Pub Date : 2025-12-06DOI: 10.1016/j.ejps.2025.107401
Malte Bøgh Senniksen , Justus Johann Lange , Wiebke Saal , Patrick O’Dwyer , Martin Kuentz , Brendan T. Griffin , Susanne Page , Jennifer Dressman , Nicole Wyttenbach
Poor aqueous solubility and thereby poor and/or variable bioavailability of drug candidates is frequently overcome by developing enabling formulations such as amorphous solid dispersions (ASDs). This study proposes a systematic, miniaturized approach to evaluate the ASD developability of an active pharmaceutical ingredient (API) based on i) assessment of glass forming ability ii) assessment of the supersaturation potential of the neat API by supersaturation/permeation testing, iii) selection of an appropriate ASD carrier system using high-throughput dissolution screening of ASD films and iv) performing high-throughput dissolution/permeation testing of ASD films. The model drug candidate, RO6897779, exhibited good glass forming ability. Eight pharmaceutical polymers (CAP, Eudragit® E, Eudragit® L100, HPMC 100LV, HPMCAS-M, PVP K25, PVP VA64, and Soluplus®) were screened as ASD carriers by high-throughput dissolution testing at drug loads of 20, 30 and 40 % [w/w]. Due to poor performance of the binary systems, ternary ASDs containing Soluplus® were prepared at surfactant loads of 4, 6 and 8 % [w/w] and subsequently, high-throughput dissolution/permeation studies were conducted on selected compositions. The composition containing RO6897779 at a drug load of 20 % in Soluplus®[w/w] with the addition of 6 % [w/w] SDS yielded the best performance, but was inferior to the permeation of supersaturated neat RO6897779. Further studies should be conducted to assess the ability of this four-step, miniaturized approach to predict optimal ASD formulations over a broad range of API physicochemical properties.
{"title":"High-throughput screening of amorphous solid dispersions: a systematic approach to enhance bioaccessibility of a poorly soluble drug","authors":"Malte Bøgh Senniksen , Justus Johann Lange , Wiebke Saal , Patrick O’Dwyer , Martin Kuentz , Brendan T. Griffin , Susanne Page , Jennifer Dressman , Nicole Wyttenbach","doi":"10.1016/j.ejps.2025.107401","DOIUrl":"10.1016/j.ejps.2025.107401","url":null,"abstract":"<div><div>Poor aqueous solubility and thereby poor and/or variable bioavailability of drug candidates is frequently overcome by developing enabling formulations such as amorphous solid dispersions (ASDs). This study proposes a systematic, miniaturized approach to evaluate the ASD developability of an active pharmaceutical ingredient (API) based on i) assessment of glass forming ability ii) assessment of the supersaturation potential of the neat API by supersaturation/permeation testing, iii) selection of an appropriate ASD carrier system using high-throughput dissolution screening of ASD films and iv) performing high-throughput dissolution/permeation testing of ASD films. The model drug candidate, RO6897779, exhibited good glass forming ability. Eight pharmaceutical polymers (CAP, Eudragit® E, Eudragit® L100, HPMC 100LV, HPMCAS-M, PVP K25, PVP VA64, and Soluplus®) were screened as ASD carriers by high-throughput dissolution testing at drug loads of 20, 30 and 40 % [w/w]. Due to poor performance of the binary systems, ternary ASDs containing Soluplus® were prepared at surfactant loads of 4, 6 and 8 % [w/w] and subsequently, high-throughput dissolution/permeation studies were conducted on selected compositions. The composition containing RO6897779 at a drug load of 20 % in Soluplus®[w/w] with the addition of 6 % [w/w] SDS yielded the best performance, but was inferior to the permeation of supersaturated neat RO6897779. Further studies should be conducted to assess the ability of this four-step, miniaturized approach to predict optimal ASD formulations over a broad range of API physicochemical properties.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107401"},"PeriodicalIF":4.7,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707092","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 : 2025-12-06DOI: 10.1016/j.ejps.2025.107402
Xiaoqing Zhuang , Jenni Virta , Heidi Liljenbäck , Lauri Paasonen , Anu J. Airaksinen , Anne Roivainen , Xiang-Guo Li
Nanofibrillar cellulose (NFC) hydrogel has emerged as a promising implantable material for therapeutic applications. In this study, the relatively longer-lived positron-emitting radionuclide zirconium-89 was chelated to the octadentate deferoxamine (DFO*)-conjugated NFC hydrogel ([89Zr]Zr-DFO*-NFC) to enable longitudinal monitoring of its in vivo fate using positron emission tomography techniques. Following subcutaneous implantation in healthy mice, [89Zr]Zr-DFO*-NFC retained radioactivity at the implant site for at least 14 days, with minimal signal detected in the kidneys, urinary bladder, and overlying skin. In contrast, mice receiving a control formulation of [89Zr]Zr-oxalate mixed with NFC hydrogel showed progressive accumulation of radioactivity in the bones, consistent with known [89Zr]Zr-oxalate distribution patterns, and only limited retention at the implant site by Day 7. These findings demonstrate that [89Zr]Zr-DFO*-NFC hydrogel implants exhibit high in vivo stability with negligible systemic release following subcutaneous implantation, supporting their potential use as safe and traceable biomaterial platforms.
{"title":"Longitudinal monitoring of nanofibrillar cellulose hydrogel medical implants in mice using positron emission tomography","authors":"Xiaoqing Zhuang , Jenni Virta , Heidi Liljenbäck , Lauri Paasonen , Anu J. Airaksinen , Anne Roivainen , Xiang-Guo Li","doi":"10.1016/j.ejps.2025.107402","DOIUrl":"10.1016/j.ejps.2025.107402","url":null,"abstract":"<div><div>Nanofibrillar cellulose (NFC) hydrogel has emerged as a promising implantable material for therapeutic applications. In this study, the relatively longer-lived positron-emitting radionuclide zirconium-89 was chelated to the octadentate deferoxamine (DFO*)-conjugated NFC hydrogel ([<sup>89</sup>Zr]Zr-DFO*-NFC) to enable longitudinal monitoring of its <em>in vivo</em> fate using positron emission tomography techniques. Following subcutaneous implantation in healthy mice, [<sup>89</sup>Zr]Zr-DFO*-NFC retained radioactivity at the implant site for at least 14 days, with minimal signal detected in the kidneys, urinary bladder, and overlying skin. In contrast, mice receiving a control formulation of [<sup>89</sup>Zr]Zr-oxalate mixed with NFC hydrogel showed progressive accumulation of radioactivity in the bones, consistent with known [<sup>89</sup>Zr]Zr-oxalate distribution patterns, and only limited retention at the implant site by Day 7. These findings demonstrate that [<sup>89</sup>Zr]Zr-DFO*-NFC hydrogel implants exhibit high <em>in vivo</em> stability with negligible systemic release following subcutaneous implantation, supporting their potential use as safe and traceable biomaterial platforms.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107402"},"PeriodicalIF":4.7,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707293","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}
Topical drug delivery to the posterior eye segment remains a significant challenge due to ocular anatomical barriers, particularly in diseases such as wet age-related macular degeneration (AMD), where treatment typically relies on frequent intravitreal (IVT) injections of anti-angiogenic agents. In this study, we present a non-invasive eye drop formulation of axitinib (AXT), a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, encapsulated within 25-nm dual-functionalized mesoporous silica nanoparticles (AXT@dual-MSNs) engineered for efficient retinal delivery. The nanoparticles feature sulfonate-functionalized mesopores that enhanced AXT loading and solubilization, along with a PEGylated/quaternary ammonium-modified surface that improved colloidal stability and favored intramesopore drug confinement. Following topical administration, AXT@dual-MSNs achieved retinal accumulation via the conjunctiva-sclera-choroid pathway, effectively bypassing the corneal route. A pharmacokinetic analysis confirmed rapid, transscleral delivery of AXT with therapeutically relevant concentrations in the retina. In a laser-induced choroidal neovascularization (CNV) mouse model, a well-established surrogate for wet AMD, AXT@dual-MSN eyedrops significantly suppressed neovascular lesion formation, outperforming free-drug eyedrops and IVT AXT injection. Notably, the formulation exhibited excellent ocular tolerance, with no evidence of local toxicity or contralateral eye exposure. This work introduces a novel nanocarrier system capable of overcoming the longstanding delivery barrier to the posterior eye segment via eyedrops, offering a safe, effective, and clinically translatable alternative to IVT injections. The modular design of AXT@dual-MSNs also holds promise for expanding topical access to other hydrophobic or labile therapeutics targeting retinal diseases.
{"title":"Dual-functionalized mesoporous silica nanoparticles for topical axitinib delivery to the posterior eye segment","authors":"Li Xu , Zih-An Chen , Cheng-Hsun Wu , Yi-Ping Chen , Si-Han Wu , Chung-Yuan Mou , Ching-Li Tseng , Yueh Chien , Hardy Wai-Hong Chan , Tien-Chun Yang , Shih-Hwa Chiou","doi":"10.1016/j.ejps.2025.107398","DOIUrl":"10.1016/j.ejps.2025.107398","url":null,"abstract":"<div><div>Topical drug delivery to the posterior eye segment remains a significant challenge due to ocular anatomical barriers, particularly in diseases such as wet age-related macular degeneration (AMD), where treatment typically relies on frequent intravitreal (IVT) injections of anti-angiogenic agents. In this study, we present a non-invasive eye drop formulation of axitinib (AXT), a potent vascular endothelial growth factor receptor (VEGFR) inhibitor, encapsulated within 25-nm dual-functionalized mesoporous silica nanoparticles (AXT@dual-MSNs) engineered for efficient retinal delivery. The nanoparticles feature sulfonate-functionalized mesopores that enhanced AXT loading and solubilization, along with a PEGylated/quaternary ammonium-modified surface that improved colloidal stability and favored intramesopore drug confinement. Following topical administration, AXT@dual-MSNs achieved retinal accumulation via the conjunctiva-sclera-choroid pathway, effectively bypassing the corneal route. A pharmacokinetic analysis confirmed rapid, transscleral delivery of AXT with therapeutically relevant concentrations in the retina. In a laser-induced choroidal neovascularization (CNV) mouse model, a well-established surrogate for wet AMD, AXT@dual-MSN eyedrops significantly suppressed neovascular lesion formation, outperforming free-drug eyedrops and IVT AXT injection. Notably, the formulation exhibited excellent ocular tolerance, with no evidence of local toxicity or contralateral eye exposure. This work introduces a novel nanocarrier system capable of overcoming the longstanding delivery barrier to the posterior eye segment via eyedrops, offering a safe, effective, and clinically translatable alternative to IVT injections. The modular design of AXT@dual-MSNs also holds promise for expanding topical access to other hydrophobic or labile therapeutics targeting retinal diseases.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107398"},"PeriodicalIF":4.7,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700086","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}
Polymeric micelles are promising nanocarriers for improving the solubility and therapeutic efficacy of poorly water-soluble drugs. In this study, bicalutamide (BIC)-loaded polymeric micelles were developed and optimized using central composite design (CCD) by varying two formulation factors: the Soluplus® percentage (%) and the Pluronic F127/Pluronic F68 ratio (w/w). The selected formulations exhibited favorable physicochemical properties with particle size (PS) below 100 nm, low polydispersity index (PDI) (≤ 0.066), and high encapsulation efficiencies (EE) (up to 90.6 %). Transmission electron microscopy (TEM) confirmed the spherical and monodisperse structure. The micelles exhibited near-neutral zeta potentials. Lyophilization with trehalose did not significantly alter particle size or uniformity. In vitro release studies demonstrated sustained drug release profiles for 72 h, and in vitro solubility measurements revealed a significant increase (∼161 to 335-fold) compared to free BIC. The formulations also remained colloidally stable upon dilution and were physically stable for up to 6 months at 4 °C, 25 °C/60 % Relative Humidity (RH), and 40 °C/75 % RH. Cellular uptake studies in the human prostate cancer (PC-3) cell line confirmed effective internalization of the micelles. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated a concentration- and time-dependent cytotoxicity. F7 exhibited superior cytotoxicity among the tested formulations, compared to free BIC, while its blank formulation showed no significant toxicity, indicating favorable biocompatibility. These results suggest that the developed polymeric micelle systems have potential as stable and biocompatible delivery systems for BIC, warranting further investigation.
{"title":"Development and optimization of Soluplus®/Pluronic-based polymeric micelles for bicalutamide delivery: characterization, lyophilization, stability, and cellular studies","authors":"Nihal Tugce Ozaksun , Tugce Tayyar , Aysun Ozdemir , Mustafa Ark , Tuba Incecayir","doi":"10.1016/j.ejps.2025.107395","DOIUrl":"10.1016/j.ejps.2025.107395","url":null,"abstract":"<div><div>Polymeric micelles are promising nanocarriers for improving the solubility and therapeutic efficacy of poorly water-soluble drugs. In this study, bicalutamide (BIC)-loaded polymeric micelles were developed and optimized using central composite design (CCD) by varying two formulation factors: the Soluplus® percentage (%) and the Pluronic F127/Pluronic F68 ratio (w/w). The selected formulations exhibited favorable physicochemical properties with particle size (PS) below 100 nm, low polydispersity index (PDI) (≤ 0.066), and high encapsulation efficiencies (EE) (up to 90.6 %). Transmission electron microscopy (TEM) confirmed the spherical and monodisperse structure. The micelles exhibited near-neutral zeta potentials. Lyophilization with trehalose did not significantly alter particle size or uniformity<em>. In vitro</em> release studies demonstrated sustained drug release profiles for 72 h, and <em>in vitro</em> solubility measurements revealed a significant increase (∼161 to 335-fold) compared to free BIC. The formulations also remained colloidally stable upon dilution and were physically stable for up to 6 months at 4 °C, 25 °C/60 % Relative Humidity (RH), and 40 °C/75 % RH. Cellular uptake studies in the human prostate cancer (PC-3) cell line confirmed effective internalization of the micelles. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated a concentration- and time-dependent cytotoxicity. F7 exhibited superior cytotoxicity among the tested formulations, compared to free BIC, while its blank formulation showed no significant toxicity, indicating favorable biocompatibility. These results suggest that the developed polymeric micelle systems have potential as stable and biocompatible delivery systems for BIC, warranting further investigation.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107395"},"PeriodicalIF":4.7,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700073","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 : 2025-12-04DOI: 10.1016/j.ejps.2025.107397
Simon Hoang Dinh , Christian Ding Fisker , Juulia Järvinen , Kati-Sisko Vellonen , Annette Bauer-Brandl , Poul Nielsen , Jarkko Rautio , Martin Brandl
Sorafenib is a multi-kinase inhibitor approved for several cancers with poor aqueous solubility, resulting in low oral bioavailability (38–49 %) despite its high permeability. As a BCS Class II compound, its absorption is solubility-/dissolution-limited. Prodrug strategies, such as phosphate esterification, can improve solubility and promote oral bioavailability upon enzymatic cleavage by intestinal alkaline phosphatase (IALP), abundantly expressed at the intestinal brush border membrane and present in the intestinal lumen. This cleavage is hypothesized to lead to a transient supersaturation of the parent drug, enhancing absorption unless (premature) precipitation prevails. Besides traditional in vitro models like Caco-2 cells, recently microdialysis-sampling has been introduced to study ALP-mediated biomimetic conversion of oral phosphate prodrugs in vitro. Microdialysis enables real-time, non-destructive sampling of molecularly dissolved drug, which allows to study the complex inter-related dynamics under (simulated) human gastrointestinal conditions.
In this study, a novel and new phosphate prodrug of sorafenib (fossorafenib) was synthesized and its physico-chemical and biopharmaceutical properties were evaluated. Fossorafenib exhibited ∼600-fold higher aqueous solubility than sorafenib in HBSS pH 7.4 and was rapidly cleaved by externally added alkaline phosphatase (ALP), yielding supersaturated sorafenib. Combined cleavage & permeability studies across Caco-2 cell monolayers demonstrated rapid bioconversion of fossorafenib in the apical compartment, with permeation of both the converted parent drug but, surprisingly, also the prodrug. Microdialysis enabled real-time monitoring of the biomimetic conversion of fossorafenib without the requirement for enzyme inactivation, thereby allowing for unprecedented mechanistic insights into the interplay between micellar solubilization and enzymatic cleavage. Microdialysis results suggest that micellar incorporation of fossorafenib into mixed micelles of bile salts and phospholipids can hinder enzymatic cleavage by intestinal ALP, thereby potentially limiting the extent of prodrug activation in the intestinal environment. Taken together with the unexpected ability of the prodrug to cross biological/biomimetic barriers, these findings suggest that fossorafenib may not follow the conventional behavior of classical phosphate-ester oral prodrugs in vivo, highlighting the need for further investigation into its unique biopharmaceutical profile.
{"title":"Synthesis, in vitro characterization and biopharmaceutical evaluation of a novel phosphate prodrug of sorafenib","authors":"Simon Hoang Dinh , Christian Ding Fisker , Juulia Järvinen , Kati-Sisko Vellonen , Annette Bauer-Brandl , Poul Nielsen , Jarkko Rautio , Martin Brandl","doi":"10.1016/j.ejps.2025.107397","DOIUrl":"10.1016/j.ejps.2025.107397","url":null,"abstract":"<div><div>Sorafenib is a multi-kinase inhibitor approved for several cancers with poor aqueous solubility, resulting in low oral bioavailability (38–49 %) despite its high permeability. As a BCS Class II compound, its absorption is solubility-/dissolution-limited. Prodrug strategies, such as phosphate esterification, can improve solubility and promote oral bioavailability upon enzymatic cleavage by intestinal alkaline phosphatase (IALP), abundantly expressed at the intestinal brush border membrane and present in the intestinal lumen. This cleavage is hypothesized to lead to a transient supersaturation of the parent drug, enhancing absorption unless (premature) precipitation prevails. Besides traditional in vitro models like Caco-2 cells, recently microdialysis-sampling has been introduced to study ALP-mediated biomimetic conversion of oral phosphate prodrugs in vitro. Microdialysis enables real-time, non-destructive sampling of molecularly dissolved drug, which allows to study the complex inter-related dynamics under (simulated) human gastrointestinal conditions.</div><div>In this study, a novel and new phosphate prodrug of sorafenib (fossorafenib) was synthesized and its physico-chemical and biopharmaceutical properties were evaluated. Fossorafenib exhibited ∼600-fold higher aqueous solubility than sorafenib in HBSS pH 7.4 and was rapidly cleaved by externally added alkaline phosphatase (ALP), yielding supersaturated sorafenib. Combined cleavage & permeability studies across Caco-2 cell monolayers demonstrated rapid bioconversion of fossorafenib in the apical compartment, with permeation of both the converted parent drug but, surprisingly, also the prodrug. Microdialysis enabled real-time monitoring of the biomimetic conversion of fossorafenib without the requirement for enzyme inactivation, thereby allowing for unprecedented mechanistic insights into the interplay between micellar solubilization and enzymatic cleavage. Microdialysis results suggest that micellar incorporation of fossorafenib into mixed micelles of bile salts and phospholipids can hinder enzymatic cleavage by intestinal ALP, thereby potentially limiting the extent of prodrug activation in the intestinal environment. Taken together with the unexpected ability of the prodrug to cross biological/biomimetic barriers, these findings suggest that fossorafenib may not follow the conventional behavior of classical phosphate-ester oral prodrugs in vivo, highlighting the need for further investigation into its unique biopharmaceutical profile.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107397"},"PeriodicalIF":4.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695903","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 : 2025-12-03DOI: 10.1016/j.ejps.2025.107396
Jingyan Hu , Jieting Wang , Junyang Zhuang , Heng Zhu , Ao Zhou , Jingyan Jia , Xueyang Ji , Yan Zhao , Luying Yu , Yu Deng , Ning Li , Fang Wang
The exclusion of chemo-drugs from their target sites, e.g. the nucleus, is a critical factor contributing to the failure of chemotherapy. Nanoparticle-based technology holds promise for specific delivery of chemo-drugs to nucleus. However, limited lysosomal escape, small size of nuclear pores and incapability of direct regulation of drug efflux-related transporters made great challenges for nanoparticles. Here, a zeolitic imidazolate framework-8 (ZIF-8)-based nanosystem was found able to disrupt lysosomes by the pH-responsiveness of ZIF-8 and mediate the nuclear entry of chemotherapeutics through promotion of their passive diffusion, resulting in the decrease of half maximal inhibitory concentration (IC50) by 3.4-fold compared to free drugs. The additional encapsulation of small interfering RNA (siRNA) to specifically silence multidrug resistance gene 1 (MDR1) for reduction of drug efflux further enhanced the chemotherapy of cancer with multidrug resistance (MDR) (IC50 reduced by 5.2-fold compared to free drugs). With a macrophage membrane biosurface coating onto the nanoparticles, targeted and potent synergistic chemo-gene therapy was achieved in mice bearing cancer with MDR. The unique function of promoting chemotherapeutic nuclear accumulation by ZIF-8-based nanoparticles to fight against MDR may deepen our understanding of the nano/bio-interactions and give novel insights into the design of smart bioresponsive nanosystems for advanced therapy.
{"title":"Enhanced nuclear enrichment of chemotherapeutics by a biomimetic ZIF-8 nanosystem for multidrug-resistant cancer treatment","authors":"Jingyan Hu , Jieting Wang , Junyang Zhuang , Heng Zhu , Ao Zhou , Jingyan Jia , Xueyang Ji , Yan Zhao , Luying Yu , Yu Deng , Ning Li , Fang Wang","doi":"10.1016/j.ejps.2025.107396","DOIUrl":"10.1016/j.ejps.2025.107396","url":null,"abstract":"<div><div>The exclusion of chemo-drugs from their target sites, <em>e.g.</em> the nucleus, is a critical factor contributing to the failure of chemotherapy. Nanoparticle-based technology holds promise for specific delivery of chemo-drugs to nucleus. However, limited lysosomal escape, small size of nuclear pores and incapability of direct regulation of drug efflux-related transporters made great challenges for nanoparticles. Here, a zeolitic imidazolate framework-8 (ZIF-8)-based nanosystem was found able to disrupt lysosomes by the pH-responsiveness of ZIF-8 and mediate the nuclear entry of chemotherapeutics through promotion of their passive diffusion, resulting in the decrease of half maximal inhibitory concentration (IC50) by 3.4-fold compared to free drugs. The additional encapsulation of small interfering RNA (siRNA) to specifically silence multidrug resistance gene 1 (MDR1) for reduction of drug efflux further enhanced the chemotherapy of cancer with multidrug resistance (MDR) (IC50 reduced by 5.2-fold compared to free drugs). With a macrophage membrane biosurface coating onto the nanoparticles, targeted and potent synergistic chemo-gene therapy was achieved in mice bearing cancer with MDR. The unique function of promoting chemotherapeutic nuclear accumulation by ZIF-8-based nanoparticles to fight against MDR may deepen our understanding of the nano/bio-interactions and give novel insights into the design of smart bioresponsive nanosystems for advanced therapy.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107396"},"PeriodicalIF":4.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687189","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 impacts of e-beam and X-ray irradiation on medical-grade high-density polyethylene (HDPE) are compared with that of gamma irradiation to evaluate their potential effects on pharmaceutical applications. An extensive suite of analytical techniques was employed to evaluate the chemical and physical transformations of irradiated HDPE. Key findings indicated that irradiation did not significantly alter the mechanical properties, as tensile strength and elongation at break remained stable across all irradiation types and doses. Thermal analysis via Differential Scanning Calorimetry (DSC) revealed a slight decrease in melting temperature at higher doses, with an equivalent melting temperature peak observed for all three irradiation technologies. Electron Spin Resonance (ESR) detected alkyl and allyl radicals, which decreased over time, showing no significant differences attributable to irradiation type or dose. Colorimetric analysis indicated yellowing in the samples, linked to specific additives. The quantification of methionine oxidized byproducts by High-Performance Liquid Chromatography (HPLC) demonstrated that the oxidation potential was equivalent for the three irradiation technologies for HDPE. The study concluded that there was a lack of significant impact of irradiation technologies on several physical, chemical and mechanical properties of HDPE.
{"title":"Comparative analysis of irradiation technologies on high-density polyethylene (HDPE) for biopharmaceutical applications","authors":"Blanche Krieguer , Fabien Girard , Samuel Dorey , Nathalie Dupuy , Sylvain R.A. Marque","doi":"10.1016/j.ejps.2025.107394","DOIUrl":"10.1016/j.ejps.2025.107394","url":null,"abstract":"<div><div>The impacts of e-beam and X-ray irradiation on medical-grade high-density polyethylene (HDPE) are compared with that of gamma irradiation to evaluate their potential effects on pharmaceutical applications. An extensive suite of analytical techniques was employed to evaluate the chemical and physical transformations of irradiated HDPE. Key findings indicated that irradiation did not significantly alter the mechanical properties, as tensile strength and elongation at break remained stable across all irradiation types and doses. Thermal analysis via Differential Scanning Calorimetry (DSC) revealed a slight decrease in melting temperature at higher doses, with an equivalent melting temperature peak observed for all three irradiation technologies. Electron Spin Resonance (ESR) detected alkyl and allyl radicals, which decreased over time, showing no significant differences attributable to irradiation type or dose. Colorimetric analysis indicated yellowing in the samples, linked to specific additives. The quantification of methionine oxidized byproducts by High-Performance Liquid Chromatography (HPLC) demonstrated that the oxidation potential was equivalent for the three irradiation technologies for HDPE. The study concluded that there was a lack of significant impact of irradiation technologies on several physical, chemical and mechanical properties of HDPE.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107394"},"PeriodicalIF":4.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676725","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 : 2025-12-01DOI: 10.1016/j.ejps.2025.107393
Tahani Saeedi , Mohannad Almikhlafi , Hossein M Elbadawy , Muayad S Albadrani , Rehab F Abdel-Rahman , Gihan F. Asaad , Fatma A Ibrahim , Aya A. Shokry , Tuba Esatbeyoglu , Sherif M. Afifi , Hany M Fayed , Marawan A. Elbaset
This study investigated the renoprotective action of linagliptin compared to doxorubicin against thioacetamide (TAA) and diethyl nitrosamine (DEN)-induced renocarcinogenesis in a rat model. Male Wistar rats were divided into control, renocarcinogenesis (RCC), doxorubicin group (7.5 mg/kg, i.p., once weekly), and linagliptin (Lina) groups (3 and 6 mg/kg/day, p.o.). The experiment included renal function parameters, oxidative stress markers, and predominant molecular pathways involved in renal pathogenesis. The RCC model significantly impaired renal function, as reflected in elevated serum levels of urea and creatinine. It also resulted in elevated oxidative stress, as reflected in increased malondialdehyde (MDA) content and decreased glutathione and superoxide dismutase (GSH and SOD) activities. The model disrupted several molecular pathways, including the AMP-activated protein kinase (AMPK) pathway, and enhanced oncogenic and inflammatory markers such as Yes-associated protein/ Transcriptional coactivator with PDZ-binding motif/ Hypoxia-inducible factor 1-alpha (YAP/TAZ/ HIF-1α), nuclear factor erythroid 2-related factor 2/ Sirtuin 1(Nrf2/SIRT1), and signal transducer and activator of transcription 3 (STAT3). Treatment with linagliptin, particularly the high dose (6 mg/kg/day), was found to be superior to doxorubicin treatment in terms of correction of renal function and markers of oxidative stress. Linagliptin effectively regulated the AMPK pathway, reduced markers of inflammation, restored the expression of genes with key roles in renal protection, reduced proliferating Cell Nuclear Antigen (PCNA), and elevated Caspase-3. The high dose of linagliptin exhibited superior results in most of the parameters, which approached control levels more than those with the lower dose and doxorubicin. These findings demonstrate that linagliptin, especially at 6 mg/kg/day, exhibits significant renoprotective activities through multifarious mechanisms involving antioxidant action and regulation of key molecular pathways. The present study presents evidence for the potential therapeutic application of linagliptin in renal manifestations of renocarcinogenesis.
{"title":"Linagliptin attenuates kidney cancer in rats via AMPK activation and suppression of YAP/TAZ/HIF-1α signaling","authors":"Tahani Saeedi , Mohannad Almikhlafi , Hossein M Elbadawy , Muayad S Albadrani , Rehab F Abdel-Rahman , Gihan F. Asaad , Fatma A Ibrahim , Aya A. Shokry , Tuba Esatbeyoglu , Sherif M. Afifi , Hany M Fayed , Marawan A. Elbaset","doi":"10.1016/j.ejps.2025.107393","DOIUrl":"10.1016/j.ejps.2025.107393","url":null,"abstract":"<div><div>This study investigated the renoprotective action of linagliptin compared to doxorubicin against thioacetamide (TAA) and diethyl nitrosamine (DEN)-induced renocarcinogenesis in a rat model. Male Wistar rats were divided into control, renocarcinogenesis (RCC), doxorubicin group (7.5 mg/kg, i.p., once weekly), and linagliptin (Lina) groups (3 and 6 mg/kg/day, p.o.). The experiment included renal function parameters, oxidative stress markers, and predominant molecular pathways involved in renal pathogenesis. The RCC model significantly impaired renal function, as reflected in elevated serum levels of urea and creatinine. It also resulted in elevated oxidative stress, as reflected in increased malondialdehyde (MDA) content and decreased glutathione and superoxide dismutase (GSH and SOD) activities. The model disrupted several molecular pathways, including the AMP-activated protein kinase (AMPK) pathway, and enhanced oncogenic and inflammatory markers such as Yes-associated protein/ Transcriptional coactivator with PDZ-binding motif/ Hypoxia-inducible factor 1-alpha (YAP/TAZ/ HIF-1α), nuclear factor erythroid 2-related factor 2/ Sirtuin 1(Nrf2/SIRT1), and signal transducer and activator of transcription 3 (STAT3). Treatment with linagliptin, particularly the high dose (6 mg/kg/day), was found to be superior to doxorubicin treatment in terms of correction of renal function and markers of oxidative stress. Linagliptin effectively regulated the AMPK pathway, reduced markers of inflammation, restored the expression of genes with key roles in renal protection, reduced proliferating Cell Nuclear Antigen (PCNA), and elevated Caspase-3. The high dose of linagliptin exhibited superior results in most of the parameters, which approached control levels more than those with the lower dose and doxorubicin. These findings demonstrate that linagliptin, especially at 6 mg/kg/day, exhibits significant renoprotective activities through multifarious mechanisms involving antioxidant action and regulation of key molecular pathways. The present study presents evidence for the potential therapeutic application of linagliptin in renal manifestations of renocarcinogenesis.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107393"},"PeriodicalIF":4.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667657","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 : 2025-11-29DOI: 10.1016/j.ejps.2025.107390
Mauro Sousa de Almeida , Amélie Bazzoni , Sandor Balog , Kata Dorbic , Céline Loussert-Fonta , Aura Maria Moreno-Echeverri , Jules Duruz , Jorge Larios , Anne-Marinette Cao , Amy Barton Alston , Reinaldo Digigow , Beat Flühmann , Alke Petri-Fink , Barbara Rothen-Rutishauser
Intravenous iron drugs are commonly used in the treatment of iron deficiency/iron deficiency anaemia. However, the cellular mechanisms underlying the uptake of these complexes remain poorly understood. This study examines the interaction of two iron complexes, iron sucrose and ferric-carboxymaltose, with murine J774A.1 and human M2a macrophages, focusing on their uptake and localization within lysosomal compartments at various time points: 45 min, 6 h, 24 h, and 5 days. We employed multiple analytical methods, including Prussian blue staining and transmission electron microscopy, to assess the intracellular iron complexes. In addition, the stability of the two complexes in cell culture medium and artificial lysosomal fluid was assessed by dynamic light scattering and transmission electron microscopy. A formation of larger aggregates for both complexes in cell culture medium was observed, likely due to interactions with serum proteins. The analysis in artificial lysosomal fluid revealed a slight, but not statistically significant, decrease in hydrodynamic diameter. Upon interaction with macrophages, our results demonstrate that iron sucrose is internalized more rapidly by both macrophage cell types compared to ferric carboxymaltose. Furthermore, the detection of ferric ions within intracellular and intralysosomal compartments occurs at a later time point following macrophage exposure to ferric carboxymaltose, suggesting slower internalization in comparison to iron sucrose. Our findings suggest that the two complexes remain intact upon reaching macrophages and, after internalization, are localized within intracellular vesicles, indicating endocytosis as the primary uptake mechanism. Iron sucrose was internalized more rapidly in comparison to ferric carboxymaltose by both macrophage types, whereas a decrease in metabolic activity was only observed for the J774A.1 macrophages in the presence of high iron sucrose concentration, i.e., 1mg/mL iron. These findings provide new insights into the dynamics of different iron-carbohydrate complexes on cellular uptake and may contribute to optimizing future drug designs.
{"title":"Comparing iron sucrose and ferric carboxymaltose interactions with murine and human macrophages: Focus on the lysosomal compartment","authors":"Mauro Sousa de Almeida , Amélie Bazzoni , Sandor Balog , Kata Dorbic , Céline Loussert-Fonta , Aura Maria Moreno-Echeverri , Jules Duruz , Jorge Larios , Anne-Marinette Cao , Amy Barton Alston , Reinaldo Digigow , Beat Flühmann , Alke Petri-Fink , Barbara Rothen-Rutishauser","doi":"10.1016/j.ejps.2025.107390","DOIUrl":"10.1016/j.ejps.2025.107390","url":null,"abstract":"<div><div>Intravenous iron drugs are commonly used in the treatment of iron deficiency/iron deficiency anaemia. However, the cellular mechanisms underlying the uptake of these complexes remain poorly understood. This study examines the interaction of two iron complexes, iron sucrose and ferric-carboxymaltose, with murine J774A.1 and human M2a macrophages, focusing on their uptake and localization within lysosomal compartments at various time points: 45 min, 6 h, 24 h, and 5 days. We employed multiple analytical methods, including Prussian blue staining and transmission electron microscopy, to assess the intracellular iron complexes. In addition, the stability of the two complexes in cell culture medium and artificial lysosomal fluid was assessed by dynamic light scattering and transmission electron microscopy. A formation of larger aggregates for both complexes in cell culture medium was observed, likely due to interactions with serum proteins. The analysis in artificial lysosomal fluid revealed a slight, but not statistically significant, decrease in hydrodynamic diameter. Upon interaction with macrophages, our results demonstrate that iron sucrose is internalized more rapidly by both macrophage cell types compared to ferric carboxymaltose. Furthermore, the detection of ferric ions within intracellular and intralysosomal compartments occurs at a later time point following macrophage exposure to ferric carboxymaltose, suggesting slower internalization in comparison to iron sucrose. Our findings suggest that the two complexes remain intact upon reaching macrophages and, after internalization, are localized within intracellular vesicles, indicating endocytosis as the primary uptake mechanism. Iron sucrose was internalized more rapidly in comparison to ferric carboxymaltose by both macrophage types, whereas a decrease in metabolic activity was only observed for the J774A.1 macrophages in the presence of high iron sucrose concentration, <em>i.e.</em>, 1mg/mL iron. These findings provide new insights into the dynamics of different iron-carbohydrate complexes on cellular uptake and may contribute to optimizing future drug designs.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"217 ","pages":"Article 107390"},"PeriodicalIF":4.7,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647884","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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