressure. However, controlled delivery and targeted administration of this reactive and hazardous gas are necessary yet challenging due to its rapid diffusivity, and toxicity at high doses. Drug delivery systems are vital for the effective administration of many active pharmaceutical excipients, and H<sub>2</sub>S donors stands to benefit significantly from the tuneable physical, chemical, and pharmacokinetic properties of various formulation systems. To date, few studies have focused on the formulation and delivery aspects of H<sub>2</sub>S and its donors. Instead, H<sub>2</sub>S usually is administered either by inhalation or via site-specific injections of donor solution. Whilst therapeutic benefit has been observed following such administration, these are not patient friendly solutions. This review focuses on highlighting the advances in H<sub>2</sub>S donor formulations and their ability in sustaining the release of H<sub>2</sub>S as well as improving drug targeting.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107408"},"PeriodicalIF":4.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735723","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号