European Journal of Pharmaceutical Sciences最新文献

{"title":"Targeting the DKK1/CSF1 signaling axis to reprogram M2 macrophages and reverse chemoresistance in head and neck squamous cell carcinoma","authors":"Chin-Sheng Huang ,&nbsp;Chih-Ming Huang ,&nbsp;Hang Huong Ling ,&nbsp;Mao-Suan Huang ,&nbsp;Ming-Shou Hsieh ,&nbsp;Jia-Hong Chen","doi":"10.1016/j.ejps.2026.107435","DOIUrl":"10.1016/j.ejps.2026.107435","url":null,"abstract":"<div><h3>Background</h3><div>Understanding the mechanisms underlying drug resistance in head and neck squamous cell carcinoma (HNSCC) is critical for the development of effective therapeutic strategies. M2-type tumor-associated macrophages (M2-TAMs), activated by colony-stimulating factor 1 (CSF1), play a pivotal role in promoting chemoresistance and metastasis through immunosuppressive signaling and tumor–immune crosstalk. However, the precise mechanisms of CSF1-driven tumor support and macrophage activation remain incompletely understood.</div></div><div><h3>Methods</h3><div>We employed humanized patient-derived xenograft (PDX) models of drug-resistant HNSCC to examine the functional roles of CSF1 and its downstream effectors. Drug-tolerant persister (DTP) cells derived from these models were subjected to transcriptomic profiling. In vitro, both direct and indirect co-culture systems were used to assess the impact of CSF1 modulation on tumor cell viability and M2 macrophage activity. The therapeutic potential of the CSF1R inhibitor pexidartinib (PLX3397), alone and in combination with cisplatin, was evaluated in vivo.</div></div><div><h3>Results</h3><div>Our findings revealed that CSF1 silencing in M2 macrophages reduced the viability of cisplatin-resistant SCC9-P and HSC3-P cells in an indirect co-culture system, indicating a paracrine survival signal. In contrast, CSF1 overexpression enhanced tumor cell proliferation. In direct co-culture, CSF1 silencing inhibited M2 macrophage activation, whereas CSF1 overexpression promoted M2 proliferation and immunosuppressive activity. In vivo, pexidartinib effectively disrupted CSF1-mediated resistance and reduced the expression of key tumor-promoting factors, including DKK1, IL10, CXCL12, and AKT1. Clinically, high DKK1 and CSF1 expression correlated with cisplatin resistance and poor prognosis.</div></div><div><h3>Conclusion</h3><div>This study underscores the dual role of CSF1 in regulating both tumor survival and M2 macrophage activation in HNSCC. Targeting the DKK1/CSF1 axis may represent a promising strategy to overcome chemoresistance by disrupting tumor–macrophage crosstalk and reprogramming the immunosuppressive microenvironment.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107435"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145965775","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}

{"title":"Assembled fixed-dose combination tablet for hypertension: A modular design inspired by LEGO® architecture","authors":"Tanikan Sangnim ,&nbsp;Kittipat Suwanpitak ,&nbsp;Pornsak Sriamornsak ,&nbsp;Kampanart Huanbutta","doi":"10.1016/j.ejps.2026.107430","DOIUrl":"10.1016/j.ejps.2026.107430","url":null,"abstract":"<div><div>Polypharmacy in chronic diseases like hypertension often compromises patient adherence and therapeutic success due to complex regimens. While conventional fixed-dose combination (FDC) tablets improve adherence, they lack the dose flexibility needed for personalized treatment. This study addresses this gap by developing and characterizing a novel, LEGO®-inspired assemblable FDC tablet system for customizable antihypertensive therapy. Using 3D-printed molds, individual, stackable modules containing either Amlodipine, Valsartan, or Hydrochlorothiazide (HCTZ) were created. The study evaluated two polymer matrices, revealing a critical dependence on the active pharmaceutical ingredient (API). Gelatin-based matrices were effective for Amlodipine and Valsartan, achieving rapid drug with USP dissolution standards; however, this matrix was incompatible release (&gt;90% within 30 min) compliant with HCTZ. Conversely, an HPMC-based matrix successfully formulated HCTZ with a controlled-release profile but was unsuitable for the other two drugs. This work validates the proof-of-concept for a modular FDC system as a promising platform for personalized polypharmacy. However, it also highlights that achieving desired drug release profiles requires careful, API-specific polymer selection, presenting a key formulation challenge for this innovative approach.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107430"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145941418","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}

{"title":"BM-164 (an H₂S-donor) modulates microRNA expression associated with reperfusion-induced ventricular fibrillation in rat hearts","authors":"E. Szabó ,&nbsp;J. Király ,&nbsp;A.B. Mondal ,&nbsp;I. Bereczki ,&nbsp;Z. Szabó ,&nbsp;Á. Tósaki","doi":"10.1016/j.ejps.2026.107433","DOIUrl":"10.1016/j.ejps.2026.107433","url":null,"abstract":"<div><div>Ventricular arrhythmias are a leading cause of sudden cardiac death in myocardial infarction and heart failure. Reperfusion following ischemia can trigger severe arrhythmias, including ventricular fibrillation (VF), and microRNAs (miRNAs) which are increasingly recognized as critical regulators of these processes.</div><div>This study aimed to identify miRNAs associated with ischemia/reperfusion (I/R)-induced ventricular fibrillation by comparing expression profiles between fibrillated (VF) and non-fibrillated (No VF) rat hearts. Nanostring-based screening (<em>n</em> = 12; 4 in each group: No I/R control, I/R no VF, and I/R VF) identified several ischemia-associated miRNAs, including rno-miR-30d, rno-miR-99a, rno-miR-130a, rno-miR-133a, rno-miR-181a, and rno-miR-191a. These candidates were subsequently validated in a larger cohort using TaqMan qRT-PCR (qPCR), including BM-164- and ascorbic acid (AA)-pretreated I/R groups administered 10 min before I/R (<em>n</em> = 6 per group). The selection of these miRNAs was guided by prior literature demonstrating their established roles in ischemia-related pathways and cardioprotection, providing a biologically grounded rationale for their inclusion.</div><div>qPCR analysis, compared with Nanostring data on a Rat miRNA panel v1.5 (425 miRNAs), revealed significant alterations in a subset of these miRNAs in I/R hearts, particularly in VF-affected samples. BM-164, an H_₂S-donor, and to a lesser extent AA, were associated with partial restoration or upregulation of these miRNAs. These findings suggest that the examined miRNAs, particularly miR-99a, miR-191a, miR-30d, and miR-181a, are likely involved in the development of reperfusion-induced ventricular arrhythmias. BM-164 pretreatment was associated with changes of these miRNAs, which have been previously implicated in autophagy and apoptosis pathways; further studies are warranted to determine whether these alterations directly mediate cardioprotection or anti-arrhythmic effects.</div><div>Given the limited sample size, these findings should be considered preliminary. Larger cohorts and additional in vivo studies are required to clarify whether these miRNA alterations causally contribute to arrhythmogenesis or represent protective responses.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107433"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942953","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}

{"title":"Impact of cocrystal dissolution-supersaturation-precipitation (DSP) behaviour on drug permeation across the PermeaPad® biomimetic barrier","authors":"Lucy May Newman ,&nbsp;Matteo Guidetti ,&nbsp;Annette Bauer-Brandl ,&nbsp;Naír Rodríguez-Hornedo ,&nbsp;Tatiane Cogo Machado","doi":"10.1016/j.ejps.2025.107426","DOIUrl":"10.1016/j.ejps.2025.107426","url":null,"abstract":"<div><div>The purpose of this study was to evaluate how the dissolution-supersaturation-precipitation (DSP) behaviour of cocrystals translates into drug permeation<strong>,</strong> employing the biomimetic PermeaPad® barrier in a side-by-side cell set-up. Building on our previous work, which demonstrated that reducing an unnecessarily high cocrystal solubility advantage (SA = S_cocrystal/S_drug) through the generation of non-stoichiometric solution conditions can significantly extend the drug supersaturation, we now investigate this approach in the presence of an absorptive environment. Our findings with the 1:1 ketoconazole (KTZ) -<em>p</em>-aminobenzoic acid (PABA) cocrystal indicate the existence of an optimal SA value (7), where KTZ-PABA dissolution performance resulted in 8-fold AUC increase, translating to a 7-fold increase in cumulative KTZ permeation after 6 h. This enhancement was achieved by dissolving cocrystal (based on the drug therapeutic dose) with an additional coformer solid phase, rationally designed using a graphical approach grounded in the cocrystal thermodynamic (K_sp, S_cocrystal, S_drug) and kinetic parameters (σ_crit). The strategy presented in this work can be readily applied during the pre-formulation stage of cocrystal development, enabling targeted selection of coformer concentrations for formulation development. Overall cocrystals offer unique flexibility as a formulation strategy for poorly water-soluble drugs, allowing for tailored DSP behaviour and drug transport over biological barriers based on mechanistic understanding<strong>,</strong> as demonstrated in this study.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107426"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896350","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}

{"title":"Calcitriol-mediated modulation of organic anion transporters: Insights from endogenous biomarkers and methotrexate pharmacokinetics","authors":"Dang-Khoa Vo,&nbsp;Thi-Thao-Linh Nguyen,&nbsp;Seul-A Joo,&nbsp;Han-Joo Maeng","doi":"10.1016/j.ejps.2026.107454","DOIUrl":"10.1016/j.ejps.2026.107454","url":null,"abstract":"<div><div>This study aimed to investigate the effects of calcitriol on endogenous biomarkers taurine and pyridoxic acid (PDA) associated with the organic anion transporters Oat1 and Oat1/3, respectively, and compare these changes with those observed for the clinical substrate, methotrexate (MTX). Male rats were administered intraperitoneal (i.p.) injections of either vehicle (maize oil) or calcitriol (2.56 nmol/kg/day) for 4 consecutive days. Plasma, urine, and tissue samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Calcitriol markedly increased plasma taurine levels, decreased its urinary excretion, and reduced taurine concentrations in most tissues. In contrast, PDA exhibited only a moderate increase in plasma levels, with no significant change in urinary excretion, but a notable increase in kidney concentrations. Additional probenecid inhibition studies supported the Oat1-mediated modulation. Intravenous (i.v.) pharmacokinetic studies of taurine (10 mg/kg) revealed altered plasma exposure, clearance, and tissue distribution following calcitriol and probenecid inhibition. In addition, calcitriol significantly affected MTX pharmacokinetics, reinforcing its effect on Oat1/3 function. Taurine induced more significant changes than PDA, indicating its greater sensitivity as an endogenous biomarker for Oat1 activity. These findings highlight the modulatory effects of calcitriol on Oat-mediated transport and demonstrate the utility of taurine and PDA as translational biomarkers for investigating transporter-mediated drug-drug interactions in drug development.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107454"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085251","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}

{"title":"Systematic optimisation of carrier particle geometry in interactive powder mixtures via a parametric design approach using Bayesian optimisation","authors":"Melvin Wostry ,&nbsp;Regina Scherließ","doi":"10.1016/j.ejps.2026.107442","DOIUrl":"10.1016/j.ejps.2026.107442","url":null,"abstract":"<div><div>In this study, a systematic approach for improving the carrier particle geometry in interactive mixtures was conducted. For the evaluation of the geometries, an in-silico model was used, which allowed the creation of a carrier particle loaded with drug particles and to investigate the crucial detachment of the latter in two different kinds of collision simulations. The carrier particle geometries were created with a parametric design tool that enabled continuous modification of the geometry. Data evaluation was performed with a Bayesian Optimisation, which could suggest potentially interesting new geometry modifications based on the evaluated results. The whole setup was implemented as a fully automated process. Particle geometry creation, procession of new geometries in the simulation software and evaluation of the results, including the setup of the following iterations, was performed by precise communication between the different software applications. As a result, it could be demonstrated that the systematic modification of the geometries improved performance in terms of drug detachment. Furthermore, characteristic geometry features responsible for the detachment could be identified.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107442"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994351","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}

{"title":"Development and in vitro/in vivo evaluation of polymeric dissolving microneedle formulation for psoriasis treatment","authors":"Meryem Kaplan ,&nbsp;Fatma Betül Arslan ,&nbsp;Süleyman Can Öztürk ,&nbsp;Sıla Ulutürk ,&nbsp;Çisel Aydın Meriçöz ,&nbsp;Güneş Esendağlı ,&nbsp;Sema Çalış ,&nbsp;Kıvılcım Öztürk","doi":"10.1016/j.ejps.2026.107429","DOIUrl":"10.1016/j.ejps.2026.107429","url":null,"abstract":"<div><div>Psoriasis is an inflammatory autoimmune skin disease that significantly impacts quality of life. The chronic and recurrent nature of the disease can last a lifetime. Current conventional treatment options have several drawbacks, including inadequate or short-lived efficacy, issues with tolerability and adherence, practical limitations associated with topical applications and phototherapy, and significant safety and cost concerns related to systemic treatments. Generally, symptomatic treatments are applied, but complete recovery is rarely achieved. Researchers are exploring alternative treatment approaches, such as biologically based therapies. These therapies specifically target the immune mechanisms involved in psoriasis and offer advantages such as more reliable disease control, noticeable improvements in patients’ quality of life, and a more favorable safety profile compared to conventional treatments. One innovative approach being investigated for the treatment of psoriasis is the use of microneedles as a transdermal drug delivery strategy, which has shown promising results in research. In this study, a biocompatible polymeric dissolving microneedle formulation composed of hyaluronic acid and sucrose was prepared using micro-molding. Microneedles were loaded with secukinumab (a human monoclonal antibody specific to IL-17A) and Stattic (a STAT3 inhibitor) for a combined treatment approach. It was expected that applying the microneedles directly to the psoriasis plaques would increase the localized drug concentration. Following <em>in vitro</em> characterization and cell culture studies, a psoriasis model was established in adult mice. The therapeutic effects of the microneedles containing secukinumab and Stattic (both individually and simultaneously loaded) were compared to control groups. Lesion progression was visually monitored and histologically examined following treatment. The results indicated that the secukinumab-loaded microneedles provided a more effective treatment at lower doses.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107429"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932971","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}

{"title":"3-D printing of chitosan-MSN@dexamethasone scaffold with enhanced properties for bone tissue engineering","authors":"Shengjie Cong ,&nbsp;Yonggang Yang ,&nbsp;Rasoul Akram","doi":"10.1016/j.ejps.2025.107423","DOIUrl":"10.1016/j.ejps.2025.107423","url":null,"abstract":"<div><div>Bone tissue engineering (BTE) is an attempt to overcome the limitations of conventional grafting through the combination of bioactive scaffolds and regenerative signals. In this study, we prepared an extrusion-based 3D-printed composite scaffold composed of chitosan (CH) combined with dexamethasone (DEX)-loaded mesoporous silica nanoparticle (MSN), (MSN@DEX) in order to compensate for both mechanical insufficiency and temporary osteoinductive signal. MSNs were synthesized by a templated sol-gel method with high drug loading efficiency and biphasic release behavior. Inclusion of MSN@DEX in chitosan resulted in scaffolds with homogeneous and interconnected porosity (310–420 μm), high compressive strength, good swelling profile, and a degradation profile consistent with the time course of bone healing. In vitro experiments with mesenchymal stem cells (MSCs) resulted in a high hemocompatibility, a sustained cell proliferation and a significantly enhanced osteogenic differentiation given by alkaline phosphatase (ALP) activity, calcium deposits and stage-dependent upregulation of RUNX2, ALP, COL1A1 and OCN genes and protein. Together, the hierarchical scaffold architecture, nanostructured reinforcement, and local sustained DEX release provide a cost-effective, stable and clinically adaptable platform for robust osteogenesis with the possibility of enhanced osteogenic induction even with lower dexamethasone release. These findings underscore the potential of CH‑MSN@DEX scaffolds for bone regeneration applications. By combining structural reinforcement with sustained osteoinductive signaling within a single printable construct, this approach represents a clear advancement over previously reported chitosan‑based or DEX‑releasing scaffold systems.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107423"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827119","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}

{"title":"Construction of in situ temperature-sensitive gel of Tegafur derivative TAK5399 and its evaluation against breast cancer","authors":"Hong Shao ,&nbsp;Wen Li ,&nbsp;Zhuohan Li ,&nbsp;Peng Shi ,&nbsp;Zheng Li ,&nbsp;Yuxiang Wang ,&nbsp;Chao Pi ,&nbsp;Lingmao Zhao ,&nbsp;Wenwu Zheng ,&nbsp;Yumeng Wei ,&nbsp;Ling Zhao","doi":"10.1016/j.ejps.2026.107452","DOIUrl":"10.1016/j.ejps.2026.107452","url":null,"abstract":"<div><div>Tegafur (FT) is widely used in the treatment of breast cancer. However, it has poor efficacy and significant toxic side effects. In this study, we first modified FT with aspirin to obtain a new FT derivative, named TAK5399. Then, TAK5399 in situ thermosensitive gel (TAK5399-TSG) was prepared using poloxamer F68 and F127 as carriers, and evaluated in vitro and in vivo. Among the five tested tumor cell lines, TAK5399 exhibited the highest sensitivity toward human breast cancer cells (MCF-7), with an inhibition rate 8.41 times higher than that of FT. Its potential anti-breast cancer mechanism may be related to inhibiting the PI3K/AKT signaling pathway to induce apoptosis and blocking the S phase of the cell cycle. The optimal formulation process for TAK5399-TSG is F127: 24.0%, F68: 6.5%, TAK5399 content of 1.25 mg/mL, and curing time of 24 hours. The maximum drug solubility, gelation temperature, and dissolution time were 1.25 mg/mL, 31 ± 0.21°C, and 6.5 ± 0.25 h, respectively. The Cmax of TAK5399-TSG administered via in situ injection was 15.5% and 23.8% of that of oral and in situ injection of TAK5399, respectively. In tumor-bearing mice, the tumor inhibition rates of oral TAK5399 and in situ injection of TAK5399-TSG were 1.28-fold and 1.82-fold higher than those of oral FT, respectively, with good biocompatibility. In conclusion, TAK5399-TSG is an in situ gel delivery system with potential for the treatment of breast cancer.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107452"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146061204","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}

{"title":"From fungistatic to cytotoxic: Nano-engineered griseofulvin triggers redox-mediated apoptosis in colon cancer","authors":"Jihad Mahmoud Alsofany ,&nbsp;Soha Osama Hassanin ,&nbsp;Ahmad S. Kodous ,&nbsp;Mohammed Aufy ,&nbsp;Maha O. Mahmoud ,&nbsp;Islam M. Adel ,&nbsp;Mohamed A. El-Nabarawi ,&nbsp;Eman Abdelhakeem","doi":"10.1016/j.ejps.2026.107447","DOIUrl":"10.1016/j.ejps.2026.107447","url":null,"abstract":"<div><div>Griseofulvin, a potent antifungal drug, has recently demonstrated potential anticancer activity in mammalian cancer cells. This study aims to comprehensively investigate the anti-cancer potential of griseofulvin encapsulated into nanospanlastics, focusing on enhanced cellular uptake, selectivity, and robust activation of multiple apoptotic pathways. Griseofulvin nanospanlastics were fabricated using a 2³ full factorial experimental design with Span 60 as the non-ionic surfactant and Tween 80 as the edge activator. Nanospanlastics were characterized for vesicle size, size distribution, zeta potential, and entrapment efficiency. The statistically optimized formulation was selected for further physical characterization and investigation of its anticancer potential via cytotoxicity, selectivity assays, and analysis of molecular pathways (p53, Bax/Bcl-2, caspase 3, pAKT, VEGFR2, ROS). The optimized formulation exhibited circular morphology without any aggregation, 143.5±15.56 nm vesicle size, 0.739±0.021 size distribution, -30±0.99 mV zeta potential, 89.07±0.11 % entrapment efficiency, and 30.2±0.14 g deformability index. In vitro drug release showed an improved drug dissolution rate, critical for cellular uptake. The optimized formulation attained exceptional therapeutic activity with a 2.29-fold improvement in cytotoxicity and an 8.1-fold enhancement in cancer cell selectivity compared to the free drug solution, while simultaneously modulating critical molecular pathways including p53 activation, Bax/Bcl-2, caspase 3, phosphorylated AKT (pAKT) inhibition, and VEGFR2. Most surprisingly, the study revealed an unexpected reduction in reactive oxygen species (ROS) levels, challenging conventional therapeutic paradigms and highlighting novel \"redox paradox\" mechanisms in cancer treatment. This comprehensive investigation highlights the remarkable apoptotic potential of nanosized griseofulvin, driven by enhanced cellular uptake, superior selectivity, and robust activation of multiple apoptotic pathways.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"218 ","pages":"Article 107447"},"PeriodicalIF":4.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003385","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}