Pub Date : 2026-01-02DOI: 10.1016/j.jddst.2025.107967
Xuelai Zhang, Zongpeng Li, Jun Ji
Conventional cancer therapies suffer from severely constrained clinical efficacy due to severe off-target toxicity, prevalent multidrug resistance, and inherent limitations of monotherapy. Phase change materials (PCMs) provide novel paradigms to overcome these constraints through thermo-responsive controlled drug release and synergistic multimodal therapeutic mechanisms. PCMs exhibit inherent biocompatibility, biodegradability, high drug-loading capacity, tunable melting points, and cost-effectiveness, effectively preventing premature payload leakage while enabling controllable thermo-responsive release, thereby enhancing therapeutic efficacy. This review comprehensively addresses the construction methodologies and design principles of PCM-based nanoplatforms, which function as stringent gatekeepers and efficient payload delivery systems. It details innovative applications in combinatorial anticancer therapies including photothermal-chemotherapy, photodynamic therapy (PDT), and chemodynamic therapy (CDT). Furthermore, surface functionalization and microenvironment modulation strategies enhance tumor-selective accumulation and deep-tissue penetration efficiency. By systematically integrating the precision release attributes of PCMs with multimodal synergistic strategies, this work establishes new paradigms for overcoming tumor resistance and reducing systemic toxicity. Its extensible design framework and performance-boosting mechanisms hold significant promise for advancing clinical translation of next-generation intelligent drug delivery systems.
{"title":"Drug delivery system based on phase change material: thermo-responsive controlled release and multimodal synergistic therapy","authors":"Xuelai Zhang, Zongpeng Li, Jun Ji","doi":"10.1016/j.jddst.2025.107967","DOIUrl":"10.1016/j.jddst.2025.107967","url":null,"abstract":"<div><div>Conventional cancer therapies suffer from severely constrained clinical efficacy due to severe off-target toxicity, prevalent multidrug resistance, and inherent limitations of monotherapy. Phase change materials (PCMs) provide novel paradigms to overcome these constraints through thermo-responsive controlled drug release and synergistic multimodal therapeutic mechanisms. PCMs exhibit inherent biocompatibility, biodegradability, high drug-loading capacity, tunable melting points, and cost-effectiveness, effectively preventing premature payload leakage while enabling controllable thermo-responsive release, thereby enhancing therapeutic efficacy. This review comprehensively addresses the construction methodologies and design principles of PCM-based nanoplatforms, which function as stringent gatekeepers and efficient payload delivery systems. It details innovative applications in combinatorial anticancer therapies including photothermal-chemotherapy, photodynamic therapy (PDT), and chemodynamic therapy (CDT). Furthermore, surface functionalization and microenvironment modulation strategies enhance tumor-selective accumulation and deep-tissue penetration efficiency. By systematically integrating the precision release attributes of PCMs with multimodal synergistic strategies, this work establishes new paradigms for overcoming tumor resistance and reducing systemic toxicity. Its extensible design framework and performance-boosting mechanisms hold significant promise for advancing clinical translation of next-generation intelligent drug delivery systems.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"117 ","pages":"Article 107967"},"PeriodicalIF":4.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908706","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 inflammatory microenvironment is an extremely dynamic and multifaceted terrain that acutely affects the development and resolution of numerous diseases, such as autoimmune diseases, chronic infections, and cancer. This environment, which is influenced by immune cells, cytokines, chemokines, adhesion molecules, and enzymes, poses extreme challenges for successful drug delivery by undermining drug bioavailability, restricting tissue penetration, and inducing off-target effects. Of these mediators, cell adhesion molecules (CAMs) hold a significant position based on their pivotal function in leukocyte trafficking and immune cell infiltration, but are relatively less characterized as therapeutic targets. This review points towards CAMs as actionable starting points for targeted and theranostic drug delivery in the inflammatory microenvironment, and in doing so, plugs a significant void in the existing literature, which has, to a large extent, concentrated on cytokines and matrix metalloproteinases. We elucidate the limitations that restrain drug efficacy within inflamed tissues and review progressive delivery methods such as nanoparticle-based carriers, stimuli-responsive systems, and biomimetic strategies.
{"title":"Targeting cell adhesion molecules: Insight towards addressing targeted drug delivery in the inflammatory microenvironment","authors":"Vivek Pandey , Nikky Sharma , Rajinder Singh Kaundal , Tejasvi Pandey","doi":"10.1016/j.jddst.2025.107975","DOIUrl":"10.1016/j.jddst.2025.107975","url":null,"abstract":"<div><div>The inflammatory microenvironment is an extremely dynamic and multifaceted terrain that acutely affects the development and resolution of numerous diseases, such as autoimmune diseases, chronic infections, and cancer. This environment, which is influenced by immune cells, cytokines, chemokines, adhesion molecules, and enzymes, poses extreme challenges for successful drug delivery by undermining drug bioavailability, restricting tissue penetration, and inducing off-target effects. Of these mediators, cell adhesion molecules (CAMs) hold a significant position based on their pivotal function in leukocyte trafficking and immune cell infiltration, but are relatively less characterized as therapeutic targets. This review points towards CAMs as actionable starting points for targeted and theranostic drug delivery in the inflammatory microenvironment, and in doing so, plugs a significant void in the existing literature, which has, to a large extent, concentrated on cytokines and matrix metalloproteinases. We elucidate the limitations that restrain drug efficacy within inflamed tissues and review progressive delivery methods such as nanoparticle-based carriers, stimuli-responsive systems, and biomimetic strategies.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"116 ","pages":"Article 107975"},"PeriodicalIF":4.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1016/j.jddst.2026.107979
Dan Liu , Yaxian Yang , Jiacheng Meng , Honglei Guo , Xinchao Shi , Xin He , Xinghua Zhao
Berberine hydrochloride (BH) is a natural alkaloid compound known for its effectiveness in treating ulcerative colitis (UC). However, the clinical application of BH was limited due to the short half-life and rapid metabolism in body. Therefore, a sustained-release solid dispersion (SD) of BH was prepared using different proportions of ethyl cellulose as carrier. PXRD, DSC, and FT-IR analyses confirmed the transition of BH from a crystalline to amorphous state. This transformation significantly improved the drug release rate of BH and the pharmacokinetic characteristics in rats. The in vitro dissolution results showed that the cumulative dissolution rates of SD (1:4) were 29.47 % and 93.88 % at 10 min and 24 h respectively, and the in vivo study demonstrated that the t1/2 (0−24) and the AUC0−24 of SD (1:4) were 5.52 times and 6.30 times greater than those of BH, respectively, indicating SD (1:4) superior sustained-release effect compared to BH. In the acetic acid (AA)-induced UC rat model, SD treatment alleviates UC by increasing colon length, improving pathological damage, and reducing both the DAI score and levels of inflammatory factors. The 16S rRNA sequencing results indicated that SD treatment reshaped gut microbiota in rats with UC, particularly increasing the abundance of probiotic Romboutsia and decreasing the abundance of pathogenic bacteria Erysipelotrichaceae, Clostridia_UCG_014 and Dubosiella. In conclusion, we successfully prepared a sustained-release SD of BH and demonstrated that its therapeutic effect on UC is achieved by regulating intestinal microbiota.
{"title":"Berberine hydrochloride sustained-release solid dispersion alleviates acetic acid-induced ulcerative colitis in rats by modulating intestinal flora","authors":"Dan Liu , Yaxian Yang , Jiacheng Meng , Honglei Guo , Xinchao Shi , Xin He , Xinghua Zhao","doi":"10.1016/j.jddst.2026.107979","DOIUrl":"10.1016/j.jddst.2026.107979","url":null,"abstract":"<div><div>Berberine hydrochloride (BH) is a natural alkaloid compound known for its effectiveness in treating ulcerative colitis (UC). However, the clinical application of BH was limited due to the short half-life and rapid metabolism in body. Therefore, a sustained-release solid dispersion (SD) of BH was prepared using different proportions of ethyl cellulose as carrier. PXRD, DSC, and FT-IR analyses confirmed the transition of BH from a crystalline to amorphous state. This transformation significantly improved the drug release rate of BH and the pharmacokinetic characteristics in rats. The <em>in vitro</em> dissolution results showed that the cumulative dissolution rates of SD (1:4) were 29.47 % and 93.88 % at 10 min and 24 h respectively, and the <em>in vivo</em> study demonstrated that the t<sub>1/2 (0−24)</sub> and the AUC<sub>0−24</sub> of SD (1:4) were 5.52 times and 6.30 times greater than those of BH, respectively, indicating SD (1:4) superior sustained-release effect compared to BH. In the acetic acid (AA)-induced UC rat model, SD treatment alleviates UC by increasing colon length, improving pathological damage, and reducing both the DAI score and levels of inflammatory factors. The 16S rRNA sequencing results indicated that SD treatment reshaped gut microbiota in rats with UC, particularly increasing the abundance of probiotic <em>Romboutsia</em> and decreasing the abundance of pathogenic bacteria <em>Erysipelotrichaceae</em>, <em>Clostridia_UCG_014</em> and <em>Dubosiella</em>. In conclusion, we successfully prepared a sustained-release SD of BH and demonstrated that its therapeutic effect on UC is achieved by regulating intestinal microbiota.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"116 ","pages":"Article 107979"},"PeriodicalIF":4.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-02DOI: 10.1016/j.jddst.2025.107973
Yong Wang , Jie Pi , Yuzi Zhao , Qingzhen Xie
Ovarian cancer (OC) remains a highly lethal malignancy with substantial clinical challenges, including severe side effects and acquired resistance associated with conventional chemotherapeutics such as carboplatin (CBP). To address these limitations, we developed a dual-therapy nanoplatform by co-loading CBP and hyaluronic acid (HA) onto hyaluronic acid-functionalized manganese-based nanoparticles via a facile incubation method. The resulting CBP@HMnO2@HA nanoparticles exhibited a uniform hydrodynamic diameter of 210.3 nm and a zeta potential of −31.2 mV, enabling effective tumor-targeted delivery for combined chemotherapy and chemodynamic therapy. In vitro studies demonstrated that the nanoparticles markedly enhanced reactive oxygen species (ROS) generation via peroxidase-like activity and triggered immunogenic cell death (ICD), as evidenced by the pronounced release of damage-associated molecular patterns (DAMPs) including ATP and HMGB1. In vivo biodistribution studies showed significant tumor-specific accumulation within 24 h post-injection, leading to potent suppression of tumor growth. Mechanistically, the antitumor efficacy was associated with activation of the cGAS-STING signaling pathway. Collectively, these results indicate that CBP@HMnO2@HA nanoparticles possess integrated chemotherapeutic, chemodynamic, and robust catalytic functionalities, offering a promising multimodal nanotherapeutic strategy for the treatment of ovarian cancer.
{"title":"Hyaluronic acid-modified mesoporous manganese dioxide combined with carboplatin synergistically enhances ovarian cancer therapy","authors":"Yong Wang , Jie Pi , Yuzi Zhao , Qingzhen Xie","doi":"10.1016/j.jddst.2025.107973","DOIUrl":"10.1016/j.jddst.2025.107973","url":null,"abstract":"<div><div>Ovarian cancer (OC) remains a highly lethal malignancy with substantial clinical challenges, including severe side effects and acquired resistance associated with conventional chemotherapeutics such as carboplatin (CBP). To address these limitations, we developed a dual-therapy nanoplatform by co-loading CBP and hyaluronic acid (HA) onto hyaluronic acid-functionalized manganese-based nanoparticles via a facile incubation method. The resulting CBP@HMnO<sub>2</sub>@HA nanoparticles exhibited a uniform hydrodynamic diameter of 210.3 nm and a zeta potential of −31.2 mV, enabling effective tumor-targeted delivery for combined chemotherapy and chemodynamic therapy. <em>In vitro</em> studies demonstrated that the nanoparticles markedly enhanced reactive oxygen species (ROS) generation via peroxidase-like activity and triggered immunogenic cell death (ICD), as evidenced by the pronounced release of damage-associated molecular patterns (DAMPs) including ATP and HMGB1. <em>In vivo</em> biodistribution studies showed significant tumor-specific accumulation within 24 h post-injection, leading to potent suppression of tumor growth. Mechanistically, the antitumor efficacy was associated with activation of the cGAS-STING signaling pathway. Collectively, these results indicate that CBP@HMnO<sub>2</sub>@HA nanoparticles possess integrated chemotherapeutic, chemodynamic, and robust catalytic functionalities, offering a promising multimodal nanotherapeutic strategy for the treatment of ovarian cancer.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"117 ","pages":"Article 107973"},"PeriodicalIF":4.9,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145924213","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 : 2025-12-30DOI: 10.1016/j.jddst.2025.107961
Sivaraj Mehnath
Bacterial biofilms are a major etiological problem in oral diseases like peri-implantitis, periodontitis, denture-associated inflammation, and dental caries. Conventional mechanical debridement and chemical antiseptics were majorly failed to achieve complete eradication of biofilms, contribute to the persistence of pathogenic bacteria, and also induce antimicrobial resistance formation. These limitations highlight the urgent requirement for alternative, noninvasive techniques capable of selectively removing pathogenic microorganisms, while also preserving oral microbial balance. Antimicrobial sonodynamic therapy (aSDT) has emerged as a promising ultrasound-mediated therapy that activates sonosensitizers to generate reactive oxygen species (ROS) and induce mechanical and thermal effects, eventually causing oxidative damage to bacterial cells and disrupting biofilm integrity. The integration of nanomaterials has further improved aSDT by enhancing the stability, bioavailability, targeting ability, and sustained release of sonosensitizers. Nanosonosensitizers and nanocarrier-based materials also offer multifunctional capabilities, including synergistic antibiofilm activity, immune stimulation, and real-time infection tracking. This review highlights current concept on the mechanistic basis of aSDT, recent technology in organic and inorganic nanosonosensitizers, and their advantages in managing oral bacterial infections. Particular emphasis is focused on emerging smart nanoplatforms development to amplify ROS generation, accomplish infection-site targeting, and control host immune responses, along with an overview of current challenges and future directions in clinical translation.
{"title":"Nanomaterial-enhanced sonodynamic therapy for oral pathogens: A new frontier in biofilm eradication","authors":"Sivaraj Mehnath","doi":"10.1016/j.jddst.2025.107961","DOIUrl":"10.1016/j.jddst.2025.107961","url":null,"abstract":"<div><div>Bacterial biofilms are a major etiological problem in oral diseases like peri-implantitis, periodontitis, denture-associated inflammation, and dental caries. Conventional mechanical debridement and chemical antiseptics were majorly failed to achieve complete eradication of biofilms, contribute to the persistence of pathogenic bacteria, and also induce antimicrobial resistance formation. These limitations highlight the urgent requirement for alternative, noninvasive techniques capable of selectively removing pathogenic microorganisms, while also preserving oral microbial balance. Antimicrobial sonodynamic therapy (aSDT) has emerged as a promising ultrasound-mediated therapy that activates sonosensitizers to generate reactive oxygen species (ROS) and induce mechanical and thermal effects, eventually causing oxidative damage to bacterial cells and disrupting biofilm integrity. The integration of nanomaterials has further improved aSDT by enhancing the stability, bioavailability, targeting ability, and sustained release of sonosensitizers. Nanosonosensitizers and nanocarrier-based materials also offer multifunctional capabilities, including synergistic antibiofilm activity, immune stimulation, and real-time infection tracking. This review highlights current concept on the mechanistic basis of aSDT, recent technology in organic and inorganic nanosonosensitizers, and their advantages in managing oral bacterial infections. Particular emphasis is focused on emerging smart nanoplatforms development to amplify ROS generation, accomplish infection-site targeting, and control host immune responses, along with an overview of current challenges and future directions in clinical translation.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"116 ","pages":"Article 107961"},"PeriodicalIF":4.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880970","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 : 2025-12-30DOI: 10.1016/j.jddst.2025.107960
Ece Guler , Humeyra Betul Yekeler , Fatima Khaled Mohammed Abobakr , Zarife Nigar Ozdemir Kumral , Gul Sinemcan Ozcan , Melike Cakir , Gulsum Ercan , Muge Sennaroglu Bostan , Mehmet Eroglu , Muhammet Emin Cam
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that mainly affects the colon and causes symptoms such as hematochezia, rectal urgency, tenesmus, and abdominal pain. UC has a multifactorial pathogenesis, characterized by a complex interplay of genetic predisposition, environmental factors, and alteration in the gut microbiota. Traditional oral therapy, such as sulfasalazine (SSZ), is usually associated with systemic side effects and poor bioavailability. In response, the current study formulated and compared two rectally administered drug delivery systems, SSZ-loaded hydrogel (SSZIH) and SSZ-loaded nanofiber (SSZNF). Comprehensive characterization using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) demonstrated the integrity of composition, stability at body temperature, and the successful incorporation of all formulation ingredients into the drug delivery systems. Biocompatibility was also evaluated using an in vitro cytotoxicity assay. Moreover, in vivo test findings, assessed in a chemically induced colitis rat model showed that these formulations dramatically lowered oxidative stress indicators including malondialdehyde (MDA) and myeloperoxidase (MPO), and enhanced antioxidant enzyme activities glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)). These results suggest that SSZ delivery through a hydrogel and nanofiber system by the rectal pathway can be a more efficient and safer treatment for UC.
{"title":"In vitro and in vivo evaluation of rectal delivery of novel sulfasalazine-loaded hydrogels and nanofibers for enhanced ulcerative colitis therapy","authors":"Ece Guler , Humeyra Betul Yekeler , Fatima Khaled Mohammed Abobakr , Zarife Nigar Ozdemir Kumral , Gul Sinemcan Ozcan , Melike Cakir , Gulsum Ercan , Muge Sennaroglu Bostan , Mehmet Eroglu , Muhammet Emin Cam","doi":"10.1016/j.jddst.2025.107960","DOIUrl":"10.1016/j.jddst.2025.107960","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that mainly affects the colon and causes symptoms such as hematochezia, rectal urgency, tenesmus, and abdominal pain. UC has a multifactorial pathogenesis, characterized by a complex interplay of genetic predisposition, environmental factors, and alteration in the gut microbiota. Traditional oral therapy, such as sulfasalazine (SSZ), is usually associated with systemic side effects and poor bioavailability. In response, the current study formulated and compared two rectally administered drug delivery systems, SSZ-loaded hydrogel (SSZIH) and SSZ-loaded nanofiber (SSZNF). Comprehensive characterization using scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) demonstrated the integrity of composition, stability at body temperature, and the successful incorporation of all formulation ingredients into the drug delivery systems. Biocompatibility was also evaluated using an <em>in vitro</em> cytotoxicity assay. Moreover, <em>in vivo</em> test findings, assessed in a chemically induced colitis rat model showed that these formulations dramatically lowered oxidative stress indicators including malondialdehyde (MDA) and myeloperoxidase (MPO), and enhanced antioxidant enzyme activities glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT)). These results suggest that SSZ delivery through a hydrogel and nanofiber system by the rectal pathway can be a more efficient and safer treatment for UC.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"116 ","pages":"Article 107960"},"PeriodicalIF":4.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921693","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 : 2025-12-30DOI: 10.1016/j.jddst.2025.107974
Karla Viehmeister , Dirk F. Richter , Maria Wiedner , Alf Lamprecht
Human eyelids are a unique and underexplored biological barrier in view of drug delivery. Preliminary clinical evidence supports direct eyelid drug application, underscoring the value of refined in vitro models for advancing targeted ocular delivery. Thus, this study investigated drug permeation and penetration in human eyelid skin. Owing to the limited availability and small size of eyelid tissue donations, comparisons were made with thigh skin under equivalent experimental conditions, using Timolol maleate (TIM) and Dorzolamide hydrochloride (DZA) as model compounds. Both full thickness skin and isolated epidermis were tested, fresh and stored frozen. Skin structure was characterized by histology and microscopic imaging, thickness measurements, and transepidermal water loss (TEWL). Eyelid skin consistently showed 1.5-fold higher TEWL than thigh skin, reflecting its thinner stratum corneum (SC). Frozen storage did not affect TEWL in thigh or full thickness eyelid skin, but increased TEWL 2.7-fold in isolated eyelid epidermis, indicating barrier damage. After 6 h, permeation was increased in fresh eyelid epidermis (TIM: 17 ± 14 μg/cm2; DZA: 28 ± 28 μg/cm2) compared to fresh thigh epidermis (TIM: 1.13 ± 0.83 μg/cm2; DZA: 0.43 ± 0.29 μg/cm2) and markedly higher in epidermis from once-frozen eyelid tissue, reflecting barrier disruption. The results emphasize that thicker-SC membranes are unsuitable surrogates in eyelid formulation development. Frozen storage of eyelid skin should be carefully considered for in vitro permeation studies.
{"title":"In vitro human eyelid permeation of Timolol and Dorzolamide distinctly differs from analogue analyses with thigh skin","authors":"Karla Viehmeister , Dirk F. Richter , Maria Wiedner , Alf Lamprecht","doi":"10.1016/j.jddst.2025.107974","DOIUrl":"10.1016/j.jddst.2025.107974","url":null,"abstract":"<div><div>Human eyelids are a unique and underexplored biological barrier in view of drug delivery. Preliminary clinical evidence supports direct eyelid drug application, underscoring the value of refined in vitro models for advancing targeted ocular delivery. Thus, this study investigated drug permeation and penetration in human eyelid skin. Owing to the limited availability and small size of eyelid tissue donations, comparisons were made with thigh skin under equivalent experimental conditions, using Timolol maleate (TIM) and Dorzolamide hydrochloride (DZA) as model compounds. Both full thickness skin and isolated epidermis were tested, fresh and stored frozen. Skin structure was characterized by histology and microscopic imaging, thickness measurements, and transepidermal water loss (TEWL). Eyelid skin consistently showed 1.5-fold higher TEWL than thigh skin, reflecting its thinner stratum corneum (SC). Frozen storage did not affect TEWL in thigh or full thickness eyelid skin, but increased TEWL 2.7-fold in isolated eyelid epidermis, indicating barrier damage. After 6 h, permeation was increased in fresh eyelid epidermis (TIM: 17 ± 14 μg/cm<sup>2</sup>; DZA: 28 ± 28 μg/cm<sup>2</sup>) compared to fresh thigh epidermis (TIM: 1.13 ± 0.83 μg/cm<sup>2</sup>; DZA: 0.43 ± 0.29 μg/cm<sup>2</sup>) and markedly higher in epidermis from once-frozen eyelid tissue, reflecting barrier disruption. The results emphasize that thicker-SC membranes are unsuitable surrogates in eyelid formulation development. Frozen storage of eyelid skin should be carefully considered for in vitro permeation studies.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"116 ","pages":"Article 107974"},"PeriodicalIF":4.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145921772","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 : 2025-12-30DOI: 10.1016/j.jddst.2025.107966
Elsayed A. Elmorsy , Sameh Saber , Norah Suliman Alsoqih , Hamad Alsaykhan , Abdulaziz A. Alsalloom , Eman Hamza , Rabab S. Hamad , Zainab H. Almansour , Mostafa M. Khodeir , Attalla F. El-kott , Esmael M. Alyami , Waleed Eltantawy , Abdelrahman El-Sayed , Alshaimaa A. Farrag , Mohamed R. Abdel-Hamed , Maha M. Amer , Manal Mohamed Hatem , Walaa A. Allam , Hatim Y. Alharbi , Ahmed Y. Kira
Neurodegeneration in Alzheimer's disease (AD) remains an unmet therapeutic challenge. Brain delivery of promising agents such as Brilliant Blue G (BBG), a selective P2X7 receptor antagonist, is limited. This study aimed to develop and optimize mucoadhesive chitosan-coated spanlastic nanovesicles (Ct-SNVs) for efficient nose-to-brain delivery of BBG. SNVs were prepared by thin-film hydration and coated with chitosan via electrostatic adsorption. A 23 factorial design optimized the coating process to minimize drug loss and vesicle size while maximizing zeta potential. The optimized formulation yielded nanosized, positively charged vesicles with high encapsulation efficiency; DSC and FTIR of the BBG-Ct-SNVs showed the absence of the drug's crystalline thermal and spectral signatures, indicating its molecularly dispersed state within the vesicles. The coated system provided diffusion-controlled sustained release, strong mucoadhesion, and superior ex vivo nasal permeation and mucosal retention compared with uncoated SNVs. In vivo, BBG-Ct-SNVs increased peak brain concentrations by approximately twofold and enhanced targeting parameters, while sustaining drug levels for 24 h compared with the uncoated formulation. Molecular readouts showed that AlCl3 increased P2X7R expression. It activated both the NLRP3 inflammasome (elevated NLRP3, caspase-1 activity, IL-1β, and IL-18) and the cGAS–STING pathway (upregulated cGAS and STING mRNA; increased phosphorylated STING, TBK1, and IRF3), leading to induction of IFN-β and CXCL10. BBG-Ct-SNVs suppressed these signals more effectively than free BBG or uncoated SNVs. They also reduced cortical oxidative stress and Aβ1–42 burden. This study provides the first in vivo evidence in an AD-like context that intranasal BBG delivered via mucoadhesive spanlastic nanovesicles suppresses cGAS–STING signaling.
阿尔茨海默病（AD）的神经退行性变仍然是一个尚未解决的治疗挑战。有前途的药物如Brilliant Blue G (BBG)（一种选择性P2X7受体拮抗剂）的脑递送是有限的。本研究旨在开发和优化粘接壳聚糖包覆的塑料纳米囊泡（Ct-SNVs），用于高效的鼻部至脑输送BBG。采用薄膜水化法制备snv，静电吸附法制备壳聚糖包被。23因子设计优化了包衣工艺，以最大限度地减少药物损失和囊泡大小，同时最大化zeta电位。优化后的配方制备出纳米级、带正电的囊泡，包封效率高；bbg - ct - snv的DSC和FTIR显示没有药物的晶体热特征和光谱特征，表明其在囊泡内的分子分散状态。与未包被的snv相比，包被系统具有弥散控制的缓释、强黏附以及更好的体外鼻渗透和粘膜保留。在体内，与未包被制剂相比，BBG-Ct-SNVs将脑内峰值浓度提高了约两倍，并增强了靶向参数，同时维持药物水平24小时。分子读数显示AlCl3增加了P2X7R的表达。它激活NLRP3炎症小体（NLRP3、caspase-1活性升高、IL-1β和IL-18）和cGAS - STING途径（上调cGAS和STING mRNA；增加磷酸化的STING、TBK1和IRF3），导致IFN-β和CXCL10的诱导。BBG- ct - snv比游离BBG或未包被snv更有效地抑制这些信号。它们还能降低皮质氧化应激和a - β1 - 42负荷。本研究首次提供了在ad样环境下的体内证据，证明通过黏附性塑料纳米囊泡传递的鼻内BBG可抑制cGAS-STING信号。
{"title":"Targeted intranasal brain delivery of brilliant blue G via mucoadhesive spanlastic nanovesicles attenuates neuroinflammation by limiting cGAS–STING signaling","authors":"Elsayed A. Elmorsy , Sameh Saber , Norah Suliman Alsoqih , Hamad Alsaykhan , Abdulaziz A. Alsalloom , Eman Hamza , Rabab S. Hamad , Zainab H. Almansour , Mostafa M. Khodeir , Attalla F. El-kott , Esmael M. Alyami , Waleed Eltantawy , Abdelrahman El-Sayed , Alshaimaa A. Farrag , Mohamed R. Abdel-Hamed , Maha M. Amer , Manal Mohamed Hatem , Walaa A. Allam , Hatim Y. Alharbi , Ahmed Y. Kira","doi":"10.1016/j.jddst.2025.107966","DOIUrl":"10.1016/j.jddst.2025.107966","url":null,"abstract":"<div><div>Neurodegeneration in Alzheimer's disease (AD) remains an unmet therapeutic challenge. Brain delivery of promising agents such as Brilliant Blue G (BBG), a selective P2X7 receptor antagonist, is limited. This study aimed to develop and optimize mucoadhesive chitosan-coated spanlastic nanovesicles (Ct-SNVs) for efficient nose-to-brain delivery of BBG. SNVs were prepared by thin-film hydration and coated with chitosan via electrostatic adsorption. A 2<sup>3</sup> factorial design optimized the coating process to minimize drug loss and vesicle size while maximizing zeta potential. The optimized formulation yielded nanosized, positively charged vesicles with high encapsulation efficiency; DSC and FTIR of the BBG-Ct-SNVs showed the absence of the drug's crystalline thermal and spectral signatures, indicating its molecularly dispersed state within the vesicles. The coated system provided diffusion-controlled sustained release, strong mucoadhesion, and superior ex vivo nasal permeation and mucosal retention compared with uncoated SNVs. <em>In vivo</em>, BBG-Ct-SNVs increased peak brain concentrations by approximately twofold and enhanced targeting parameters, while sustaining drug levels for 24 h compared with the uncoated formulation. Molecular readouts showed that AlCl<sub>3</sub> increased P2X7R expression. It activated both the NLRP3 inflammasome (elevated NLRP3, caspase-1 activity, IL-1β, and IL-18) and the cGAS–STING pathway (upregulated cGAS and STING mRNA; increased phosphorylated STING, TBK1, and IRF3), leading to induction of IFN-β and CXCL10. BBG-Ct-SNVs suppressed these signals more effectively than free BBG or uncoated SNVs. They also reduced cortical oxidative stress and Aβ<sub>1</sub>–<sub>42</sub> burden. This study provides the first in vivo evidence in an AD-like context that intranasal BBG delivered via mucoadhesive spanlastic nanovesicles suppresses cGAS–STING signaling.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"116 ","pages":"Article 107966"},"PeriodicalIF":4.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881099","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}
Gender-affirming hormone therapy (GAHT) faces challenges such as fluctuating hormone levels and patient discomfort associated with conventional administration routes. Estradiol valerate (EV), a first-line hormone used in GAHT, exhibits poor aqueous solubility and limited compatibility with traditional delivery systems, underscoring the need for alternative transdermal delivery strategies. This study aimed to develop and evaluate an innovative transdermal drug delivery system using detachable dissolving microneedles (dMNs) loaded with EV-encapsulated polymeric micelles (EV-PMs). PMs significantly enhanced EV solubility, achieving an entrapment efficiency of approximately 100.67 ± 3.06 %. EV-PMs demonstrated spherical morphology, appropriate particle size (153 ± 3 nm), low polydispersity (0.36 ± 0.01), and stable zeta potential (−24.59 ± 2.10 mV). dMNs incorporating EV-PMs were fabricated using a micromolding technique, yielding dMN arrays with consistent mechanical properties and dimensions (height: 588.86 ± 0.89 μm; base width: 308.10 ± 0.11 μm). Mechanical tests demonstrated robust needle rigidity and skin penetration capability, achieving 100 % penetration in porcine skin. Histological analysis validated effective dMNs embedding at approximately 370.45 ± 13.67 μm depth. In vitro release studies showed a sustained EV release profile (43.71 ± 12.69 % over 120 h), following zero-order kinetics. Enhanced skin permeation (16.91 ± 3.58 %) and deposition (111.48 ± 11.49 μg) were observed with EV-PMs-loaded dMNs. This pioneering transdermal dMNs formulation presents a patient-friendly alternative, offering controlled hormone delivery with potentially significant improvements in adherence and therapeutic outcomes for transgender women undergoing feminizing hormone therapy.
{"title":"Fabrication of detachable polymeric microneedle patches incorporating estradiol valerate-loaded N-naphthyl-N,O-succinyl chitosan micelles for gender-affirming hormone therapy","authors":"Phuvamin Suriyaamporn , Teeratas Kansom , Warayuth Sajomsang , Tanasait Ngawhirunpat , Praneet Opanasopit , Boonnada Pamornpathomkul","doi":"10.1016/j.jddst.2025.107971","DOIUrl":"10.1016/j.jddst.2025.107971","url":null,"abstract":"<div><div>Gender-affirming hormone therapy (GAHT) faces challenges such as fluctuating hormone levels and patient discomfort associated with conventional administration routes. Estradiol valerate (EV), a first-line hormone used in GAHT, exhibits poor aqueous solubility and limited compatibility with traditional delivery systems, underscoring the need for alternative transdermal delivery strategies. This study aimed to develop and evaluate an innovative transdermal drug delivery system using detachable dissolving microneedles (dMNs) loaded with EV-encapsulated polymeric micelles (EV-PMs). PMs significantly enhanced EV solubility, achieving an entrapment efficiency of approximately 100.67 ± 3.06 %. EV-PMs demonstrated spherical morphology, appropriate particle size (153 ± 3 nm), low polydispersity (0.36 ± 0.01), and stable zeta potential (−24.59 ± 2.10 mV). dMNs incorporating EV-PMs were fabricated using a micromolding technique, yielding dMN arrays with consistent mechanical properties and dimensions (height: 588.86 ± 0.89 μm; base width: 308.10 ± 0.11 μm). Mechanical tests demonstrated robust needle rigidity and skin penetration capability, achieving 100 % penetration in porcine skin. Histological analysis validated effective dMNs embedding at approximately 370.45 ± 13.67 μm depth. <em>In vitro</em> release studies showed a sustained EV release profile (43.71 ± 12.69 % over 120 h), following zero-order kinetics. Enhanced skin permeation (16.91 ± 3.58 %) and deposition (111.48 ± 11.49 μg) were observed with EV-PMs-loaded dMNs. This pioneering transdermal dMNs formulation presents a patient-friendly alternative, offering controlled hormone delivery with potentially significant improvements in adherence and therapeutic outcomes for transgender women undergoing feminizing hormone therapy.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"116 ","pages":"Article 107971"},"PeriodicalIF":4.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145880646","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 : 2025-12-30DOI: 10.1016/j.jddst.2025.107972
Hao Sui , Shuhui Kang , Gang Wang, Xiaoya Pang, Ruixuan Wang, Li Zhang, Yunlan Li, Min Zhang, Qingping Tian
Clinical therapy for androgen alopecia (AGA) with single prescription is difficult to achieve satisfactory results. Previous studies have found ginsenoside Rg3 (Rg3) can enhance the efficacy of minoxidil (MXD). For investigating synergistic effect mechanism and obtaining reliable conclusions, this paper also selected glycyrrhizic acid (GA) with similar structure and activity to Rg3 for research. Firstly, the inhibition of Rg3 and GA on 5-α reductase (5-αR) and their antagonism to androgen receptor (AR) were pre-evaluated by molecular docking. Then, with Rg3 and GA as lipid flowing agents, transfersomes (TFs) with and without MXD were prepared (Rg3-MXD@TFs, Rg3@TFs, GA-MXD@TFs, GA@TFs) to assess the synergistic impact of Rg3 and GA in the therapy of AGA with MXD. It was found that local administration of testosterone (TTE) in mice could block Wnt/β-catenin pathway, and activating this pathway is the key to treat AGA. Although Rg3 and GA had good 5-αR inhibition and AR antagonism, which can eliminate the etiology of AGA, they had weak repair effect on damaged hair follicles (HFs), and their curative effect was lower than MXD when used alone. The synergistic effect of Rg3 and GA combined with MXD was related to up-regulating signal pathway and promoting the proliferation of HF cells, while the levels of ROS and inflammatory factors may be regulated by these processes. In conclusion, the combined application of Rg3 and GA with MXD can achieve the effect of treating both the symptoms and root causes of AGA, which would provide theoretical basis for guiding clinical combined medication.
{"title":"Mechanism exploration of the combined use of minoxidil with natural compounds ginsenoside Rg3 and glycyrrhizic acid for enhancing androgenic alopecia therapy","authors":"Hao Sui , Shuhui Kang , Gang Wang, Xiaoya Pang, Ruixuan Wang, Li Zhang, Yunlan Li, Min Zhang, Qingping Tian","doi":"10.1016/j.jddst.2025.107972","DOIUrl":"10.1016/j.jddst.2025.107972","url":null,"abstract":"<div><div>Clinical therapy for androgen alopecia (AGA) with single prescription is difficult to achieve satisfactory results. Previous studies have found ginsenoside Rg3 (Rg3) can enhance the efficacy of minoxidil (MXD). For investigating synergistic effect mechanism and obtaining reliable conclusions, this paper also selected glycyrrhizic acid (GA) with similar structure and activity to Rg3 for research. Firstly, the inhibition of Rg3 and GA on 5-α reductase (5-αR) and their antagonism to androgen receptor (AR) were pre-evaluated by molecular docking. Then, with Rg3 and GA as lipid flowing agents, transfersomes (TFs) with and without MXD were prepared (Rg3-MXD@TFs, Rg3@TFs, GA-MXD@TFs, GA@TFs) to assess the synergistic impact of Rg3 and GA in the therapy of AGA with MXD. It was found that local administration of testosterone (TTE) in mice could block Wnt/β-catenin pathway, and activating this pathway is the key to treat AGA. Although Rg3 and GA had good 5-αR inhibition and AR antagonism, which can eliminate the etiology of AGA, they had weak repair effect on damaged hair follicles (HFs), and their curative effect was lower than MXD when used alone. The synergistic effect of Rg3 and GA combined with MXD was related to up-regulating signal pathway and promoting the proliferation of HF cells, while the levels of ROS and inflammatory factors may be regulated by these processes. In conclusion, the combined application of Rg3 and GA with MXD can achieve the effect of treating both the symptoms and root causes of AGA, which would provide theoretical basis for guiding clinical combined medication.</div></div>","PeriodicalId":15600,"journal":{"name":"Journal of Drug Delivery Science and Technology","volume":"116 ","pages":"Article 107972"},"PeriodicalIF":4.9,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881031","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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