European Journal of Pharmaceutical Sciences最新文献

{"title":"Development, characterization and evaluation of antibacterial efficacy of actively targeted gold-polydopamine nanoparticle formulations for tuberculosis treatment.","authors":"Eda Turan-Ayhan, Merve Çalımcı, Yasin Turanlı, Funda Şahin, Gülnur Tarhan, Ugur Tamer, Sibel Ilbasmis-Tamer","doi":"10.1016/j.ejps.2025.107219","DOIUrl":"10.1016/j.ejps.2025.107219","url":null,"abstract":"<p><p>Tuberculosis (TB) is one of the oldest known diseases in the world and it remains a significant public health challenge. The increasing resistance of microorganisms to antibiotics underlines the necessity of appropriate use of antibiotics and correct dosage in treatment. In some cases, frequent and high-dose drug therapy is required, which can lead to serious organ damage in the liver and kidneys in long-term treatment. However, this problem can be overcome by using appropriate drug delivery systems that allow more effective treatments at lower doses. Here, we developed a drug delivery system specifically targeting tuberculosis using gold (Au)-polydopamine (PDA) nanoparticles and modified with polyethylene glycol (PEG), a targeting agent (antibody), and the antibiotic linezolid, resulting in Au-PDA-PEG-Antibody-Linezolid nanoparticles. We successfully developed and characterized these active targeted nanoparticles using UV-Vis absorbance spectroscopy, Fourier-transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS), zeta potential measurements, and surface-enhanced Raman spectroscopy (SERS) measurements. Additionally, the developed formulations were compared with the commercial product through in vitro release studies, and antibacterial efficacy studies were conducted on multidrug-resistant tuberculosis (MDR-TB) strains. The targeted drug delivery system might be able to reduce side effects by increasing treatment effectiveness at lower doses. Additionally, our study is the one of the first example to feature actively targeted nanoparticle formulations using the active ingredient linezolid and PEGs with different chemical structures.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107219"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144774969","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":"Hydroxypropyl cellulose-based lyospheres accelerate dissolution of aprepitant combined with its supersaturation for oral delivery.","authors":"Jan Kožák, Paul Bühlbecker, Annika Rautenberg, Claire Chrétien, Yann Pellequer, Edmont Stoyanov, Alf Lamprecht","doi":"10.1016/j.ejps.2025.107220","DOIUrl":"10.1016/j.ejps.2025.107220","url":null,"abstract":"<p><p>Spray freeze-drying (SFD) leads to a free-flowing lyophilized powder, providing new therapeutic options. In this work, non-aqueous SFD particles are produced with dimethyl sulfoxide as a spray solvent for obtaining amorphous solid dispersions (ASDs) for oral administration of a poorly water-soluble drug, aprepitant. The SFD process was conducted with the low viscosity hydroxypropyl cellulose grades HPC-SSL or HPC-UL to achieve rapidly dissolving aprepitant powder. Besides different HPC grades, varying solid contents (5 and 10 %) and drug-excipient ratios (20/80, 40/60 and 100/0) were explored and compared to film casted ASDs and analysed regarding particle morphology and characteristics, storage stability, in vitro dissolution and in vivo pharmacokinetic studies in rats. Median particle size of the powder formulations ranged between 300 and 500 µm, increasing HPC content led to amorphous formulations, that remained amorphous for 12 months of storage at 25 °C. Dissolution at pH 1.2 revealed supersaturation across all SFD samples with concentration values twofold and fourfold the saturation concentration for 40/60 and 20/80 drug-excipient ratios respectively. After oral administration to rats, t_max, c_max and AUC varied between 2.5-4 h, 1.04-1.24 µg/ml and 5.4-8.1 µg*h/ml respectively. Pharmacokinetic parameters were not affected by HPC grade, but indicate a possible relationship between a decrease of geometric particle density and an increase in bioavailability. Low viscosity HPC grades proved to be suitable excipients for the use in non-aqueous SFD to produce amorphous, rapidly dissolving, low density powders.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107220"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764714","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":"Diabetic Retinopathy in Focus: Update on Treatment Advances, Pharmaceutical Approaches, and New Technologies.","authors":"Adela Laura Ciorba, Sameh Saber, Amir Mohamed Abdelhamid, Noha Keshk, Fatma Elnaghy, Elsayed A Elmorsy, Rasha Abu-Khudir, Rabab S Hamad, Mustafa Ahmed Abdel-Reheim, Alshaimaa A Farrag, Attalla F El-Kott, Sally Negm, Kareem Morsy, Mohammed A AlShehri, Ahmed Gaafar, Simona Cavalu","doi":"10.1016/j.ejps.2025.107307","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107307","url":null,"abstract":"<p><p>This review provides an updated overview of the pathogenesis, classification, current management, and emerging therapies for diabetic retinopathy (DR). DR development involves dysregulation of the polyol pathway, formation of advanced glycation end products, activation of protein kinase C, and upregulation of vascular endothelial growth factor (VEGF). Disruption of the retinal neurovascular unit, including neurons, glial cells, and vascular elements, also plays a pivotal role, leading to microvascular damage, neurodegeneration, and inflammation. DR progresses from non-proliferative (NPDR) to proliferative stages (PDR) characterized by retinal neovascularization. Management emphasizes glycemic and blood pressure control, with advanced stages treated using laser photocoagulation, vitrectomy, and intravitreal anti-VEGF injections. Novel imaging technologies like optical coherence tomography angiography (OCTA) and electroretinography (ERG) enable early diagnosis and disease monitoring. Genetic factors, including VEGF polymorphisms and genes linked to oxidative stress and angiogenesis, significantly influence DR susceptibility. Innovative treatments under investigation include nanotechnology-based drug delivery, microRNA-targeted therapies, and AAV-mediated gene therapies aimed at anti-angiogenic pathways. Stem cell-based strategies utilizing adipose, bone marrow, amniotic, and umbilical cord-derived. It shows promise for retinal repair and neuroprotection. Future directions encompass CRISPR-Cas9 gene editing for precise genomic interventions, personalized medicine approaches, and integrated screening programs powered by artificial intelligence. A multifaceted approach involving risk factor modification, lifestyle interventions, advanced therapeutics, and cost-effectiveness analysis is essential to reduce the public health burden of diabetic retinopathy.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107307"},"PeriodicalIF":4.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225101","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":"Physiologically-based Pharmacokinetic Modeling of Natalizumab for Multiple Sclerosis Patients to Predict the Withdrawal Time in Pregnancy and Vaccine Time in Infants.","authors":"Peilin Zhou, Chenming Zhong, Wanhong Wu, Meng Ke, Jianwen Xu, Rongfang Lin, Pinfang Huang, Cuihong Lin","doi":"10.1016/j.ejps.2025.107301","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107301","url":null,"abstract":"<p><p>Natalizumab (NAT) is a monoclonal antibody that targets integrin α4 (anti-ITGA-4), approved by the FDA for treating multiple sclerosis (MS). However, the optimal timing of the final dose during pregnancy and the postponement of vaccinations for infants remains open to discussion. This study aimed to analyze variations in plasma concentrations of NAT in pregnant women and infants using a physiologically based pharmacokinetic (PBPK) model. Additionally, it provided informed guidelines on drug cessation timing and vaccination schedules. A PBPK model was developed and validated by comparison with drug concentrations in clinical data. The results showed that most observed values were within 0.5 to 2 times the predicted values, indicating that the model successfully predicted the concentration-time profiles of NAT in pregnant women, fetuses, and infants. The findings revealed that plasma NAT concentration in pregnant women was lower than that in the general population, and the drug clearance time in infants was influenced by age and physiological changes. The simulation suggested extending the dosing interval for pregnant women to eight weeks, and withdrawing the drug within 5.5 weeks before delivery. Furthermore, the model predicted that live vaccine administration should be delayed for infants up to eight months after birth. This study provides a theoretical basis for the safe use of NAT during pregnancy and helps to establish more rational clinical dosing regimens. By utilizing precise pharmacokinetic modeling, clinicians can better evaluate the risks and benefits of NAT treatment in pregnant women and infants, ultimately enhancing the safety and efficacy of the therapy.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107301"},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212149","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 Optimization and Real-Time Size Monitoring in the Semi-Continuous Production of Edaravone-Loaded Lipid-Based Nanocarriers Using the Microfluidizer® Technology: Part 2.","authors":"Christina Glader, Ramona Jeitler, Yan Wang, Jesús Alberto Afonso Urich, Carolin Tetyczka, Philippe Caisse, Steve Mesite, Vanessa Bourgeaux, Johannes Khinast, Eva Roblegg","doi":"10.1016/j.ejps.2025.107306","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107306","url":null,"abstract":"<p><p>Recently, we established a semi-continuous top-down process enabling the solvent-free production of drug-free lipid-based nanosystems. In this study, the applicability of the established process line to drug-loaded nanosystems was evaluated, focusing on whether process parameters require adjustment upon drug incorporation. Edaravone was selected as a model drug and encapsulated in nanostructured lipid carriers (NLC) composed of Precirol® ATO 5 or Gelucire® 43/01 as solid lipids, combined with Labrafac™ Lipophile WL 1349 or Capryol® 90 as liquid lipids, as well as in nanoemulsions (NEs) consisting solely of the liquid lipids. Integration of the NanoFlowSizer enabled real-time size monitoring via spatially resolved dynamic light scattering (SR-DLS) during Microfluidizer® processing and allowed detection of potential formulation instabilities caused by altered intermolecular interactions following drug incorporation. Design of Experiments (DoE) was employed to optimize encapsulation efficiency (EE%) and loading capacity (LC%). Initial lipid screening revealed superior compatibility of Labrafac™ Lipophile WL 1349 over Capryol® 90 with both solid lipids and edaravone. Gelucire®-based NLC achieved EE% and LC% up to 47% and 0.9%, respectively, while Labrafac™-based NEs reached 86% EE% and 1.7% LC%. Higher drug concentrations (2%) led to increased NLC sizes compared to lower concentrations (0.8%). Lipid type was identified as the most influential formulation parameter, while the solid to liquid lipid ratio and drug concentration had minor effects. Combining inline and offline SR-DLS measurements enabled early detection of subtle instabilities such as micelle formation and particle agglomeration, outperforming conventional offline DLS. Overall, the findings underscore the versatility and robustness of the semi-continuous, solvent-free production line with integrated SR-DLS as a powerful platform for the efficient development of lipid-based nanocarriers with improved drug loading, stability, and process control.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107306"},"PeriodicalIF":4.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212129","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":"A quantitative systems pharmacology model to inform clinical translation of dynamic PKPD relationships of engineered IL-15.","authors":"Louis R Joslyn, Mohammad Jafarnejad, Rajbharan Yadav, Patrick G Holder, Shomyseh Sanjabi, Vittal Shivva, Ke Liu, Irene Leung, Nargess Kiabi, Suzanne Schubbert, Matthew J Bernett, John R Desjarlais, Saroja Ramanujan, Iraj Hosseini","doi":"10.1016/j.ejps.2025.107303","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107303","url":null,"abstract":"<p><p>Interleukin-15 (IL-15) is a key pleiotropic cytokine involved in innate and adaptive immunity, promoting proliferation, differentiation, and effector function in lymphocytes. The biologic functions of IL-15 provide a rationale for developing IL-15 agonists as potential cancer treatment, however, IL-15 exhibits a short half-life thereby limiting its therapeutic potential. Recombinant human IL-15 therapies have faced challenges in pharmacokinetics (PK), pharmacodynamics (PD), and safety due to a lack of understanding of the mechanisms leading to expansion of specific immune cell subpopulations following IL-15 therapies. In this work, we develop a quantitative systems pharmacology (QSP) model to capture the dynamics of lymphocyte expansion in response to three engineered IL-15/IL-15Rα therapeutics: a potency engineered Fc-fusion referred to as Efbalropendekin alfa; a heterodimeric, PD-1 targeted cytokine assessed in non-clinical studies (PD1/IL15 TaCk); and an anti-respiratory syncytial virus targeted cytokine that serves as a non-binding isotype control (RSV/IL15 TaCk). The QSP model is able to capture systemic PK and lymphocyte expansion to each of the molecules across different dose levels, thereby offering insights into the complex relationship between PK and PD for these molecules. At molar matched doses, model simulations predict greater drug exposure in the terminal phase of the PK profile following treatment with Efbalropendekin alfa compared to PD1/IL15 TaCk due to the high levels of T cell expansion following administration of PD1/IL15 TaCk. Additionally, our results suggest that while the cell expansion levels in the blood are reflective of dynamics in the tissue, Efbalropendekin alfa and PD1/IL15 TaCk bind to different cell populations in the blood but similar cell populations in the tissue due to the relatively large number of PD1 expressing CD4+ and CD8+ T cells in tissue. Finally, we leverage our QSP modeling framework to generate virtual cohorts with various translational scenarios to make clinical PK/PD predictions in response to PD1/IL15 TaCk treatment. Overall, the systems modeling presented herein offers a novel approach to integrate non-clinical datasets, aid in translation, and support dosing decisions for cytokine-based therapies that activate the immune system and display a dynamic PK/PD relationship.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107303"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205962","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":"Activation of nicotinamide phosphoribosyltransferase protects against unilateral renal ischemia-reperfusion injury via the NAD+/SIRT1/PGC-1α signaling pathway and modulation of NFκB/TNF-α/IL-6","authors":"Elsayed A. Elmorsy ,&nbsp;Mostafa M Khodeir ,&nbsp;Manal M. Kamal ,&nbsp;Mohamed El-Sayed ,&nbsp;Mariam S. Alharbi ,&nbsp;Hamad Alsaykhan ,&nbsp;Rabab S. Hamad ,&nbsp;Mustafa Ahmed Abdel-Reheim ,&nbsp;Hanan Eissa ,&nbsp;Attia M. Gabr ,&nbsp;Mohamed F. Hindawy ,&nbsp;Mohamed R. Abdel-Hamed ,&nbsp;Maha M. Amer ,&nbsp;Amel Ahmed ,&nbsp;Alshaimaa A. Farrag ,&nbsp;Ahmed Kaid Alantry ,&nbsp;Basem H. Elesawy ,&nbsp;Abdel-Rahman Youssef ,&nbsp;Ahmed Sameh ,&nbsp;Sameh Saber","doi":"10.1016/j.ejps.2025.107302","DOIUrl":"10.1016/j.ejps.2025.107302","url":null,"abstract":"<div><div>Renal ischemia is a common cause of acute kidney injury (AKI), particularly in critical care settings, and remains a major challenge in nephrology due to the lack of effective therapeutic options. In AKI, there is an overstimulation of NAD⁺-consuming enzymes leading to NAD⁺ depletion. To help replenish cellular NAD⁺ stores, this study explores for the first time the therapeutic potential of activating nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD⁺ salvage pathway, in a rat model of unilateral renal ischemia-reperfusion injury (IRI). Our findings demonstrate that SBI797812 (SBI)-induced NAMPT activation significantly improves renal function post-IRI, primarily through the NAD⁺/SIRT1/PGC-1α signaling pathway. NAMPT activation resulted in significant improvement in kidney function, including restored urine flow rate, reduced creatinine and blood urea nitrogen (BUN) levels, and decreased kidney injury biomarkers such as KIM-1 and NGAL. Additionally, SBI led to a reduction in inflammatory markers (NFκB, TNF-α and IL-6), oxidative stress markers, and caspase-3, indicating enhanced renal protection. Western blot analysis further revealed upregulation of key mitochondrial biogenesis markers, including SIRT1, PGC-1α, and TFAM, highlighting the link between NAD⁺ restoration and improved mitochondrial function. In contrast, the inhibition of NAMPT with FK866 exacerbates injury, as indicated by worsened histological features, increased inflammation, and tubular necrosis, confirming the crucial role of NAMPT in mitigating ischemic damage. Considering the importance of NAD metabolism in mitochondrial function and cellular resiliency to tissue injury, these results underscore NAMPT activation as a promising therapeutic strategy for renal IRI, offering new insights for the management of ischemic AKI.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107302"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205954","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":"High dose dry powder inhalation of itraconazole nanocrystals: Impact of drug load and inhalation device","authors":"Ann-Cathrin Willmann ,&nbsp;Kai Berkenfeld ,&nbsp;Georg Boeck ,&nbsp;Herbert Wachtel ,&nbsp;Karl G. Wagner","doi":"10.1016/j.ejps.2025.107305","DOIUrl":"10.1016/j.ejps.2025.107305","url":null,"abstract":"<div><div>The aerosol performance of dry powders for inhalation depends on the interplay between formulation, device, primary packaging, and patient inhalation profile. This study evaluated a particle engineered formulation for high dose delivery of itraconazole (ITZ), manufactured via wet media milling and consecutive spray drying with mannitol (MAN) as a matrix former.</div><div>Key objectives included preserving ITZ nanocrystals and assessing the effects of drug load and inhaler type (HandiHaler® vs. GyroHaler®) on aerosol performance using cascade impaction after automated filling with a drum filler.</div><div>Drum filling was suitable for media-milled and spray-dried particles (nano-in-microparticles) but not for jet-milled (JM) or jet-milled and spray-dried (JM SD) samples due to their cohesiveness. Samples JM and JM SD showed significantly lower fine particle fractions (FPF ≤ 26 %) compared to engineered formulations (FPF up to 49 % with the HandiHaler®). The ITZ:MAN ratio did not affect the FPFs of the nano-in-microparticles therefore the fine particle dose (FPD) was primarily determined by the drug loading. The GyroHaler® consistently yielded lower FPFs. The highest FPD of up to 4 mg and highest FPF were achieved with a formulation without MAN using the HandiHaler®, likely due to optimized particle morphology (e.g., low density, smooth surface). Drug loading had no relevant impact on aerosolization as other factors such as particle morphology, surface roughness and the dispersion force of the device were supposed to have the major effect. Nevertheless, higher MAN content improved nanoparticle redispersion: the higher the MAN content, the faster the reconstitution. An ITZ:MAN ratio of 75:25 (resulting in a drug loading of 65 % (w/w) ITZ) was identified as superior formulation with an optimal balance between a high FPD and nearly complete reconstitution of the nanoparticles.</div><div>In conclusion, media milling in combination with consecutive spray drying is a suitable formulation technology for high dose dry powder aerosol therapy. Poorly water-soluble compounds with challenging aerosolization parameters could be transformed into particles with much improved aerosol properties superior to those using a conventional jet-milling process. MAN as matrix former increased the redispersibility of the nanoparticles incorporated. The choice of an inhalation device was found crucial for an optimal aerosol performance irrespectively of the dry powder formulation.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107305"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205965","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":"Enhancing spinal cord injury recovery with functional liposomal nanomedicine: A neuroprotective and anti-inflammatory approach","authors":"Yuxing Jiang ,&nbsp;Yiyang Hou ,&nbsp;Shuaijie Pei ,&nbsp;Haisheng Wu ,&nbsp;Dilmurat Gheyret ,&nbsp;Yongqiang Xu ,&nbsp;Hongtao Rong ,&nbsp;Tao Zhu","doi":"10.1016/j.ejps.2025.107304","DOIUrl":"10.1016/j.ejps.2025.107304","url":null,"abstract":"<div><h3>Background</h3><div>Spinal cord injury (SCI) triggers severe secondary damage and persistent neurological deficits, exemplified by unacceptably high functional loss where &gt;80 % of patients experience irreversible lower limb paralysis with &lt;20 % achieving meaningful recovery, driven by pro-inflammatory M1 microglia that secrete inflammatory cytokines and reactive oxygen species (ROS). Thalidomide’s anti-inflammatory potential is hindered by low bioavailability and systemic toxicity, necessitating targeted delivery strategies to address this unmet Level 1 clinical need for restoring acceptable function in specific SCI scenarios.</div></div><div><h3>Methods</h3><div>To address these challenges, we developed RLNPP@Tha, a CD44-targeted, ROS-responsive liposomal nanomedicine, to selectively deliver thalidomide to the SCI microenvironment. RLNPP@Tha’s physicochemical properties, drug release, cellular uptake, and anti-inflammatory/neuroprotective effects were characterized in vitro. Its therapeutic efficacy, including locomotor recovery, inflammation modulation, tissue repair, and biosafety, was evaluated in a rat SCI model.</div></div><div><h3>Results</h3><div>RLNPP@Tha exhibited ROS-dependent thalidomide release (92 % at 400 μM H₂O₂ in 12 h) and selective uptake by activated BV2 microglia. In vitro, it reduced intracellular ROS by ∼70 %, suppressed pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) by 50–70 %, and protected SH-SY5Y neurons from oxidative apoptosis (85 % viability vs. 30 % in controls). In vivo, RLNPP@Tha improved Basso-Beattie-Bresnahan (BBB) scores to 18–19 (vs. 5–6 for saline), reduced cytokine levels by 45–60 %, preserved spinal cord morphology, enhanced neuronal survival, inhibited glial scarring, and promoted M2 microglial polarization. Biosafety assessments confirmed minimal systemic toxicity.</div></div><div><h3>Conclusion</h3><div>RLNPP@Tha’s dual CD44/ROS-responsive mechanism enables precise modulation of the SCI inflammatory microenvironment, providing sufficient improvements in secondary injury markers (Levels 2–4 of the design constraint hierarchy) to potentially address Level 1 clinical challenges, such as unacceptable functional loss in moderate contusion SCI cases. This nanomedicine offers preliminary evidence toward solving unmet needs in neuroprotection, paving the way for advanced targeted therapies.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107304"},"PeriodicalIF":4.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205970","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":"Soft Mist Inhaler Nebulization by Rayleigh-breakup Largely Preserves Functional Integrity of Liposomal mRNA in Respirable Aerosols.","authors":"Achim Biesel, Sabine Maamari, Nils Salaw, Imco Sibum, Nicolas Buchmann, Brigitta Loretz, Elisabeth M Zeisberg, Claus-Michael Lehr","doi":"10.1016/j.ejps.2025.107300","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107300","url":null,"abstract":"<p><p>Inhalable mRNA is an emerging field holding great potential for applications as mucosal vaccination, antiviral therapy or protein replacement therapies, but efficient delivery remains a bottleneck. In this study, we explore the use of a Soft Mist Inhaler (SMI), based on Rayleigh-breakup, for pulmonary mRNA delivery. We found that the SMI successfully aerosolized GFP mRNA encapsulated in liposomes while maintaining colloidal stability, mRNA integrity and in vitro transfection efficiency in A549 cells. Furthermore, the device enabled simultaneous delivery of nucleic acids in various sizes using a model CRISPR/Cas13d system. The formulation could be reproducibly aerosolized with a low geometric standard deviation (GSD) and optimal aerosol droplet size for lung delivery. Based on the aerosol data, lung deposition modeling was conducted, indicating high lung deposition with minimal exhaled fraction. In comparison, aerosolization by a conventional Vibrating Mesh Nebulizer led to significant loss of nanoparticles and transfection efficiency. Utilizing SMIs may facilitate pulmonary delivery of mRNA nanoparticle formulations by lowering stability-associated hurdles while providing intrinsically high deposition in the lungs.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107300"},"PeriodicalIF":4.7,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198836","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}