European Journal of Pharmaceutical Sciences最新文献

{"title":"Targeting neuroinflammation in Parkinson's disease: Immunomodulatory effects of a hyaluronic acid-based nanoreinforced hydrogel loaded with GDNF and mesenchymal stem cells","authors":"Rubén del Campo-Montoya ,&nbsp;Xavier Mulet i Piera ,&nbsp;Silvia Romero-Murillo ,&nbsp;Enrique Santamaría ,&nbsp;Elisa Garbayo ,&nbsp;María J. Blanco-Prieto","doi":"10.1016/j.ejps.2025.107368","DOIUrl":"10.1016/j.ejps.2025.107368","url":null,"abstract":"<div><div>Like other neurodegenerative disorders, Parkinson's disease is marked by widespread neuroinflammation, which may contribute to its etiology and is a key component of its progression. Consequently, anti-inflammatory strategies, which can incorporate regenerative and cell therapy components, are promising therapeutic candidates for the management of the disease. To this end, we have developed a supramolecular hydrogel (HG) based on modified hyaluronic acid that combines nanoencapsulated GDNF (NPs GDNF), a potent neurotrophic factor with a less well-studied anti-inflammatory potential, and mesenchymal stem cells (MSCs). We have evaluated the anti-inflammatory effect of the HG by quantifying the NO produced by a murine microglia cell line against LPS. In addition, we have corroborated these functional results by transcriptomic analyses, where we have also been able to delve deeper into the mechanisms by which the HG exerts this anti-inflammatory effect. We have observed that both HG components (GDNF and MSCs) and the combination of all of them (HG-NPs GDNF-MSCs) are able to decrease NO production in microglia insulted with LPS. Furthermore, we have been able to corroborate these results at the transcriptional level, where HG was able to decrease most of the pathways commonly associated with inflammation, such as interferon regulators or the interleukins IL-1 or TNF-α. In conclusion, the developed HG was able to reduce inflammation in a murine microglial cell line, both transcriptionally, with the suppression of pro-inflammatory pathways, and functionally, with a reduction in nitric oxide production.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107368"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145476936","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":"ROS-responsive diselenide exosomes restore mitophagy to resolve sterile inflammation in liver IRI","authors":"Tao Zhou ,&nbsp;Zhiwei Jiang ,&nbsp;Qingluan Hu ,&nbsp;Siqi Qiu ,&nbsp;Junda Gao ,&nbsp;Jianjun Zhang ,&nbsp;Feng Xue ,&nbsp;Lin Lu ,&nbsp;Ling Chang","doi":"10.1016/j.ejps.2026.107457","DOIUrl":"10.1016/j.ejps.2026.107457","url":null,"abstract":"<div><div>Liver ischemia–reperfusion injury (IRI) drives graft dysfunction and postsurgical morbidity. We show that hepatocellular MST1 is markedly upregulated in IRI and exacerbates damage by blocking PINK1-dependent mitophagy. Defective mitochondrial clearance causes mtDNA leakage, which activates macrophage cGAS–STING signaling and fuels inflammatory injury. Curcumin inhibits this MST1–PINK1 axis, restoring mitophagy and limiting mtDNA release. To translate these insights, we engineered Curcumin@EV@Se—stem-cell–derived extracellular vesicles surface-modified with diselenide-PEG for ROS-responsive, “stealth” delivery. In oxygen–glucose deprivation/reoxygenation models, Curcumin@EV@Se improved hepatocyte viability, preserved mitochondrial potential, reduced ROS and inflammatory cytokines, and promoted reparative/angiogenic programs. In a murine hepatic IRI model, systemic Curcumin@EV@Se decreased necrosis and TUNEL positivity and improved serum transaminases and histology, indicating enhanced liver function and regeneration. These data identify MST1-mediated mitophagy blockade with secondary cGAS–STING activation as a central pathogenic axis in IRI and present Curcumin@EV@Se as a mechanism-guided therapy that restores mitochondrial quality control and dampens innate immune activation, with translational promise for liver transplantation and acute hepatic injury.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107457"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118256","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":"Holistic evaluation of particle formation induced by physical stress in liquid peptide solutions","authors":"Patrick Schlossbauer ,&nbsp;Stefanie Schopf ,&nbsp;Katrin Lindner,&nbsp;Anna Müller,&nbsp;Ingo Presser,&nbsp;Maximilian Wittmann","doi":"10.1016/j.ejps.2026.107455","DOIUrl":"10.1016/j.ejps.2026.107455","url":null,"abstract":"<div><div>Insufficient physical stability remains a major challenge regarding the development of liquid therapeutics as aggregation and degradation of the drug substance can lead to patient safety concerns through increased immunogenicity or reduced potency. During its lifetime, a drug product (DP) containing for example a therapeutically active peptide can be exposed to various types of physical stress. Here, several methods to induce diverse forms of physical stress on liquid solutions were developed using a buffer solution and implemented by testing different therapeutically active peptides in a tool formulation. Methods to investigate the influence of stress induction during stirring, different kinds of shaking, pumping, and freezing and thawing of the peptide solutions were investigated. The establishment with buffer solution allowed fine-tuning of the parameters to not damage materials like glass vials and tubing themselves. Repeated peristaltic pumping at 110 rpm for 2 h led to time-dependent formation of subvisible particles (SVPs) in each peptide-containing sample. More peptide-specific results were achieved with stirring experiments at 600 rpm over three days. Shaking in glass vials on an orbital shaker at 420 rpm for 10 days did in most cases not introduce enough stress to trigger any response. When switching to a shaking motion induced by a microplate shaker at 1200 rpm, the distinguishability of samples could be increased over the same period due to increased interfacial stress. Freezing and thawing in glass vials at - 50°C led to the formation of SVPs already in peptide-free solutions, possibly due to glass delamination. Subsequent evaluation of visual appearance, absorbance at 620 nm, peptide concentration and covalently bound multimers revealed further insights into stress-induced particle formation of peptide drugs in solution.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107455"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097004","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":"Long-term clinical outcomes of 0.015 % tacrolimus HPβCD eye drops in ocular surface inflammatory disorders","authors":"María Puente-Iglesias ,&nbsp;Andrea Cuartero-Martínez ,&nbsp;Rosario Touriño-Peralba ,&nbsp;María Teresa Rodríguez-Ares ,&nbsp;María Jesús Giráldez ,&nbsp;Eva Yebra-Pimentel ,&nbsp;Eva Torres-Sangiao ,&nbsp;Miguel González-Barcia ,&nbsp;Irene Zarra-Ferro ,&nbsp;Francisco J Otero-Espinar ,&nbsp;Anxo Fernández-Ferreiro ,&nbsp;Ana Castro-Balado","doi":"10.1016/j.ejps.2026.107459","DOIUrl":"10.1016/j.ejps.2026.107459","url":null,"abstract":"<div><h3>Background</h3><div>Topical tacrolimus offers potent anti-inflammatory effects across a spectrum of ocular surface diseases, but its ophthalmic use has been limited by formulation challenges. This study evaluated 0.015 % tacrolimus/hydroxypropyl-β-cyclodextrin eye drops (TCD) long-term performance.</div></div><div><h3>Methods</h3><div>In a prospective, open-label, sequential design, 56 patients treated ≥6 months with 0.03 % tacrolimus ethanol-based formulation (TE) were switched to TCD and followed for 12 months. Assessments of efficacy and safety at baseline (TE) and month 12 (TCD) included concomitant corticosteroid use, distance best-corrected visual acuity, slit-lamp grading of conjunctival and corneal signs, Oxford staining, tear meniscus height (TMH), non-invasive break-up time, ocular redness, intraocular pressure, NEI VFQ-25 (National Eye Institute Visual Function Questionnaire) scores, symptom visual analog scales and adherence. In addition, a comparative evaluation of microbiological stability in use was performed for both eye drops.</div></div><div><h3>Results</h3><div>Concomitant corticosteroids declined from 21.4 % to 5 %; two-thirds of eyes maintained or improved visual acuity; ≥80 % showed stable or improved (TMH p&lt;0.0001) corneal/conjunctival. TMH increased significantly (median 0.25 to 0.29 mm; p&lt;0.0001), while break-up time and intraocular pressure remained stable. VFQ-25 total score rose from 82.8 to 87.8 (p&lt;0.001); burning, photophobia and foreign-body sensation decreased (p&lt;0.05), thereby promoting adherence to treatment. Both tacrolimus formulations were similarly contaminated due to improper manipulation by the patients.</div></div><div><h3>Conclusions</h3><div>The 0.015 % tacrolimus/HPβCD formulation proves efficacy, and safety over 12 months for the treatment of diverse ocular inflammatory conditions, delivering sustained clinical stability and patient-reported benefits with reduced steroid reliance.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107459"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131888","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":"Identification of pyrrolo[2,3-d]pyrimidine-based dual MERTK and FLT3 inhibitor: Hit-to-lead, machine learning, modeling, synthesis, and biological evaluation","authors":"Abdellah Yamani ,&nbsp;Paweł Maliszewski ,&nbsp;Natalia Piórkowska ,&nbsp;Patrycja Olejkowska-Podgórska ,&nbsp;Wojciech Pietruś ,&nbsp;Mario Luigi Naitana ,&nbsp;Agata Mitkowska ,&nbsp;Artur Łaszek ,&nbsp;Delfina Popiel ,&nbsp;Agata Mikołajczyk ,&nbsp;Tomasz Kornatowski ,&nbsp;Kinga Jastrzębska ,&nbsp;Filip Mituła ,&nbsp;Jakub Dominowski ,&nbsp;Artur Janusz ,&nbsp;Michał Górka ,&nbsp;Joanna Hucz-Kalitowska ,&nbsp;Małgorzata Teska-Kamińska ,&nbsp;Aleksandra Stańczak ,&nbsp;Monika Delis ,&nbsp;Maciej Wieczorek","doi":"10.1016/j.ejps.2025.107421","DOIUrl":"10.1016/j.ejps.2025.107421","url":null,"abstract":"<div><div>Overexpression of MERTK and FLT3 plays a crucial role in activating signal transduction pathways in various human hematological malignancies. These signaling pathways have been extensively studied and have shown significant potential as a promising therapeutic target for the treatment of acute myeloid leukemia (AML). In this study, we employed a modern medicinal chemistry approach, hybridizing machine learning (ML) with a bioisosterism strategy, to design and synthesize a new series of pyrrolo[2,3-<em>d</em>] pyridine derivatives as potent dual inhibitors of MERTK and FLT3. Through successive structure-activity relationship (SAR) studies, we successfully identified the lead compound 31l as a highly potent and selective MERTK/FLT3 dual inhibitor. Compound 31l exhibited remarkable kinase inhibitory activity against MERTK and FLT3 with IC₅₀ values of 2.58 and 0.86 nM, respectively, and potential anti-proliferative activity against MOLM-13 cell lines (IC₅₀ value of 7.50 nM). Furthermore, compound 31l displayed a favorable metabolic stability profile in both human and mouse liver microsome screens and an oral bioavailability of 56%. This finding suggests that lead compound 31l is a promising tool for further optimization and development as a potential MERTK/FLT3 dual inhibitor anti-AML drug candidate.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107421"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096970","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":"Formulation and evaluation of semi-solid extrusion (SSE) 3D-printed drug preparations using poloxamers and polyethylene oxide as co-printed carrier polymers","authors":"Kristiine Roostar ,&nbsp;Oleh Koshovyi ,&nbsp;Ivo Laidmäe ,&nbsp;Jaan Aruväli ,&nbsp;Urve Paaver ,&nbsp;Jyrki Heinämäki","doi":"10.1016/j.ejps.2026.107458","DOIUrl":"10.1016/j.ejps.2026.107458","url":null,"abstract":"<div><div>Semi-solid extrusion (SSE) 3D printing offers a versatile platform for preparing personalised pharmaceutical dosage forms. We investigated the applicability of the three different grades of poloxamers combined with polyethylene oxide (PEO) in pharmaceutical SSE 3D printing. The binary mixtures of poloxamers (F68, F87, and F108) and PEO at a ratio of 55:45 (w/w) were used in preparing the aqueous gels for SSE 3D printing. Acetylsalicylic acid (ASA) was used as a model drug in the concentrations 5%, 7%, and 9% (w/w). The physicochemical properties, printability, geometric accuracy, structural fidelity, and in-vitro drug-release behaviour of SSE 3D-printed 4 × 4 grids and axially perforated tablets were studied. We found that poloxamer F108 as a co-printed carrier polymer (with PEO) formed high-viscosity gels, which were feasible for SSE 3D-printing. The poloxamer F68- and F87-based gel formulations in turn showed reduced print fidelity. FTIR spectroscopy analysis confirmed compatibility between ASA, PEO, and all three poloxamers studied. The SSE 3D-printed grid preparations exhibited immediate-release behaviour with an initial burst release of the drug (ASA), followed by a diffusion- and erosion-controlled drug release in vitro. The release rates decreased in order of poloxamer grade: F87 &gt; F68 &gt; F108. Overall, poloxamer grade F108 was the most feasible carrier polymer to be combined with PEO for the SSE 3D printing of ASA-loaded dosage forms. The present poloxamer and PEO co-printed formulations provide an alternative printing platform for aqueous-based SSE 3D printing of immediate-release oral drug preparations applicable in personalized medicine or compounding settings.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107458"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146187080","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":"VA1213, a selective COX-2 inhibitor, exhibits antitumor activity by suppressing EGFR, AKT, and ERK1/2 phosphorylation","authors":"Valerio Ciccone ,&nbsp;Claudia Cecchin ,&nbsp;Maria Frosini ,&nbsp;Mario Saletti ,&nbsp;Samuele Maramai ,&nbsp;Germano Giuliani ,&nbsp;Marco Paolino ,&nbsp;Andrea Cappelli ,&nbsp;Maurizio Anzini ,&nbsp;Sandra Donnini ,&nbsp;Lucia Morbidelli","doi":"10.1016/j.ejps.2025.107422","DOIUrl":"10.1016/j.ejps.2025.107422","url":null,"abstract":"<div><div>Cyclooxygenase-2 (COX-2) is overexpressed in various cancers and has emerged as a promising target in oncological pharmacotherapy.</div><div>This study investigates the in vitro antitumor properties and mechanism of action of novel vicinal diaryl-substituted heterocyclic COX-2 inhibitors, with a focus on <strong>VA1213</strong>, in comparison to celecoxib, a widely marketed COX-2 inhibitor known for its off-target effects. We assessed cytotoxicity, apoptosis induction, cell-cycle distribution, antimetastatic activity, and alterations in key signaling pathways in HT-29 colorectal carcinoma and MDA-MB-231 breast carcinoma cell lines. Among the novel compounds, <strong>VA1213</strong> exhibited the most potent growth-inhibitory activity, demonstrating time-dependent cytotoxicity with a lower IC₅₀ after 48–72 h of treatment compared to <strong>VA692</strong> and <strong>VA694</strong>, and consistent with that observed for celecoxib.</div><div>Unlike celecoxib, which produced rapid cytotoxic effects, <strong>VA1213</strong> required prolonged exposure, suggesting a distinct mechanism of action. <strong>VA1213</strong> induced G₀/G₁ phase cell cycle arrest and apoptosis via caspase-3 activation. Furthermore, it impaired EGFR downstream signaling by reducing ERK1/2 and AKT phosphorylation, without directly inhibiting EGFR itself. At sub-cytotoxic concentrations, <strong>VA1213</strong> was more effective than celecoxib in inhibiting cell migration and demonstrated a comparable reduction in clonogenic potential. These findings highlight <strong>VA1213</strong> as a COX-2 inhibitor with noteworthy in vitro antitumor efficacy, comparable to that of celecoxib. Its ability to interfere with multiple cancer-associated signaling pathways and reduce tumor cell aggressiveness underscores its potential as a promising therapeutic candidate. Further in vivo studies are warranted to confirm its efficacy and assess potential off-target effects.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107422"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145818640","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":"Scoping review to identify data needs and environmental hotspots for future LCA Studies: Insights into pharmaceutical excipients and processes","authors":"Anja Autzen Virtanen ,&nbsp;Satu Lakio ,&nbsp;Atif Madi ,&nbsp;Mia Sivén","doi":"10.1016/j.ejps.2026.107453","DOIUrl":"10.1016/j.ejps.2026.107453","url":null,"abstract":"<div><div>In recent years, the environmental assessment and optimization of pharmaceutical dosage forms have received increasing attention. Consequently, interest in Life Cycle Assessments (LCA) has grown, and LCA is rapidly becoming the standard method of environmental evaluations across many industries, including the pharmaceutical sector. LCA is, however, a high entry barrier method requiring expertise, software- and database access, and process specific experimentally obtained performance data (e.g. electricity consumption). In the context of pharmaceuticals, significant challenges arise due to the limited availability of input data. Because of these limitations, we wanted to investigate the feasibility of using a scoping review as an alternative to LCA for evaluating the environmental implications of pharmaceuticals. In this literature review, a total of 8788 articles were screened, of which 117 were relevant. The search was anchored in a formulation previously developed. In this formulation, 3.0 mm minitablets were manufactured by direct compression from a spray-dried amorphous solid dispersion of indomethacin in polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) with the additional use of milled lactose monohydrate (LACT), microcrystalline cellulose (MCC) and magnesium stearate (MgSt) as tablet excipients. Through the systematic literature review, relevant environmental information was found for most of the processes and excipients investigated. Research currently undertaken at the intersection of environmental review and pharmaceutical manufacturing shows an upward trend. Most notably, recent research indicates that excipients generally regarded as safe (GRAS) may not necessarily be without environmental concern. Furthermore, excipients may be manufactured through multiple different routes which muddles the environmental comparison of different options. Still, this literature review identified a marked absence of sustainability-themed research specific to pharmaceutical manufacturing. With the issues uncovered, more research is sorely needed to provide guidance in formulation choices.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107453"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085218","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":"3D printed intrauterine device development containing dual anticancer drugs for the treatment of uterine cancer","authors":"Cem Varan ,&nbsp;Davut Aksüt ,&nbsp;Murat Şen ,&nbsp;Erem Bilensoy","doi":"10.1016/j.ejps.2026.107456","DOIUrl":"10.1016/j.ejps.2026.107456","url":null,"abstract":"<div><div>Uterine cancer is a major global health problem and treatment frequently includes invasive surgery that severely compromises fertility. Current systemic chemotherapeutic drugs, such as paclitaxel (PCX) and carboplatin (CBP), lack an established standard protocol and their efficacy is limited. This study focuses on the development of a personalized, local drug delivery system for the treatment of uterine cancer.</div><div>The intrauterine devices (IUDs) were prepared using polycaprolactone (PCL) filaments containing PCX and CBP complexed to cyclodextrin (CD) to enhance the stability and solubility of the drugs during the printing process. The fused filament fabrication (FFF) type 3D printing technique, owing to its precise computer-aided layer deposition, successfully provided a platform for geometric and dosage personalization, achieving high dimensional accuracy. Physicochemical characterization studies showed that CD inclusion complexes maintained drug stability during the printing process, confirmed by the absence of free crystalline drug. Furthermore, drug:CD complexes significantly enhanced the mechanical properties of PCL, thereby increasing strength and toughness, which are critical for intrauterine stability. <em>In vitro</em> release studies demonstrated a sustained, controlled release profile, exceeding 80% over 9 months for PCX and 4 months for CBP. Cytotoxicity studies showed that drug-free IUDs were non-cytotoxic and non-genotoxic to healthy L929 mouse fibroblast cells. Furthermore, <em>in vivo</em> studies demonstrated that IUDs did not cause dermal irritation. The drug-containing IUDs were found to be at least as effective as the drug solution on HEC-1B endometrial cancer cells. Lastly, <em>ex vivo</em> studies confirmed favorable bioadhesion of IUDs and high drug retention within uterine tissue. All these findings validate the FFF-type 3D printing as a promising and flexible approach for preparing personalized, biocompatible, and effective local drug delivery systems for the treatment of uterine cancer.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"219 ","pages":"Article 107456"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099930","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":"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}