{"title":"Corrigendum to \"Preparation of thrombin-loaded calcium alginate microspheres with dual-mode imaging and study on their embolic properties in vivo\" [Eur. J. Pharm. Biopharm. 189 (2023) 98-108].","authors":"Tingting Han, Luping Chen, Fengyuan Gao, Song Wang, Jian Li, Guangwen Fan, Hailin Cong, Bing Yu, Youqing Shen","doi":"10.1016/j.ejpb.2025.114689","DOIUrl":"https://doi.org/10.1016/j.ejpb.2025.114689","url":null,"abstract":"","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":" ","pages":"114689"},"PeriodicalIF":4.4,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572569","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 : 2025-03-03DOI: 10.1016/j.ejpb.2025.114687
Paraskevi Kyriaki Monou, Eirini Saropoulou, Laura Andrade Junqueira, Siva Satyanarayana Kolipaka, Eleftherios G Andriotis, Emmanouil Tzimtzimis, Dimitrios Tzetzis, Chrysanthi Bekiari, Nikolaos Bouropoulos, Bethany Harding, Orestis L Katsamenis, Andreas Bramböck, Daniel Treffer, Dennis Douroumis, Dimitrios G Fatouros
Dissolving microneedles (MNs) are promising transdermal drug delivery systems that can effectively increase the absorption of the drugs. They bypass the first layer of the skin, the stratum corneum (SC) and deliver the drugs directly into the dermis, by dissolving inside the interstitial fluid and releasing the active. The traditional ways of MN fabrication involve primarily micromolding, which basically uses silicone molds. Drugs and polymer mixture solutions are poured into these molds and after drying the MN arrays are carefully removed. In the present study, a novel molding process was employed to fabricate dissolving MNs containing rivastigmine (RIV). RIV is available as an oral tablet and a transdermal patch. The patch (Exelon®), used for managing Alzheimer's symptoms in mild to moderate dementia, releases only about 50 % of its drug content, raising concerns about dose wastage, environmental impact, and patient costs. Thus, RIV was selected as the model drug to fabricate MNs by combining to novel processes, Digital Light Processing and Free-D Molding, a Vacuum Compression Molding (VCM) Technique provided by MeltPrep®. The developed arrays were evaluated regarding their physiochemical characteristics and their ability to penetrate the skin without breaking or creating fragments, as they can withstand forces up to 600 N. The MNs were visualized using optical microscopy, SEM, and CLSM to examine their geometry, surface and length (0.708 mm). Permeability studies verified that the MNs can increase significantly RIV transportation across the skin, up to 9-fold. Histological analysis was conducted to ensure that the produced MNs are safe for transdermal applications. Overall, the present study suggests that Free-D molding, a combination of 3D printing and VCM can produce dissolving MN arrays that are effective and safe for transdermal applications.
{"title":"Fabrication and characterization of dissolving microneedles combining Digital light processing and vacuum compression molding technique for the transdermal delivery of rivastigmine.","authors":"Paraskevi Kyriaki Monou, Eirini Saropoulou, Laura Andrade Junqueira, Siva Satyanarayana Kolipaka, Eleftherios G Andriotis, Emmanouil Tzimtzimis, Dimitrios Tzetzis, Chrysanthi Bekiari, Nikolaos Bouropoulos, Bethany Harding, Orestis L Katsamenis, Andreas Bramböck, Daniel Treffer, Dennis Douroumis, Dimitrios G Fatouros","doi":"10.1016/j.ejpb.2025.114687","DOIUrl":"https://doi.org/10.1016/j.ejpb.2025.114687","url":null,"abstract":"<p><p>Dissolving microneedles (MNs) are promising transdermal drug delivery systems that can effectively increase the absorption of the drugs. They bypass the first layer of the skin, the stratum corneum (SC) and deliver the drugs directly into the dermis, by dissolving inside the interstitial fluid and releasing the active. The traditional ways of MN fabrication involve primarily micromolding, which basically uses silicone molds. Drugs and polymer mixture solutions are poured into these molds and after drying the MN arrays are carefully removed. In the present study, a novel molding process was employed to fabricate dissolving MNs containing rivastigmine (RIV). RIV is available as an oral tablet and a transdermal patch. The patch (Exelon®), used for managing Alzheimer's symptoms in mild to moderate dementia, releases only about 50 % of its drug content, raising concerns about dose wastage, environmental impact, and patient costs. Thus, RIV was selected as the model drug to fabricate MNs by combining to novel processes, Digital Light Processing and Free-D Molding, a Vacuum Compression Molding (VCM) Technique provided by MeltPrep®. The developed arrays were evaluated regarding their physiochemical characteristics and their ability to penetrate the skin without breaking or creating fragments, as they can withstand forces up to 600 N. The MNs were visualized using optical microscopy, SEM, and CLSM to examine their geometry, surface and length (0.708 mm). Permeability studies verified that the MNs can increase significantly RIV transportation across the skin, up to 9-fold. Histological analysis was conducted to ensure that the produced MNs are safe for transdermal applications. Overall, the present study suggests that Free-D molding, a combination of 3D printing and VCM can produce dissolving MN arrays that are effective and safe for transdermal applications.</p>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":" ","pages":"114687"},"PeriodicalIF":4.4,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566400","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 : 2025-03-02DOI: 10.1016/j.ejpb.2025.114685
Magdy M Abdelquader, Shu Li, Gavin P Andrews, David S Jones
Therapeutic deep eutectic solvents (THEDES) are the liquids produced upon mixing two solid materials, where at least one of them is an active pharmaceutical ingredient. The strong hydrogen bonding (HB) between the parent materials is the reason for such profound depression in their melting points. THEDES formation can improve drugs' solubility and permeation characteristics. However, this can be limited by their encapsulation within drug delivery platforms e.g., polymeric matrices which might disrupt the HB network of THEDES by introducing new HB active sites into the mixture. Despite this, the effects of polymers on THEDES stability are not well-documented. In addition, the polymers' impact on THEDES formation during end-to-end production has not been studied. In this work, these issues were addressed by employing thermal processing of polymers and drugs. The dually active lidocaine: flurbiprofen (1:1) THEDES was utilized in addition to model polymers, namely polyethylene-co-vinyl acetate (PEVA), polyethylene oxide (PEO) and Eudragit® RL PO (EuRLPO). Firstly, probing the interaction between the polymers and the individual components of THEDES revealed that PEVA has no affinity towards both drugs while PEO can interact with flurbiprofen, and EuRLPO can interact with lidocaine. Then, to study the effect of the polymers on THEDES formation and stability, a valid in-situ method was developed to quantify THEDES in its mixture using modulated temperature differential scanning calorimetry (MTDSC). MTDSC data showed that the three polymers retarded THEDES formation in the following order PEVA < EuRLPO < PEO. This retardation was attributed to increased medium viscosity and the subsequent reduction in THEDES formation rate. Increasing the heating time led to complete THEDES formation in the case of PEVA and EuRLPO but not with PEO. This result was explained based on the polymers' interaction with THEDES parent drugs and inputs from polymers' viscoelastic properties. On the other hand, introducing the polymer after THEDES formation mitigated their viscosity effect but their interaction with the parent drugs remained an issue, where PEO and EuRLPO were able to destabilize the pre-formed THEDES to variable extents. Long-term storage stability study further confirmed this conclusion. Therefore, this study will provide valuable information regarding the interaction (or lack of) of THEDES with model pharmaceutical polymers that have been thermally processed and will provide recommendations regarding the rational choice of polymers to maintain THEDES stability.
{"title":"Studying the effects of polymers on therapeutic deep eutectic solvents' formation and stability: A thermal analysis-based approach to optimise polymer selection.","authors":"Magdy M Abdelquader, Shu Li, Gavin P Andrews, David S Jones","doi":"10.1016/j.ejpb.2025.114685","DOIUrl":"https://doi.org/10.1016/j.ejpb.2025.114685","url":null,"abstract":"<p><p>Therapeutic deep eutectic solvents (THEDES) are the liquids produced upon mixing two solid materials, where at least one of them is an active pharmaceutical ingredient. The strong hydrogen bonding (HB) between the parent materials is the reason for such profound depression in their melting points. THEDES formation can improve drugs' solubility and permeation characteristics. However, this can be limited by their encapsulation within drug delivery platforms e.g., polymeric matrices which might disrupt the HB network of THEDES by introducing new HB active sites into the mixture. Despite this, the effects of polymers on THEDES stability are not well-documented. In addition, the polymers' impact on THEDES formation during end-to-end production has not been studied. In this work, these issues were addressed by employing thermal processing of polymers and drugs. The dually active lidocaine: flurbiprofen (1:1) THEDES was utilized in addition to model polymers, namely polyethylene-co-vinyl acetate (PEVA), polyethylene oxide (PEO) and Eudragit® RL PO (EuRLPO). Firstly, probing the interaction between the polymers and the individual components of THEDES revealed that PEVA has no affinity towards both drugs while PEO can interact with flurbiprofen, and EuRLPO can interact with lidocaine. Then, to study the effect of the polymers on THEDES formation and stability, a valid in-situ method was developed to quantify THEDES in its mixture using modulated temperature differential scanning calorimetry (MTDSC). MTDSC data showed that the three polymers retarded THEDES formation in the following order PEVA < EuRLPO < PEO. This retardation was attributed to increased medium viscosity and the subsequent reduction in THEDES formation rate. Increasing the heating time led to complete THEDES formation in the case of PEVA and EuRLPO but not with PEO. This result was explained based on the polymers' interaction with THEDES parent drugs and inputs from polymers' viscoelastic properties. On the other hand, introducing the polymer after THEDES formation mitigated their viscosity effect but their interaction with the parent drugs remained an issue, where PEO and EuRLPO were able to destabilize the pre-formed THEDES to variable extents. Long-term storage stability study further confirmed this conclusion. Therefore, this study will provide valuable information regarding the interaction (or lack of) of THEDES with model pharmaceutical polymers that have been thermally processed and will provide recommendations regarding the rational choice of polymers to maintain THEDES stability.</p>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":" ","pages":"114685"},"PeriodicalIF":4.4,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556322","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 : 2025-03-02DOI: 10.1016/j.ejpb.2025.114684
Diana Tavares-Valente , Helena Moreira , Pedro Sousa , Manuela Amorim , António Conde , Manuela Pintado , João Fernandes , João Azevedo-Silva
Glucans, structural polysaccharides in the yeast cell wall, are known for their biological and immunomodulatory capacities, helping in prevention and management of infections. Herpes simplex virus type 1 (HSVI) is a prevalent infection that causes great comorbidity and is challenging to treat due to the adverse effects of standard antiviral drugs like acyclovir. This study assessed the potential of yeast glucans extracted from two different origins − a steviol-glycoside producing strain and a wild-type strain- to circumvent HSVI infection, either in vitro and ex vivo. Treatment with glucans in keratinocytes and macrophages in vitro reduced cell infection similarly to acyclovir. However, unlike acyclovir, glucans demonstrated an immunostimulatory effect, increasing the production of IL-1β, TNF-α and IL-6. Additionally, both glucans were formulated with squalane for skin application. This formulation improved glucans penetration in the skin, restored skin structure and reduced the cytopathic effect of HSVI infection. In summary, this study highlights yeast glucans as a natural therapeutic alternative for HSVI treatment, offering an option with an excellent safety profile. Moreover, using glucans from industrial side-streams promotes a sustainable approach, contributing to the circular economy.
{"title":"Breaking the virus: Yeast glucans as an effective alternative to acyclovir in HSVI treatment","authors":"Diana Tavares-Valente , Helena Moreira , Pedro Sousa , Manuela Amorim , António Conde , Manuela Pintado , João Fernandes , João Azevedo-Silva","doi":"10.1016/j.ejpb.2025.114684","DOIUrl":"10.1016/j.ejpb.2025.114684","url":null,"abstract":"<div><div>Glucans, structural polysaccharides in the yeast cell wall, are known for their biological and immunomodulatory capacities, helping in prevention and management of infections. Herpes simplex virus type 1 (HSVI) is a prevalent infection that causes great comorbidity and is challenging to treat due to the adverse effects of standard antiviral drugs like acyclovir. This study assessed the potential of yeast glucans extracted from two different origins − a steviol-glycoside producing strain and a wild-type strain- to circumvent HSVI infection, either <em>in vitro</em> and <em>ex vivo</em>. Treatment with glucans in keratinocytes and macrophages <em>in vitro</em> reduced cell infection similarly to acyclovir. However, unlike acyclovir, glucans demonstrated an immunostimulatory effect, increasing the production of IL-1β, TNF-α and IL-6. Additionally, both glucans were formulated with squalane for skin application. This formulation improved glucans penetration in the skin, restored skin structure and reduced the cytopathic effect of HSVI infection. In summary, this study highlights yeast glucans as a natural therapeutic alternative for HSVI treatment, offering an option with an excellent safety profile. Moreover, using glucans from industrial side-streams promotes a sustainable approach, contributing to the circular economy.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"210 ","pages":"Article 114684"},"PeriodicalIF":4.4,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-03-01DOI: 10.1016/j.ejpb.2025.114686
Ziru Zhang , Sheng Feng , Rasha El-Kanayati , Indrajeet Karnik , Sateesh Kumar Vemula , Michael A. Repka
The first-pass effect and low water solubility are crucial limitations that hinder the drug from being absorbed into the systemic circulation, followed by oral administration. The mucoadhesive buccal delivery system offers direct drug absorption through the mucosa, reaching systemic circulation and bypassing the hepatic first-pass metabolism. This approach ensures high bioavailability and overcomes the swallowing difficulties associated with traditional oral delivery systems. Here, we developed mucoadhesive buccal films for oral delivery of poorly water-soluble drugs using hot-melt extrusion (HME). Poly(2-ethyl-2-oxazoline) (PEtOx), a potential pharmaceutical excipient with high biocompatibility and versatility, was used as the primary matrix for solubility enhancement. Fenofibrate (FB), a typical Biopharmaceutics Classification System (BCS) class II drug with virtually insolubility in water, was used as the model drug. Hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and polyethylene oxide (PEO) were combined with PEtOx to adjust the mucoadhesive property. The prepared films were in vitro characterized to delineate the impact of key formulation factors on the mechanical properties, bioadhesion, and solubility enhancement effect. We demonstrated that the complexation of PEtOx with 20% PEO (F8) resulted in over 95% drug release within 2 h, representing an over 5-fold enhancement in solubility compared to the free drug. This F8 formulation exhibited significant bioadhesion among the other formulations, with a 2.2- to 2.7-fold increase in Peak Force (PAF) and work of adhesion (WAD) relative to the control group. This study investigates HME as a continuous fabrication process for developing PEtOx-based buccal film, demonstrating a potential bioadhesive drug delivery system with a solubility improvement effect.
{"title":"Novel development of Poly(2-ethyl-2-oxazoline)-based mucoadhesive buccal film for poorly water-soluble drug delivery via hot-melt extrusion","authors":"Ziru Zhang , Sheng Feng , Rasha El-Kanayati , Indrajeet Karnik , Sateesh Kumar Vemula , Michael A. Repka","doi":"10.1016/j.ejpb.2025.114686","DOIUrl":"10.1016/j.ejpb.2025.114686","url":null,"abstract":"<div><div>The first-pass effect and low water solubility are crucial limitations that hinder the drug from being absorbed into the systemic circulation, followed by oral administration. The mucoadhesive buccal delivery system offers direct drug absorption through the mucosa, reaching systemic circulation and bypassing the hepatic first-pass metabolism. This approach ensures high bioavailability and overcomes the swallowing difficulties associated with traditional oral delivery systems. Here, we developed mucoadhesive buccal films for oral delivery of poorly water-soluble drugs using hot-melt extrusion (HME). Poly(2-ethyl-2-oxazoline) (PEtOx), a potential pharmaceutical excipient with high biocompatibility and versatility, was used as the primary matrix for solubility enhancement. Fenofibrate (FB), a typical Biopharmaceutics Classification System (BCS) class II drug with virtually insolubility in water, was used as the model drug. Hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), and polyethylene oxide (PEO) were combined with PEtOx to adjust the mucoadhesive property. The prepared films were <em>in vitro</em> characterized to delineate the impact of key formulation factors on the mechanical properties, bioadhesion, and solubility enhancement effect. We demonstrated that the complexation of PEtOx with 20% PEO (F8) resulted in over 95% drug release within 2 h, representing an over 5-fold enhancement in solubility compared to the free drug. This F8 formulation exhibited significant bioadhesion among the other formulations, with a 2.2- to 2.7-fold increase in Peak Force (PAF) and work of adhesion (WAD) relative to the control group. This study investigates HME as a continuous fabrication process for developing PEtOx-based buccal film, demonstrating a potential bioadhesive drug delivery system with a solubility improvement effect.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"210 ","pages":"Article 114686"},"PeriodicalIF":4.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535177","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 : 2025-02-24DOI: 10.1016/j.ejpb.2025.114676
Yu-Chu Su , Yi-Cheng Chen , Yi-Hsuan Lo , Chien-Hsiang Chang , Yu-Fon Chen
This study introduces a novel targeted chemotherapy approach employing biocompatible nanogels engineered from hyaluronic acid (HA) and pitaya-derived DNA. Both polymers were functionalized with aldehyde groups, enabling crosslinking and subsequent encapsulation of doxorubicin (DOX). The incorporation of DNA significantly enhanced DOX loading, achieving a remarkable encapsulation efficiency of 93.3%. Notably, the integration of a hydrophobic 4,4′-dithiodianiline (DTD) linker facilitated controlled drug release within the reductive tumor microenvironment, with 36% of DOX released within 24 h in response to glutathione (GSH). These nanogels demonstrated targeted delivery to CD44-overexpressing cancer organoids, exhibiting a 6.7- to 15-fold increase in cellular uptake compared to free DOX. This enhanced intracellular DOX delivery significantly increased apoptosis in both cancer cells and organoids, as evidenced by increased condensed DNA and a 1.86- to 6.9-fold increase in poly ADP-ribose polymerase (PARP) expression. Importantly, hydrophobic interactions between the DTD linker and the cell membrane were found to significantly contribute to the efficient cellular uptake of the nanogels, resulting in a 2.6- to 9.1-fold reduction in IC50 values compared to free DOX. These findings highlight the potential of HA-based nanogels with cleavable linkers as promising platforms for targeted drug delivery and enhanced cancer therapy.
{"title":"Hydrophobic interactions enhance doxorubicin delivery from hyaluronic acid nanogels","authors":"Yu-Chu Su , Yi-Cheng Chen , Yi-Hsuan Lo , Chien-Hsiang Chang , Yu-Fon Chen","doi":"10.1016/j.ejpb.2025.114676","DOIUrl":"10.1016/j.ejpb.2025.114676","url":null,"abstract":"<div><div>This study introduces a novel targeted chemotherapy approach employing biocompatible nanogels engineered from hyaluronic acid (HA) and pitaya-derived DNA. Both polymers were functionalized with aldehyde groups, enabling crosslinking and subsequent encapsulation of doxorubicin (DOX). The incorporation of DNA significantly enhanced DOX loading, achieving a remarkable encapsulation efficiency of 93.3%. Notably, the integration of a hydrophobic 4,4′-dithiodianiline (DTD) linker facilitated controlled drug release within the reductive tumor microenvironment, with 36% of DOX released within 24 h in response to glutathione (GSH). These nanogels demonstrated targeted delivery to CD44-overexpressing cancer organoids, exhibiting a 6.7- to 15-fold increase in cellular uptake compared to free DOX. This enhanced intracellular DOX delivery significantly increased apoptosis in both cancer cells and organoids, as evidenced by increased condensed DNA and a 1.86- to 6.9-fold increase in poly ADP-ribose polymerase (PARP) expression. Importantly, hydrophobic interactions between the DTD linker and the cell membrane were found to significantly contribute to the efficient cellular uptake of the nanogels, resulting in a 2.6- to 9.1-fold reduction in IC<sub>50</sub> values compared to free DOX. These findings highlight the potential of HA-based nanogels with cleavable linkers as promising platforms for targeted drug delivery and enhanced cancer therapy.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"210 ","pages":"Article 114676"},"PeriodicalIF":4.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515104","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 : 2025-02-22DOI: 10.1016/j.ejpb.2025.114675
Shun Tian , Yun Liu , Yandi Tan , Xinwu Cui , Rong Liu , Chaoqi Liu , Yun Zhao , Kui Xu , Jun Zhou
Purpose
Breast cancer (BC) is a global threat to female health. Sonodynamic therapy (SDT) has been shown to induce apoptosis in tumor cells and trigger immunogenic cell death, leading to the activation of antitumor immunity. However, the immunogenicity of this process may be compromised by oxidative stress and proteolysis. Necroptosis caused by ultrasound-targeted nanobubble destruction (UTND) could boost immunity. Therefore, we tested if necroptosis-inducible nanobubbles (NB) could enhance sonodynamic immunotherapy for BC. We also assessed whether O2-filled NB could address tumor hypoxia and enhance SDT efficacy.
Methods
A novel multifunctional nano-system, comprising NB for UTND encapsulating chlorin e6 (Ce6) for SDT and O2 for hypoxia alleviation was established. Ce6-O2NB cytocompatibility and intracellular uptake was studied in vitro, as well as whether Ce6-O2NB could generated reactive oxygen species when exposed to ultrasound irradiation in order to induce apoptosis in tumor cells. In vivo pharmacokinetics, therapeutic efficacy, and immune activation after Ce6-O2NB treatment were studied in 4T1 tumor-bearing mice.
Results
Ce6-O2NB had a well-designed core–shell structure and desirable biocompatibility and safe therapeutic effects. Ce6-O2NB was able to load both ce6 and oxygen to increase ce6 and oxygen accumulation in tumors. After triggering by ultrasound, Ce6-O2NB generated reactive oxygen species (ROS) and acted as sonosensitizers for SDT, promoting tumor cell death through apoptotic and/or necrotic mechanisms. Furthermore, antitumor immunity was activated by stimulation of spleen lymphocyte proliferation and cytotoxicity, and increasing cytotoxic T lymphocyte numbers. Combination of oxygen with SDT ultimately strengthened its antitumor effects. In addition, Ce6-O2NB alleviated tumor hypoxia, induced increased ROS generation, and improved immune responses and therapeutic efficacy of SDT. Ce6-O2NB also facilitated fluorescence and contrast-enhanced ultrasound imaging.
Conclusions
Ce6-O2NB can mitigate tumor hypoxia, enhance SDT, and activate antitumor immunity by inducing simultaneous immunogenic apoptosis and necroptosis, ultimately activating antitumor immunity and inhibiting breast tumor growth in mice.
{"title":"Necroptosis-inducing nanobubbles for effective oxygen delivery and enhanced sonodynamic immunotherapy of breast cancer via UTND","authors":"Shun Tian , Yun Liu , Yandi Tan , Xinwu Cui , Rong Liu , Chaoqi Liu , Yun Zhao , Kui Xu , Jun Zhou","doi":"10.1016/j.ejpb.2025.114675","DOIUrl":"10.1016/j.ejpb.2025.114675","url":null,"abstract":"<div><h3>Purpose</h3><div>Breast cancer (BC) is a global threat to female health. Sonodynamic therapy (SDT) has been shown to induce apoptosis in tumor cells and trigger immunogenic cell death, leading to the activation of antitumor immunity. However, the immunogenicity of this process may be compromised by oxidative stress and proteolysis. Necroptosis caused by ultrasound-targeted nanobubble destruction (UTND) could boost immunity. Therefore, we tested if necroptosis-inducible nanobubbles (NB) could enhance sonodynamic immunotherapy for BC. We also assessed whether O<sub>2</sub>-filled NB could address tumor hypoxia and enhance SDT efficacy.</div></div><div><h3>Methods</h3><div>A novel multifunctional nano-system, comprising NB for UTND encapsulating chlorin e6 (Ce6) for SDT and O<sub>2</sub> for hypoxia alleviation was established. Ce6-O<sub>2</sub>NB cytocompatibility and intracellular uptake was studied <em>in vitro</em>, as well as whether Ce6-O<sub>2</sub>NB could generated reactive oxygen species when exposed to ultrasound irradiation in order to induce apoptosis in tumor cells. <em>In vivo</em> pharmacokinetics, therapeutic efficacy, and immune activation after Ce6-O<sub>2</sub>NB treatment were studied in 4T1 tumor-bearing mice.</div></div><div><h3>Results</h3><div>Ce6-O<sub>2</sub>NB had a well-designed core–shell structure and desirable biocompatibility and safe therapeutic effects. Ce6-O<sub>2</sub>NB was able to load both ce6 and oxygen to increase ce6 and oxygen accumulation in tumors. After triggering by ultrasound, Ce6-O<sub>2</sub>NB generated reactive oxygen species (ROS) and acted as sonosensitizers for SDT, promoting tumor cell death through apoptotic and/or necrotic mechanisms. Furthermore, antitumor immunity was activated by stimulation of spleen lymphocyte proliferation and cytotoxicity, and increasing cytotoxic T lymphocyte numbers. Combination of oxygen with SDT ultimately strengthened its antitumor effects. In addition, Ce6-O<sub>2</sub>NB alleviated tumor hypoxia, induced increased ROS generation, and improved immune responses and therapeutic efficacy of SDT. Ce6-O<sub>2</sub>NB also facilitated fluorescence and contrast-enhanced ultrasound imaging.</div></div><div><h3>Conclusions</h3><div>Ce6-O<sub>2</sub>NB can mitigate tumor hypoxia, enhance SDT, and activate antitumor immunity by inducing simultaneous immunogenic apoptosis and necroptosis, ultimately activating antitumor immunity and inhibiting breast tumor growth in mice.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"210 ","pages":"Article 114675"},"PeriodicalIF":4.4,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143491425","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}
Lipid nanoparticles (LNPs) have gained much attention as non-viral gene delivery systems due to their large payload capacity, reduced immunogenicity, and cost-effective manufacturing. Surface modification of LNPs by covalent attachment of receptor ligands can improve their tissue specificity and reduce off-target effects. In the present work, DNA-LNPs were therefore designed to target breast cancer, particularly the invasive HER2-positive subtype. Targeting was mediated by trastuzumab (Herceptin®) a monoclonal antibody binding to the extracellular domain of the human epidermal growth factor receptor protein (HER2). To overcome intrinsic trastuzumab resistance for some patients with HER2 positive breast cancer, a dual-targeting strategy was employed by combining Herceptin with folate to enhance LNP uptake by cancer cells.
Dual-targeted LNPs encapsulating plasmid DNA, coding for a fluorescent reporter protein (tdTomato or EGFP), were prepared using folate-conjugated PEGylated lipids. Subsequently, thiolated Herceptin was conjugated to the surface of the LNPs. At an N/P ratio of 6, small and uniform targeted LNPs were obtained, with a slightly negative ζ-potential. Cellular uptake and transgene expression were characterized in vitro using three breast cancer cell lines (MCF7, MDA-mb453, SKBR3), which express varying level of the HER2 receptor. Cellular uptake correlated with HER2 expression levels and was significantly increased when Herceptin was combined with folate. In all tested breast cancer cell lines, dual-targeted LNPs led to an enhanced transgene expression compared to single-targeted LNPs. Furthermore, in vivo zebrafish xenograft studies confirmed superior targeting and transfection efficiency of Dual-LNPs under physiological conditions.
Our findings highlight the superior performance of dual-targeted LNPs to deliver a DNA expression plasmid to HER2 positive breast cancer cells, emphasizing their potential as an improved targeting and transfection strategy.
{"title":"Dual targeted lipid nanoparticles for enhanced DNA delivery and transfection of breast cancer cells","authors":"Claudia Lotter , Megan Anna Stierli , Ramya Deepthi Puligilla, Jörg Huwyler","doi":"10.1016/j.ejpb.2025.114674","DOIUrl":"10.1016/j.ejpb.2025.114674","url":null,"abstract":"<div><div>Lipid nanoparticles (LNPs) have gained much attention as non-viral gene delivery systems due to their large payload capacity, reduced immunogenicity, and cost-effective manufacturing. Surface modification of LNPs by covalent attachment of receptor ligands can improve their tissue specificity and reduce off-target effects. In the present work, DNA-LNPs were therefore designed to target breast cancer, particularly the invasive HER2-positive subtype. Targeting was mediated by trastuzumab (Herceptin®) a monoclonal antibody binding to the extracellular domain of the human epidermal growth factor receptor protein (HER2). To overcome intrinsic trastuzumab resistance for some patients with HER2 positive breast cancer, a dual-targeting strategy was employed by combining Herceptin with folate to enhance LNP uptake by cancer cells.</div><div>Dual-targeted LNPs encapsulating plasmid DNA, coding for a fluorescent reporter protein (tdTomato or EGFP), were prepared using folate-conjugated PEGylated lipids. Subsequently, thiolated Herceptin was conjugated to the surface of the LNPs. At an N/P ratio of 6, small and uniform targeted LNPs were obtained, with a slightly negative ζ-potential. Cellular uptake and transgene expression were characterized <em>in<!--> <!-->vitro</em> using three breast cancer cell lines (MCF7, MDA-mb453, SKBR3), which express varying level of the HER2 receptor. Cellular uptake correlated with HER2 expression levels and was significantly increased when Herceptin was combined with folate. In all tested breast cancer cell lines, dual-targeted LNPs led to an enhanced transgene expression compared to single-targeted LNPs. Furthermore, <em>in<!--> <!-->vivo</em> zebrafish xenograft studies confirmed superior targeting and transfection efficiency of Dual-LNPs under physiological conditions.</div><div>Our findings highlight the superior performance of dual-targeted LNPs to deliver a DNA expression plasmid to HER2 positive breast cancer cells, emphasizing their potential as an improved targeting and transfection strategy.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"209 ","pages":"Article 114674"},"PeriodicalIF":4.4,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Approximately 90 % of NCEs in development and 40 % of recently approved drugs are poorly water-soluble. To improve solubility and stability, co-amorphous systems (CAMs) are used, involving the amorphization of an API with a co-former through interactions like hydrogen bonding. This study explores the co-amorphization of Raloxifene HCl (RLX) and Naringin (NRG). RLX, a BCS class II drug, has limited oral bioavailability of only 2 % due to its poor solubility (0.5 μg/mL) and extensive pre-systemic metabolism. Additionally, it interacts with CYP3A4 and P-glycoprotein (P-gp). NRG, a compound found in citrus fruits, inhibits both CYP3A4 and P-gp. Therefore, utilizing NRG to prepare RLX CAMs could result in a compound with improved solubility and enhanced bioavailability. CAMs were prepared using the solvent evaporation technique, followed by solid-state characterization at the molecular level. Solubility, drug release, and both ex vivo and in vitro studies were conducted. CAMs showed a 3.5-fold solubility increase and a 10-fold increase in ex-vivo permeation compared to RLX. In vivo studies showed an 8.1-fold improvement in Cmax and a 2.8-fold increase in AUC, indicating significantly enhanced bioavailability. These results suggest that co-amorphization could be a viable platform technology for improving API properties at the molecular level.
{"title":"Raloxifene HCl – Naringin co-amorphous system: Preparation, characterization and pharmacokinetic studies","authors":"Navya Sree Kola Srinivas , Dani Lakshman Yarlagadda , Brahmam Bheemishetty , Shaila Lewis , Swapnil Jayant Dengale , Krishnamurthy Bhat","doi":"10.1016/j.ejpb.2025.114667","DOIUrl":"10.1016/j.ejpb.2025.114667","url":null,"abstract":"<div><div>Approximately 90 % of NCEs in development and 40 % of recently approved drugs are poorly water-soluble. To improve solubility and stability, co-amorphous systems (CAMs) are used, involving the amorphization of an API with a co-former through interactions like hydrogen bonding. This study explores the co-amorphization of Raloxifene HCl (RLX) and Naringin (NRG). RLX, a BCS class II drug, has limited oral bioavailability of only 2 % due to its poor solubility (0.5 μg/mL) and extensive pre-systemic metabolism. Additionally, it interacts with CYP3A4 and P-glycoprotein (P-gp). NRG, a compound found in citrus fruits, inhibits both CYP3A4 and P-gp. Therefore, utilizing NRG to prepare RLX CAMs could result in a compound with improved solubility and enhanced bioavailability. CAMs were prepared using the solvent evaporation technique, followed by solid-state characterization at the molecular level. Solubility, drug release, and both ex vivo and in vitro studies were conducted. CAMs showed a 3.5-fold solubility increase and a 10-fold increase in ex-vivo permeation compared to RLX. In vivo studies showed an 8.1-fold improvement in Cmax and a 2.8-fold increase in AUC, indicating significantly enhanced bioavailability. These results suggest that co-amorphization could be a viable platform technology for improving API properties at the molecular level.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"209 ","pages":"Article 114667"},"PeriodicalIF":4.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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