Pub Date : 2026-01-19DOI: 10.1016/j.ejpb.2026.115003
Abdelrahman A. Elfarouny, Yusuf A. Haggag, Ebtessam A. Essa, Sanaa A. El-Gizawy
Simvastatin/Ezetimibe (SIM/EZE) is a widely prescribed hypolipidemic drug combination that provides substantial cardiovascular protection, particularly in high-risk patients. However, its poor dissolution and extensive first-pass metabolism limit gastrointestinal bioavailability, necessitating higher doses and thereby increasing the risk of adverse effects. In this study, we report a facile, robust, and easily scalable cholesterol–surfactant based nanocarrier system to enhance the oral delivery of SIM/EZE. Nanoparticles were prepared using Span 60 or Tween 80 in combination with cholesterol and optimized via a 23 factorial experimental design. The effects of surfactant type, surfactant-to-cholesterol ratio, and sonication time on formulation characteristics were systematically investigated. The optimized formulation, prepared with 1200 mg Span 60, 300 mg cholesterol, 40 mg SIM, and 10 mg EZE and sonicated for 40 min, exhibited spherical morphology, a small particle size (109.6 nm), a zeta potential of (−37.91 mV), and high encapsulation efficiency (97.39 % for SIM and 88.79 % for EZE). Stability testing confirmed the absence of degradation under physiological conditions and showed no significant changes over three months of storage. In vivo evaluation in a hyperlipidemic rat model demonstrated that the optimized formulation significantly reduced total cholesterol levels compared with both the marketed product (Inegy™) and the drug suspension, indicating enhanced oral absorption. These findings highlight the potential of this nanoparticle system as an effective platform to improve the therapeutic efficacy of the SIM/EZE fixed-dose combination.
{"title":"Facile Formulation of an Oral Nanovesicular Carrier Co-Encapsulating Simvastatin and Ezetimibe for Enhanced Lipid-Lowering Effect","authors":"Abdelrahman A. Elfarouny, Yusuf A. Haggag, Ebtessam A. Essa, Sanaa A. El-Gizawy","doi":"10.1016/j.ejpb.2026.115003","DOIUrl":"10.1016/j.ejpb.2026.115003","url":null,"abstract":"<div><div>Simvastatin/Ezetimibe (SIM/EZE) is a widely prescribed hypolipidemic drug combination that provides substantial cardiovascular protection, particularly in high-risk patients. However, its poor dissolution and extensive first-pass metabolism limit gastrointestinal bioavailability, necessitating higher doses and thereby increasing the risk of adverse effects. In this study, we report a facile, robust, and easily scalable cholesterol–surfactant based nanocarrier system to enhance the oral delivery of SIM/EZE. Nanoparticles were prepared using Span 60 or Tween 80 in combination with cholesterol and optimized <em>via</em> a 2<sup>3</sup> factorial experimental design. The effects of surfactant type, surfactant-to-cholesterol ratio, and sonication time on formulation characteristics were systematically investigated. The optimized formulation, prepared with 1200 mg Span 60, 300 mg cholesterol, 40 mg SIM, and 10 mg EZE and sonicated for 40 min, exhibited spherical morphology, a small particle size (109.6 nm), a zeta potential of (−37.91 mV), and high encapsulation efficiency (97.39 % for SIM and 88.79 % for EZE). Stability testing confirmed the absence of degradation under physiological conditions and showed no significant changes over three months of storage. In vivo evaluation in a hyperlipidemic rat model demonstrated that the optimized formulation significantly reduced total cholesterol levels compared with both the marketed product (Inegy™) and the drug suspension, indicating enhanced oral absorption. These findings highlight the potential of this nanoparticle system as an effective platform to improve the therapeutic efficacy of the SIM/EZE fixed-dose combination.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"221 ","pages":"Article 115003"},"PeriodicalIF":4.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-18DOI: 10.1016/j.ejpb.2026.114989
Kathrin Schorr, Johannes Konrad, Jan Birringer, Carsten Damm, Miriam Breunig, Achim Goepferich
Nanoparticles are frequently designed as carriers to mediate the active transport of their cargo to the site of action, thereby serving as effector particles. However, after their in vivo administration, they become quickly recognized by immune cells and are cleared from the systemic circulation. This significantly impairs the nanoparticles’ targeting efficiency and shifts the target/off-target ratio toward metabolizing organs. As engineering-driven strategies, such as the PEGylation of their surface, require major modifications of the nanoparticles’ structure and do not appear to achieve the desired level of effectiveness, synergistic approaches are attracting increasing attention. They rely on the transient blockade of the immune system through endocytosis inhibitors or decoy nanomaterials. In the present study, we introduce a further development of these synergistic approaches by loading lipid nanocapsules (LNCs) as decoy nanoparticles with the endocytosis inhibitor chloroquine. Two principal advantages can be ascribed to this refined synergistic approach: First, encapsulation of the endocytosis inhibitor paves the way for pioneering subcutaneous application as a novel route of administration for the effector nanoparticles, as phagocytic cells within the lymphatic system can be selectively targeted. Second, the established co-administration regime constitutes a transferable concept across diverse settings without the need for structural modifications of the respective effector nanoparticles. Here, we report the successful in vitro establishment of this refined coadministration regime. Preincubation with chloroquine-loaded LNCs led to a statistically significant uptake inhibition of model effector nanoparticles into macrophages. Moreover, we investigated, for the first time, the incorporation of 1,2-Dioleoyl-sn-glycero-3-phosphoserine as a macrophage-specific targeting structure into the decoy LNCs’ envelope and its effect on the phagocytosis activity of macrophages.
{"title":"A refined coadministration regime to mitigate immunological clearance of biomedical nanoparticles","authors":"Kathrin Schorr, Johannes Konrad, Jan Birringer, Carsten Damm, Miriam Breunig, Achim Goepferich","doi":"10.1016/j.ejpb.2026.114989","DOIUrl":"10.1016/j.ejpb.2026.114989","url":null,"abstract":"<div><div>Nanoparticles are frequently designed as carriers to mediate the active transport of their cargo to the site of action, thereby serving as effector particles. However, after their in vivo administration, they become quickly recognized by immune cells and are cleared from the systemic circulation. This significantly impairs the nanoparticles’ targeting efficiency and shifts the target/off-target ratio toward metabolizing organs. As engineering-driven strategies, such as the PEGylation of their surface, require major modifications of the nanoparticles’ structure and do not appear to achieve the desired level of effectiveness, synergistic approaches are attracting increasing attention. They rely on the transient blockade of the immune system through endocytosis inhibitors or decoy nanomaterials. In the present study, we introduce a further development of these synergistic approaches by loading lipid nanocapsules (LNCs) as decoy nanoparticles with the endocytosis inhibitor chloroquine. Two principal advantages can be ascribed to this refined synergistic approach: First, encapsulation of the endocytosis inhibitor paves the way for pioneering subcutaneous application as a novel route of administration for the effector nanoparticles, as phagocytic cells within the lymphatic system can be selectively targeted. Second, the established co-administration regime constitutes a transferable concept across diverse settings without the need for structural modifications of the respective effector nanoparticles. Here, we report the successful in vitro establishment of this refined coadministration regime. Preincubation with chloroquine-loaded LNCs led to a statistically significant uptake inhibition of model effector nanoparticles into macrophages. Moreover, we investigated, for the first time, the incorporation of 1,2-Dioleoyl-<em>sn</em>-glycero-3-phosphoserine as a macrophage-specific targeting structure into the decoy LNCs’ envelope and its effect on the phagocytosis activity of macrophages.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"221 ","pages":"Article 114989"},"PeriodicalIF":4.3,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146009357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-17DOI: 10.1016/j.ejpb.2026.114990
Maria Lteif , Sara Abratanska , Isabelle Turbica , Marc Pallardy
Immunogenicity is a major challenge to the development of biotherapeutics, and it is now well admitted that aggregation of therapeutic antibodies contributes to inducing an immunogenic response. The aim of this work was to investigate the THP-1 cell line as a model to evaluate antibodies (Ab) aggregates’ immunological effects, by studying internalization and cell activation. We generated aggregates by submitting infliximab (IFX), an immunogenic anti–TNF-α chimeric Ab, to a heat stress for various time of incubation. Of importance, some IFX aggregates, that were generated in mild conditions, altered THP-1 phenotype. Our results also showed that IFX aggregates are more internalized by THP-1 compared to the native antibody. Larger IFX aggregates, in particular, were able to modify THP-1 cells phenotype through the activation of the FcγRIIa-Syk pathway and to activate Syk in a Src-dependent manner. ERK kinase was also activated. Taken together, our results highlight the possibility of using the THP-1 cell line to assess the biological effects of Abs aggregates by measuring membrane markers and internalization.
免疫原性是生物疗法发展的一个主要挑战，目前公认治疗性抗体的聚集有助于诱导免疫原性反应。本研究的目的是通过研究内化和细胞活化，研究THP-1细胞系作为模型来评估抗体（Ab）聚集体的免疫效应。我们通过将免疫原性抗tnf -α嵌合抗体英夫利昔单抗（IFX）置于不同孵育时间的热应激中产生聚集体。重要的是，在温和条件下产生的一些IFX聚集体改变了THP-1表型。我们的研究结果还表明，与天然抗体相比，IFX聚集物更容易被THP-1内化。特别是，较大的IFX聚集体能够通过激活fc - γ riia -Syk途径来修饰THP-1细胞的表型，并以src依赖的方式激活Syk。ERK激酶也被激活。综上所述，我们的研究结果强调了利用THP-1细胞系通过测量膜标记和内化来评估Abs聚集体生物学效应的可能性。
{"title":"The THP-1 cell line as a model for the assessment of monoclonal antibodies aggregates’ immunological effects","authors":"Maria Lteif , Sara Abratanska , Isabelle Turbica , Marc Pallardy","doi":"10.1016/j.ejpb.2026.114990","DOIUrl":"10.1016/j.ejpb.2026.114990","url":null,"abstract":"<div><div>Immunogenicity is a major challenge to the development of biotherapeutics, and it is now well admitted that aggregation of therapeutic antibodies contributes to inducing an immunogenic response. The aim of this work was to investigate the THP-1 cell line as a model to evaluate antibodies (Ab) aggregates’ immunological effects, by studying internalization and cell activation. We generated aggregates by submitting infliximab (IFX), an immunogenic anti–TNF-α chimeric Ab, to a heat stress for various time of incubation. Of importance, some IFX aggregates, that were generated in mild conditions, altered THP-1 phenotype. Our results also showed that IFX aggregates are more internalized by THP-1 compared to the native antibody. Larger IFX aggregates, in particular, were able to modify THP-1 cells phenotype through the activation of the FcγRIIa-Syk pathway and to activate Syk in a Src-dependent manner. ERK kinase was also activated. Taken together, our results highlight the possibility of using the THP-1 cell line to assess the biological effects of Abs aggregates by measuring membrane markers and internalization.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"221 ","pages":"Article 114990"},"PeriodicalIF":4.3,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146002875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1016/j.ejpb.2026.114993
Caden Maners , Anthony J. Kyser , Davis Verhoeven , Bassam Fotouh , Arielle Greiner , Nicole M. Gilbert , Hermann B. Frieboes
Catheter-associated urinary tract infections (CAUTI) represent a large healthcare burden, accounting for a substantial portion of hospital-acquired infections in the United States. Solutions such as intermittent catheterization and catheter surface coatings with antibiotics or silver nanoparticles have offered limited success in preventing uropathogen biofilm formation on the catheter or in promoting a healthy urinary tract. This study explores a novel self-coating biomaterial approach for CAUTI applications, with the goal to promote antibacterial interference. A new fabrication technique is developed to incorporate thermally sensitive Lactobacillus bacteria into a silicone-based polymer. These species are known for their probiotic capabilities and were selected as a means for the material to self-coat with them. Using 3D-printed CAD-designed molds and bio-injection molding, “living probiotic carrier” catheter segments were formed with the probiotic-containing bioink. Lactobacillus-containing segments immersed in artificial urine media (AUM) increased in mass up to 7 days and remained stable at physiological conditions. Increased absorbance via crystal-violet staining indicated biomass accumulation while SEM imaging revealed a visibly large probiotic presence on the segment intraluminal surface over 7-day submersion in AUM. Mechanical integrity testing yielded Shore A hardness values within clinically acceptable ranges. TGA and DSC thermal stability analyses suggested that probiotic presence could affect silicone crosslinking, highlighting the need to fine-tune loading amount and composition of bacterial species to achieve desired polymeric degradation. Overall, the results demonstrate promising biomaterial properties along with lactobacilli biofilm formation, highlighting the potential for silicone catheters self-coated by thermally sensitive lactobacilli to offer a bacterial interference strategy against CAUTI.
{"title":"Fabrication of bioprints self-coated with thermally sensitive lactobacilli for CAUTI applications","authors":"Caden Maners , Anthony J. Kyser , Davis Verhoeven , Bassam Fotouh , Arielle Greiner , Nicole M. Gilbert , Hermann B. Frieboes","doi":"10.1016/j.ejpb.2026.114993","DOIUrl":"10.1016/j.ejpb.2026.114993","url":null,"abstract":"<div><div>Catheter-associated urinary tract infections (CAUTI) represent a large healthcare burden, accounting for a substantial portion of hospital-acquired infections in the United States. Solutions such as intermittent catheterization and catheter surface coatings with antibiotics or silver nanoparticles have offered limited success in preventing uropathogen biofilm formation on the catheter or in promoting a healthy urinary tract. This study explores a novel self-coating biomaterial approach for CAUTI applications, with the goal to promote antibacterial interference. A new fabrication technique is developed to incorporate thermally sensitive <em>Lactobacillus</em> bacteria into a silicone-based polymer. These species are known for their probiotic capabilities and were selected as a means for the material to self-coat with them. Using 3D-printed CAD-designed molds and bio-injection molding, “living probiotic carrier” catheter segments were formed with the probiotic-containing bioink. <em>Lactobacillus</em>-containing segments immersed in artificial urine media (AUM) increased in mass up to 7 days and remained stable at physiological conditions. Increased absorbance via crystal-violet staining indicated biomass accumulation while SEM imaging revealed a visibly large probiotic presence on the segment intraluminal surface over 7-day submersion in AUM. Mechanical integrity testing yielded Shore A hardness values within clinically acceptable ranges. TGA and DSC thermal stability analyses suggested that probiotic presence could affect silicone crosslinking, highlighting the need to fine-tune loading amount and composition of bacterial species to achieve desired polymeric degradation. Overall, the results demonstrate promising biomaterial properties along with lactobacilli biofilm formation, highlighting the potential for silicone catheters self-coated by thermally sensitive lactobacilli to offer a bacterial interference strategy against CAUTI.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"221 ","pages":"Article 114993"},"PeriodicalIF":4.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Magnetic nanoparticle hyperthermia (MNP-HT) has emerged as a promising non-invasive technique for targeted cancer therapy. This study presents a comprehensive computational analysis of the influence of urine volume on the efficacy of MNP-HT for the treatment of T1 non-muscle-invasive bladder cancer (NMIBC). A two-dimensional axisymmetric finite element model was developed, coupling solid tissue heat transfer with intravesical fluid dynamics. Magnetite (Fe3O4) nanoparticles with a mean diameter of 19 nm were excited using an alternating magnetic field at a frequency of 100 kHz. Four clinically relevant urine volumes (60, 120, 240, and 400 mL) were simulated to evaluate their effects on magnetic field distribution, nanoparticle power dissipation, convective heat transfer, and temperature distributions in both tumor and surrounding healthy tissues. Tissue heating was modeled using the Pennes bioheat equation, while urine flow and thermal transport were governed by the Navier–Stokes and energy equations. The results demonstrate a clear inverse relationship between urine volume and hyperthermia efficiency. Average tumor temperatures decreased from 41.89 °C at 60 mL to 41.51 °C at 400 mL due to enhanced convective cooling and reduced magnetic field–dependent nanoparticle power dissipation, while healthy tissue temperatures remained within safe therapeutic limits. These findings highlight urine volume as a critical physiological parameter influencing MNP-HT performance. To optimize thermal efficacy, clinical protocols should aim to minimize bladder urine volume before and during treatment through bladder emptying strategies and careful monitoring of bladder refilling.
{"title":"Computational analysis of the impact of urine volume on magnetic nanoparticle hyperthermia in the treatment of non-muscle-invasive bladder cancer","authors":"Sahar Marami , Mohammad Hossein Tavakoli , Abdolazim Sedighi Pashaki , Safoora Nikzad","doi":"10.1016/j.ejpb.2026.114992","DOIUrl":"10.1016/j.ejpb.2026.114992","url":null,"abstract":"<div><div>Magnetic nanoparticle hyperthermia (MNP-HT) has emerged as a promising non-invasive technique for targeted cancer therapy. This study presents a comprehensive computational analysis of the influence of urine volume on the efficacy of MNP-HT for the treatment of T1 non-muscle-invasive bladder cancer (NMIBC). A two-dimensional axisymmetric finite element model was developed, coupling solid tissue heat transfer with intravesical fluid dynamics. Magnetite (Fe<sub>3</sub>O<sub>4</sub>) nanoparticles with a mean diameter of 19 nm were excited using an alternating magnetic field at a frequency of 100 kHz. Four clinically relevant urine volumes (60, 120, 240, and 400 mL) were simulated to evaluate their effects on magnetic field distribution, nanoparticle power dissipation, convective heat transfer, and temperature distributions in both tumor and surrounding healthy tissues. Tissue heating was modeled using the Pennes bioheat equation, while urine flow and thermal transport were governed by the Navier–Stokes and energy equations. The results demonstrate a clear inverse relationship between urine volume and hyperthermia efficiency. Average tumor temperatures decreased from 41.89 °C at 60 mL to 41.51 °C at 400 mL due to enhanced convective cooling and reduced magnetic field–dependent nanoparticle power dissipation, while healthy tissue temperatures remained within safe therapeutic limits. These findings highlight urine volume as a critical physiological parameter influencing MNP-HT performance. To optimize thermal efficacy, clinical protocols should aim to minimize bladder urine volume before and during treatment through bladder emptying strategies and careful monitoring of bladder refilling.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"221 ","pages":"Article 114992"},"PeriodicalIF":4.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-13DOI: 10.1016/j.ejpb.2026.114991
Chengke Ding, Huiting Li, Pengbo Han, Yan Zhao
Tyrosinase-related protein 2 (Trp2) peptide-based vaccines hold great promise for melanoma immunotherapy, however, their application is often limited by inefficient antigen delivery, inadequate dendritic cell (DC)-mediated immune activation, and an immunosuppressive tumor microenvironment. To address these challenges, we developed an engineered cationic liposome vaccine platform for co-delivering Trp2 and a manganese-based adjuvant (MnJ). The Trp2-DOTAP-Lipo/MnJ system facilitates efficient antigen delivery to antigen-presenting cells via electrostatic interactions between the cationic lipid bilayer and negatively charged cell membranes, significantly enhancing antigen uptake, promoting DC maturation, stimulating the secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and levels of interleukin-6 (IL-6), and increasing cytotoxic T lymphocyte infiltration. Acting as a key amplifier of antigen-specific immunity, MnJ enhances antigen presentation and effector functions, which together with its role in localizing cytokine production, potently enhances anti-tumor immunity while minimizing systemic toxicity. In a murine melanoma model, Trp2-DOTAP-Lipo/MnJ exhibited significantly improved tumor suppression and extended survival. By combining nanocarrier engineering with innate immune activation, this strategy offers a robust combinatory therapeutic approach for melanoma, leveraging efficient antigen delivery and localized immunomodulation to overcome key obstacles in cancer immunotherapy.
{"title":"Trp2 cationic liposomes doped with manganese adjuvant potently activate dendritic cells to enhance antitumor activity against melanoma in mice","authors":"Chengke Ding, Huiting Li, Pengbo Han, Yan Zhao","doi":"10.1016/j.ejpb.2026.114991","DOIUrl":"10.1016/j.ejpb.2026.114991","url":null,"abstract":"<div><div>Tyrosinase-related protein 2 (Trp2) peptide-based vaccines hold great promise for melanoma immunotherapy, however, their application is often limited by inefficient antigen delivery, inadequate dendritic cell (DC)-mediated immune activation, and an immunosuppressive tumor microenvironment. To address these challenges, we developed an engineered cationic liposome vaccine platform for co-delivering Trp2 and a manganese-based adjuvant (MnJ). The Trp2-DOTAP-Lipo/MnJ system facilitates efficient antigen delivery to antigen-presenting cells via electrostatic interactions between the cationic lipid bilayer and negatively charged cell membranes, significantly enhancing antigen uptake, promoting DC maturation, stimulating the secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and levels of interleukin-6 (IL-6), and increasing cytotoxic T lymphocyte infiltration. Acting as a key amplifier of antigen-specific immunity, MnJ enhances antigen presentation and effector functions, which together with its role in localizing cytokine production, potently enhances anti-tumor immunity while minimizing systemic toxicity. In a murine melanoma model, Trp2-DOTAP-Lipo/MnJ exhibited significantly improved tumor suppression and extended survival. By combining nanocarrier engineering with innate immune activation, this strategy offers a robust combinatory therapeutic approach for melanoma, leveraging efficient antigen delivery and localized immunomodulation to overcome key obstacles in cancer immunotherapy.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"221 ","pages":"Article 114991"},"PeriodicalIF":4.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145976675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.ejpb.2026.114987
David S. Jones, M. Westwood, S. Li, Gavin P. Andrews
This study describes the surface, mechanical, swelling, microbial anti-adherence and drug release properties of rifampicin-containing interpenetrating hydrogel networks (IHNs) composed of either poly(hydroxyethylmethacrylate, p(HEMA)) or poly(methacrylic acid, p(MAA)) and Poloxamer block copolymers (grades F127, P123 and L121), prepared using free radical polymerisation and designed as coatings for urinary medical devices. The swelling and mechanical properties of the IHNs were affected by the polymethacrylate type, Poloxamer grade and concentration. Incorporation of Poloxamers decreased the crosslink density and increased the pore size of the hydrogels at pH 7.2 (calculated from swelling data), leading to enhanced IHN swelling and reduced ultimate tensile strength and Young’s Modulus. The static contact angles of the IHNs depended on the type of polymethacrylate but not on the Poloxamer grade/concentration. In particular, the contact angles of p(HEMA) IHNs were greater than for p(MAA) IHNs. The contact angles of p(MAA) IHNs at pH 4 were greater than those at pH 7.2. ATR-FTIR confirmed the presence of PEO at the surface of p(MAA)/F127 IHNs. Drug loading into (by swelling) and subsequent release at pH 7.2 buffer depended on polymethacrylate type, grade and concentration of Poloxamers. Rifampicin release from p(MAA) IHNs was significantly greater than from comparator p(HEMA) IHNs, due to both the greater loading of rifampicin and the increased pore size of these hydrogels. The mass of rifampicin loaded into the hydrogels was greater for p(MAA) IHNs Release of rifampicin from p(MAA) hydrogels at pH 4 (pre-swollen in rifampicin solutions at pH 7.2) involved burst release (dependent on and reduced by increasing concentration of Poloxamer), followed by slow, controlled release, again affected by Poloxamer concentration. p(HEMA) p(HEMA) IHNs significantly decreased microbial adherence, with the inclusion of rifampicin inhibiting microbial adherence at 4 h (for selected IHNs) and 24 h. Microbial adherence to rifampicin-containing p(MAA) IHNs following a 4-hour contact time was inhibited; however, given the rapid drug release, prolonged anti-adherence is unlikely. Conversely, the ability of Poloxamers to enhance and offer both greater control of rifampicin release from p(HEMA) IHNs and the more prolonged anti-adherence effects make these platforms more suitable for urinary application.
{"title":"Rifampicin-containing interpenetrating hydrogel networks (IHNs) based on poly(methacrylates) and Poloxamers, and their potential as short-duration use antimicrobial medical device biomaterials","authors":"David S. Jones, M. Westwood, S. Li, Gavin P. Andrews","doi":"10.1016/j.ejpb.2026.114987","DOIUrl":"10.1016/j.ejpb.2026.114987","url":null,"abstract":"<div><div>This study describes the surface, mechanical, swelling, microbial anti-adherence and drug release properties of rifampicin-containing interpenetrating hydrogel networks (IHNs) composed of either poly(hydroxyethylmethacrylate, p(HEMA)) or poly(methacrylic acid, p(MAA)) and Poloxamer block copolymers (grades F127, P123 and L121), prepared using free radical polymerisation and designed as coatings for urinary medical devices. The swelling and mechanical properties of the IHNs were affected by the polymethacrylate type, Poloxamer grade and concentration. Incorporation of Poloxamers decreased the crosslink density and increased the pore size of the hydrogels at pH 7.2 (calculated from swelling data), leading to enhanced IHN swelling and reduced ultimate tensile strength and Young’s <em>Modulus</em>. The static contact angles of the IHNs depended on the type of polymethacrylate but not on the Poloxamer grade/concentration. In particular, the contact angles of p(HEMA) IHNs were greater than for p(MAA) IHNs. The contact angles of p(MAA) IHNs at pH 4 were greater than those at pH 7.2. ATR-FTIR confirmed the presence of PEO at the surface of p(MAA)/F127 IHNs. Drug loading into (by swelling) and subsequent release at pH 7.2 buffer depended on polymethacrylate type, grade and concentration of Poloxamers. Rifampicin release from p(MAA) IHNs was significantly greater than from comparator p(HEMA) IHNs, due to both the greater loading of rifampicin and the increased pore size of these hydrogels. The mass of rifampicin loaded into the hydrogels was greater for p(MAA) IHNs Release of rifampicin from p(MAA) hydrogels at pH 4 (pre-swollen in rifampicin solutions at pH 7.2) involved burst release (dependent on and reduced by increasing concentration of Poloxamer), followed by slow, controlled release, again affected by Poloxamer concentration. p(HEMA) p(HEMA) IHNs significantly decreased microbial adherence, with the inclusion of rifampicin inhibiting microbial adherence at 4 h (for selected IHNs) and 24 h. Microbial adherence to rifampicin-containing p(MAA) IHNs following a 4-hour contact time was inhibited; however, given the rapid drug release, prolonged anti-adherence is unlikely. Conversely, the ability of Poloxamers to enhance and offer both greater control of rifampicin release from p(HEMA) IHNs and the more prolonged anti-adherence effects make these platforms more suitable for urinary application.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"221 ","pages":"Article 114987"},"PeriodicalIF":4.3,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.ejpb.2026.114988
Zhiling Chen , Huiling Zhou , Jie Song, Ben Xu, Can Wang, Fengchun He, Guisen Zhang, Tao Zhuang
Because the monotherapy of currently available pain killers often shows serious adverse effects or limited efficacy for treating neuropathic pain, multimodal analgesia has been highly recommended to gain improved antinociceptive effects and reduce dose-dependent side effects. Drug-drug co-amorphous systems emerge as a useful strategy for ameliorating the physicochemical properties of drug substances and achieving clinical benefits compared with individual components. New drug-drug co-amorphous products IMI-CEL at different ratios were prepared from imipramine hydrochloride (IMI) and a poorly water-soluble anti-inflammatory drug–celecoxib (CEL) by melt-quenching method, which were characterized by XRPD, DSC and IR. Co-amorphous product IMI-CEL (1:1) displayed notable improvement in the solubility (64.4 times) and dissolution rate (3.1 times) than crystalline CEL in pH 6.8 buffer, and IMI-CEL exhibited good physical stability under long-term storage conditions. Isobolographic analysis demonstrated that IMI-CEL (1:1) showed synergistic analgesic effects in paclitaxel-induced neuropathic pain in mice. Moreover, the oral bioavailability of 1:1 IMI-CEL was improved 1.396 times in rats when compared to the single drug. Above results suggested the potential of IMI-CEL to produce synergistic analgesic effects through developing drug-drug co-amorphous systems.
{"title":"A new drug-drug co-amorphous system of imipramine and celecoxib with improved solubility and synergistic antinociceptive effects","authors":"Zhiling Chen , Huiling Zhou , Jie Song, Ben Xu, Can Wang, Fengchun He, Guisen Zhang, Tao Zhuang","doi":"10.1016/j.ejpb.2026.114988","DOIUrl":"10.1016/j.ejpb.2026.114988","url":null,"abstract":"<div><div>Because the monotherapy of currently available pain killers often shows serious adverse effects or limited efficacy for treating neuropathic pain, multimodal analgesia has been highly recommended to gain improved antinociceptive effects and reduce dose-dependent side effects. Drug-drug co-amorphous systems emerge as a useful strategy for ameliorating the physicochemical properties of drug substances and achieving clinical benefits compared with individual components. New drug-drug co-amorphous products IMI-CEL at different ratios were prepared from imipramine hydrochloride (IMI) and a poorly water-soluble anti-inflammatory drug–celecoxib (CEL) by melt-quenching method, which were characterized by XRPD, DSC and IR. Co-amorphous product IMI-CEL (1:1) displayed notable improvement in the solubility (64.4 times) and dissolution rate (3.1 times) than crystalline CEL in pH 6.8 buffer, and IMI-CEL exhibited good physical stability under long-term storage conditions. Isobolographic analysis demonstrated that IMI-CEL (1:1) showed synergistic analgesic effects in paclitaxel-induced neuropathic pain in mice. Moreover, the oral bioavailability of 1:1 IMI-CEL was improved 1.396 times in rats when compared to the single drug. Above results suggested the potential of IMI-CEL to produce synergistic analgesic effects through developing drug-drug co-amorphous systems.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114988"},"PeriodicalIF":4.3,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1016/j.ejpb.2026.114980
Paula Gonzalez-Fernandez , Luca Morici , Luca Simula , Rajhi Takwa , Aya Benabdellah , Eric Allémann , Olivier Jordan
Osteoarthritis (OA) is the most common joint disease worldwide causing cartilage loss, inflammation and pain. Lorecivivint (LOR) is a new disease-modifying osteoarthritis drug (DMOAD) that targets the Wnt pathway to improve cartilage regeneration and reduce the pro-inflammatory cytokines production. However, its advancement in the clinical evaluation is facing certain challenges due to poor solubility and fast clearance from the joint. Our study is the first to improve LOR delivery using cationic liposomes for intra-articular injection.
DSPC-Chol-DOTAP-based liposomes were formulated using microfluidics with an encapsulation efficiency (EE) of 36 % of LOR and increasing the drug solubility over 120-fold in PBS and 100-fold in simulated synovial fluid. In a physiological environment, a prolonged release of 17 % of the LOR over 14 days was achieved, while faster release of 65 to 86 %, respectively, was observed in simulated synovial fluid. The surface charge of + 35 mV and the size of 145 nm were influential in increasing cartilage uptake in bovine explant of 1.4-fold and 3.6-fold compared to free LOR solution and suspension, respectively.
In vitro study by flow cytometry revealed there was no cytotoxicity at 10 nM in human chondrocytes (hCHs) and in human mesenchymal stem cells (MSCs). Nevertheless, some toxicity-related morphological changes in hCHs spheroids were observed at 300 nM, which corresponds to the IC80 of LOR. The safer liposomal concentration of 10 nM maintained the drug bioactivity and reduced by half TGF-β and IL-6 levels in two-dimensional hCHs and MSCs cell culture, which confirmed the anti-fibrotic and anti-inflammatory effects. An in vivo pilot study was conducted using a severe ACLT-hMnX rat model showing preliminary evidence of an alleviated osteophyte formation and reduced cartilage matrix loss in the medial tibial plateau. Overall, Lipo-LOR improved drug solubility, release and cartilage retention, which are critical requirements for implementing a localized intra-articular OA therapy.
{"title":"Cationic liposome-mediated intra-articular delivery of lorecivivint for osteoarthritis treatment","authors":"Paula Gonzalez-Fernandez , Luca Morici , Luca Simula , Rajhi Takwa , Aya Benabdellah , Eric Allémann , Olivier Jordan","doi":"10.1016/j.ejpb.2026.114980","DOIUrl":"10.1016/j.ejpb.2026.114980","url":null,"abstract":"<div><div>Osteoarthritis (OA) is the most common joint disease worldwide causing cartilage loss, inflammation and pain. Lorecivivint (LOR) is a new disease-modifying osteoarthritis drug (DMOAD) that targets the Wnt pathway to improve cartilage regeneration and reduce the pro-inflammatory cytokines production. However, its advancement in the clinical evaluation is facing certain challenges due to poor solubility and fast clearance from the joint. Our study is the first to improve LOR delivery using cationic liposomes for intra-articular injection.</div><div>DSPC-Chol-DOTAP-based liposomes were formulated using microfluidics with an encapsulation efficiency (EE) of 36 % of LOR and increasing the drug solubility over 120-fold in PBS and 100-fold in simulated synovial fluid. In a physiological environment, a prolonged release of 17 % of the LOR over 14 days was achieved, while faster release of 65 to 86 %, respectively, was observed in simulated synovial fluid. The surface charge of + 35 mV and the size of 145 nm were influential in increasing cartilage uptake in bovine explant of 1.4-fold and 3.6-fold compared to free LOR solution and suspension, respectively.</div><div><em>In vitro</em> study by flow cytometry revealed there was no cytotoxicity at 10 nM in human chondrocytes (hCHs) and in human mesenchymal stem cells (MSCs). Nevertheless, some toxicity-related morphological changes in hCHs spheroids were observed at 300 nM, which corresponds to the IC80 of LOR. The safer liposomal concentration of 10 nM maintained the drug bioactivity and reduced by half TGF-β and IL-6 levels in two-dimensional hCHs and MSCs cell culture, which confirmed the anti-fibrotic and anti-inflammatory effects. An <em>in vivo</em> pilot study was conducted using a severe ACLT-hMnX rat model showing preliminary evidence of an alleviated osteophyte formation and reduced cartilage matrix loss in the medial tibial plateau. Overall, Lipo-LOR improved drug solubility, release and cartilage retention, which are critical requirements for implementing a localized intra-articular OA therapy.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114980"},"PeriodicalIF":4.3,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Volumetric muscle loss (VML) results in permanent functional deficits for which current therapeutic strategies are insufficient. We hypothesized that an injectable, thermoresponsive hydrogel enabling localized delivery of agmatine sulfate (AgS) and hyaluronic acid (HA) could synergistically promote robust neuromuscular regeneration. A poloxamer-based thermogel was systematically optimized using a 32 full factorial design. The lead formulation exhibited a physiologically advantageous gelation temperature (27 ± 1.03°C) and time (42 ± 1.4 s), with rapid bioactive release (85–90% within 18–24 h) matched to the critical satellite cell activation window. In vitro degradation studies confirmed complete gel erosion, providing burst delivery during the acute injury phase. In a rat tibialis anterior VML model, the AgS-HA combination therapy demonstrated profound synergistic effects, restoring grip strength and normalizing complex gait parameters to near-control levels. This functional recovery was corroborated by significantly reduced serum creatine kinase, indicating reduced muscle damage. Histopathological analysis revealed near-complete restitution of mature, organized myofiber architecture with minimal fibrosis, contrasting with extensive scar tissue in control groups. Notably, functional recovery occurred without significant modulation of systemic inflammatory markers (IL-6, IL-10, TNF-α), suggesting regeneration proceeds through direct pro-myogenic, anti-fibrotic, and neurovascular mechanisms rather than systemic anti-inflammatory effects. These findings demonstrate that a thermoresponsive hydrogel platform for rapid AgS and HA delivery effectively promotes comprehensive structural and functional recovery, representing a potent and clinically translatable strategy for VML.
{"title":"Injectable poloxamer-based thermogel as a delivery platform for agmatine and hyaluronic acid in muscle tissue engineering","authors":"Mohammad Qutub , Amol Tatode , Tanvi Premchandani , Jayshree Taksande , Milind Umekar","doi":"10.1016/j.ejpb.2026.114983","DOIUrl":"10.1016/j.ejpb.2026.114983","url":null,"abstract":"<div><div>Volumetric muscle loss (VML) results in permanent functional deficits for which current therapeutic strategies are insufficient. We hypothesized that an injectable, thermoresponsive hydrogel enabling localized delivery of agmatine sulfate (AgS) and hyaluronic acid (HA) could synergistically promote robust neuromuscular regeneration. A poloxamer-based thermogel was systematically optimized using a 3<sup>2</sup> full factorial design. The lead formulation exhibited a physiologically advantageous gelation temperature (27 ± 1.03°C) and time (42 ± 1.4 s), with rapid bioactive release (85–90% within 18–24 h) matched to the critical satellite cell activation window. In vitro degradation studies confirmed complete gel erosion, providing burst delivery during the acute injury phase. In a rat tibialis anterior VML model, the AgS-HA combination therapy demonstrated profound synergistic effects, restoring grip strength and normalizing complex gait parameters to near-control levels. This functional recovery was corroborated by significantly reduced serum creatine kinase, indicating reduced muscle damage. Histopathological analysis revealed near-complete restitution of mature, organized myofiber architecture with minimal fibrosis, contrasting with extensive scar tissue in control groups. Notably, functional recovery occurred without significant modulation of systemic inflammatory markers (IL-6, IL-10, TNF-α), suggesting regeneration proceeds through direct pro-myogenic, anti-fibrotic, and neurovascular mechanisms rather than systemic anti-inflammatory effects. These findings demonstrate that a thermoresponsive hydrogel platform for rapid AgS and HA delivery effectively promotes comprehensive structural and functional recovery, representing a potent and clinically translatable strategy for VML.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"220 ","pages":"Article 114983"},"PeriodicalIF":4.3,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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