European Journal of Pharmaceutical Sciences最新文献_第3页

BM-164 (an H₂S-donor) modulates microRNA expression associated with reperfusion-induced ventricular fibrillation in rat hearts BM-164（一种H₂s供体）调节与大鼠心脏再灌注诱导心室颤动相关的microRNA表达。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-08 DOI: 10.1016/j.ejps.2026.107433

E. Szabó , J. Király , A.B. Mondal , I. Bereczki , Z. Szabó , Á. Tósaki

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.

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 (n = 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 (n = 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.

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.

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.

室性心律失常是心肌梗死和心力衰竭中心源性猝死的主要原因。缺血后的再灌注可引发严重的心律失常，包括心室颤动（VF）和越来越被认为是这些过程的关键调节因子的microrna （mirna）。本研究旨在通过比较纤颤（VF）和非纤颤（No VF）大鼠心脏的表达谱，鉴定与缺血/再灌注（I/R）诱导的心室颤动相关的mirna。基于纳米串的筛选（n = 12,4组：无I/R对照，I/R无VF和I/R VF）鉴定出几种与缺血相关的mirna，包括rno-miR-30d， rno-miR-99a, rno-miR-130a, rno-miR-133a， rno-miR-181a和rno-miR-191a。随后使用TaqMan qRT-PCR （qPCR）在更大的队列中验证这些候选物，包括BM-164和抗坏血酸（AA）预处理的I/R组，在I/R前10分钟给药（n = 每组6）。这些mirna的选择是由先前的文献指导的，这些文献证明了它们在缺血相关途径和心脏保护中的既定作用，为它们的纳入提供了生物学基础的理论依据。qPCR分析与大鼠miRNA面板v1.5 （425 miRNA）上的Nanostring数据进行了比较，揭示了I/R心脏中这些miRNA子集的显著变化，特别是在vf影响样本中。BM-164，一个H₂s供体，在较小程度上AA，与这些mirna的部分恢复或上调有关。这些发现表明，检测的mirna，特别是miR-99a， miR-191a， miR-30d和miR-181a，可能参与再灌注诱导的室性心律失常的发展。BM-164预处理与这些mirna的变化相关，这些mirna先前涉及自噬和凋亡途径；需要进一步的研究来确定这些改变是否直接介导心脏保护或抗心律失常的作用。鉴于样本量有限，这些发现应被认为是初步的。需要更大的队列和更多的体内研究来澄清这些miRNA改变是导致心律失常还是代表保护反应。

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引用次数: 0

Targeting PPP1R15B and ATF4 axis in hepatocellular carcinoma: A novel strategy for overcoming lenvatinib-tolerant persister cells through GPX4-mediated ferroptosis induction 在肝细胞癌中靶向PPP1R15B和ATF4轴：通过gpx4介导的铁凋亡诱导克服lenvatinib耐受持久性细胞的新策略

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-08 DOI: 10.1016/j.ejps.2026.107434

Ming-Yao Chen , Shiue-Wei Lai , Yi-Chiao Cheng , Vijesh Kumar Yadav , Iat-Hang Fong , Kuang-Tai Kuo , Kuen-Haur Lee , Yih-Giun Cherng

Background

Lenvatinib is a first-line therapy for advanced hepatocellular carcinoma (HCC), yet the emergence of lenvatinib-tolerant persister cells (LTPCs) contributes to therapeutic failure and tumor relapse. The molecular programs that sustain this tolerant state remain insufficiently defined. Here, we investigated the role of the PPP1R15B–ATF4 stress-response axis in mediating lenvatinib tolerance and ferroptosis resistance.

Methods

LTPCs were generated from multiple HCC cell lines through continuous lenvatinib exposure and confirmed by phenotypic and molecular profiling. Transcriptomic analysis (RNA-seq) was performed to identify pathways enriched in LTPCs. Functional relevance of the PPP1R15B–ATF4–GPX4 axis was evaluated using genetic perturbation (siRNA/CRISPR) and pharmacologic inhibition. Redox homeostasis, lipid peroxidation, and ferroptosis susceptibility were assessed through biochemical and imaging assays. An LTPC xenograft mouse model was used to evaluate in vivo therapeutic efficacy.

Results

RNA-seq revealed that LTPCs exhibit robust activation of the PPP1R15B–ATF4–GPX4 signaling axis, accompanied by enhanced redox buffering and suppression of ferroptotic vulnerability. Mechanistic studies demonstrated that PPP1R15B stabilizes ATF4, which in turn transcriptionally upregulates GPX4, thereby sustaining the drug-tolerant persister phenotype. Genetic or pharmacological inhibition of PPP1R15B disrupted ATF4–GPX4 signaling, impaired redox homeostasis, increased lipid peroxidation, and effectively re-sensitised LTPCs to ferroptosis and lenvatinib. In vivo, PPP1R15B inhibition significantly reduced LTPC survival and restored lenvatinib responsiveness in xenograft models.

Conclusion

The PPP1R15B–ATF4–GPX4 axis is a key determinant of lenvatinib tolerance in HCC by orchestrating redox adaptation and ferroptosis resistance. Targeting PPP1R15B represents a promising therapeutic strategy to eliminate lenvatinib-tolerant persister cells and overcome acquired resistance in HCC.

背景：Lenvatinib是晚期肝细胞癌（HCC）的一线治疗药物，然而Lenvatinib耐受持续性细胞（LTPCs）的出现导致了治疗失败和肿瘤复发。维持这种耐受状态的分子程序仍然没有得到充分的定义。在这里，我们研究了PPP1R15B-ATF4应激响应轴在介导lenvatinib耐受性和铁下垂抗性中的作用。方法：通过连续暴露lenvatinib，从多个HCC细胞系中产生LTPCs，并通过表型和分子分析证实。转录组学分析（RNA-seq）用于鉴定LTPCs中富集的通路。使用遗传扰动（siRNA/CRISPR）和药物抑制来评估PPP1R15B-ATF4-GPX4轴的功能相关性。通过生化和成像分析评估氧化还原稳态、脂质过氧化和铁下垂易感性。采用LTPC异种移植小鼠模型评价其体内治疗效果。结果：RNA-seq显示，LTPCs表现出PPP1R15B-ATF4-GPX4信号轴的强大激活，伴随着氧化还原缓冲的增强和铁致易感性的抑制。机制研究表明PPP1R15B稳定ATF4， ATF4反过来转录上调GPX4，从而维持耐药持久性表型。遗传或药理学抑制PPP1R15B破坏ATF4-GPX4信号，破坏氧化还原稳态，增加脂质过氧化，并有效地使LTPCs对铁中毒和lenvatinib再敏感。在体内，PPP1R15B抑制显著降低了异种移植模型中LTPC的存活，并恢复了lenvatinib的反应性。结论：PPP1R15B-ATF4-GPX4轴是HCC中lenvatinib耐受的关键决定因素，通过协调氧化还原适应和铁凋亡抵抗。靶向PPP1R15B是一种很有前景的治疗策略，可以消除肝癌中lenvatinib耐受的持久性细胞并克服获得性耐药。

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引用次数: 0

Safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of a novel anti-TSLP bispecific antibody (GR2002) in healthy Chinese adults: A randomized, placebo-controlled phase 1 trial 一种新型抗tslp双特异性抗体（GR2002）在中国健康成人中的安全性、耐受性、药代动力学、药效学和免疫原性：一项随机、安慰剂对照的1期试验

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-08 DOI: 10.1016/j.ejps.2026.107432

Rui Ding , Fan Huang , Ziyan Ding , Yanting Li , Qun Gu , Fang Men , Chongyou Lee , Jiaojiao Zhang , Wenyan Zhao , Qian Wang , Yian Liu , Shuang Li , Qingshan Zheng , Haifeng Song , Liming Chen , Wei Wang , Suping Niu , Yi Fang

Background

GR2002 is a novel bispecific antibody targeting dual epitopes on thymic stromal lymphopoietin (TSLP). We aimed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of GR2002 in healthy Chinese adults.

Methods

In this randomized, double-blind, placebo-controlled, dose-escalation, phase 1 trial of GR2002, healthy adults were enrolled and assigned to one of five dose cohorts. Within each cohort, participants were randomized (4:1) to receive a single subcutaneous dose of GR2002 (35, 70, 140, 280, or 420 mg) or placebo and were followed for 85 days. The primary endpoints included safety and tolerability. Secondary endpoints comprised PK, PD, and immunogenicity.

Results

Fifty eligible subjects were enrolled and randomized to receive either GR2002 (n = 40) or placebo (n = 10). A total of 92 treatment-emergent adverse events (TEAEs) were reported, with comparable incidence between the GR2002 and placebo groups. TEAEs were generally mild to moderate in severity and did not exhibit dose dependency. The most common treatment-related adverse event was upper respiratory tract infection, occurring in 7/40 (17.5%) participants in the GR2002 group and 2/10 (20%) in the placebo group. GR2002 displayed linear PK across the dose range tested, with a mean half-life ranging from 26.0 to 58.9 days. Dose-dependent reductions in serum TSLP levels from baseline were observed in the 140–420 mg dose groups. Anti-drug antibodies were detected in six subjects (15%) following GR2002 administration.

Conclusions

Single-dose subcutaneous administration of GR2002 demonstrated favorable safety and tolerability, linear PK, and low immunogenicity. These findings warrant the subsequent clinical development of GR2002.

背景：GR2002是一种针对胸腺基质淋巴生成素（TSLP）双表位的新型双特异性抗体。我们旨在评估GR2002在中国健康成人中的安全性、耐受性、药代动力学（PK）、药效学（PD）和免疫原性。方法：在这项随机、双盲、安慰剂对照、剂量递增的GR2002一期试验中，招募了健康成人，并将其分配到五个剂量队列中的一个。在每个队列中，参与者随机（4:1）接受单次皮下剂量GR2002（35、70、140、280或420 mg）或安慰剂，随访85天。主要终点包括安全性和耐受性。次要终点包括PK、PD和免疫原性。结果：50名符合条件的受试者入组并随机接受GR2002 （n=40）或安慰剂（n=10）。总共报告了92例治疗中出现的不良事件（teae）， GR2002组和安慰剂组的发生率相当。teae的严重程度一般为轻至中度，不表现出剂量依赖性。最常见的治疗相关不良事件是上呼吸道感染，在GR2002组中有7/40（17.5%）的参与者发生，在安慰剂组中有2/10（20%）的参与者发生。GR2002在测试的剂量范围内显示线性PK，平均半衰期为26.0至58.9天。140-420 mg剂量组血清TSLP水平较基线呈剂量依赖性降低。使用GR2002后，6例（15%）检测到抗药物抗体。结论：GR2002单次皮下给药具有良好的安全性和耐受性，线性PK和低免疫原性。这些发现为后续的STSA-1002临床开发提供了依据。

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引用次数: 0

Thermosensitive in situ gels for ocular drug delivery: Advances in polymer-based formulations 用于眼部给药的热敏原位凝胶：聚合物基配方的进展。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-08 DOI: 10.1016/j.ejps.2026.107439

Raghad Alsheikh , Dániel Nemes , Pálma Fehér , Zoltán Ujhelyi , Ádám Haimhoffer , Ádám Papp , Ildikó Bácskay

Ocular drug delivery presents significant challenges due to the unique anatomical and physiological barriers of the human eye, with the rapid precorneal elimination, limiting the bioavailability of conventional eye drops. Thermosensitive in situ gels have emerged as a promising delivery system to overcome these limitations by undergoing a reversible sol-to-gel transition upon contact with ocular surface temperature, which facilitates ease of administration as a liquid and subsequent transformation into a gel, thereby enhancing precorneal residence time, prolonging the drug release, and improving therapeutic efficacy. This review provides a comprehensive overview of thermos-responsive polymer-based ocular delivery systems, with a specific focus on poloxamers, poly(N-isopropylacrylamide), and cellulose derivatives. Particular attention is given to the physicochemical mechanisms of thermogelation, such as poloxamer micellization and micelle packing, as well as the role of auxiliary polymers in enhancing mucoadhesion, mechanical strength, and gel retention. Additionally, the review synthesizes findings from multiple experimental studies to highlight the critical formulation parameters essential for developing effective in situ gels, including sol–gel transition temperature and time, clarity, rheological behavior, gelling capacity, isotonicity, and ocular biocompatibility. By selecting an optimized thermosensitive in situ gel formulation with suitable characteristics, it becomes possible to develop effective delivery systems targeting both the anterior and posterior segments of the eye.

由于人眼独特的解剖和生理屏障，角膜前快速消除限制了传统滴眼液的生物利用度，眼部给药面临重大挑战。热敏原位凝胶作为一种很有前途的递送系统已经出现，通过在接触眼表温度时经历可逆的溶胶到凝胶的转变来克服这些限制，这有利于以液体形式给药和随后转化为凝胶，从而延长角膜前停留时间，延长药物释放，提高治疗效果。这篇综述提供了热响应聚合物为基础的眼部传递系统的全面概述，特别关注poloxamers，聚（n -异丙基丙烯酰胺）和纤维素衍生物。特别关注热凝胶化的物理化学机制，如波洛沙姆胶束化和胶束堆积，以及辅助聚合物在增强黏附、机械强度和凝胶保留方面的作用。此外，本文综合了多项实验研究的结果，强调了开发有效原位凝胶所需的关键配方参数，包括溶胶-凝胶转变温度和时间、透明度、流变行为、胶凝能力、等渗性和眼生物相容性。通过选择具有合适特性的优化热敏原位凝胶配方，可以开发针对眼睛前段和后段的有效递送系统。

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引用次数: 0

Assembled fixed-dose combination tablet for hypertension: A modular design inspired by LEGO® architecture 组合式高血压固定剂量组合片剂：模块化设计，灵感来自乐高®架构

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-07 DOI: 10.1016/j.ejps.2026.107430

Tanikan Sangnim , Kittipat Suwanpitak , Pornsak Sriamornsak , Kampanart Huanbutta

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 (>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.

由于复杂的治疗方案，高血压等慢性病的多药治疗往往会影响患者的依从性和治疗成功率。虽然传统的固定剂量组合（FDC）片剂提高了依从性，但它们缺乏个性化治疗所需的剂量灵活性。本研究通过开发和表征一种新颖的、受LEGO®启发的可组装FDC片剂系统来解决这一空白，该系统可用于定制抗高血压治疗。使用3d打印模具，可以创建含有氨氯地平、缬沙坦或氢氯噻嗪（HCTZ）的单个可堆叠模块。该研究评估了两种聚合物基质，揭示了对活性药物成分（API）的关键依赖。明胶基质对氨氯地平和缬沙坦有效，快速出药符合USP溶出度标准；然而，该基质与HCTZ不相容释放（30 min内90%）。相反，基于hpmc的基质成功地配制了具有控释特征的HCTZ，但不适合用于其他两种药物。这项工作验证了模块化FDC系统作为个性化多药的有前途的平台的概念验证。然而，它也强调了实现所需的药物释放谱需要仔细的api特异性聚合物选择，这对这种创新方法提出了关键的配方挑战。

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引用次数: 0

Corrigendum to “Physiologically-based pharmacokinetic modeling of natalizumab for multiple sclerosis patients to predict the withdrawal time in pregnancy and vaccine time in infants” [European Journal of Pharmaceutical Sciences, 215 (2025), 107301] “基于生理的纳塔珠单抗用于多发性硬化症患者的药代动力学建模，以预测妊娠期停药时间和婴儿疫苗接种时间”的勘误表[European Journal of Pharmaceutical Sciences， 215 (2025), 107301]

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-07 DOI: 10.1016/j.ejps.2025.107420

Peilin Zhou , Chenming Zhong , Wanhong Wu , Meng Ke , Jianwen Xu , Rongfang Lin , Pinfang Huang , Cuihong Lin

引用次数: 0

Novel porphyrin photosensitizer LD4-PDT alleviates asthma airway remodeling by inhibiting EGR1-dependent TGF-β1/Smad signaling 新型卟啉光敏剂LD4-PDT通过抑制egr1依赖性TGF-β1/Smad信号通路缓解哮喘气道重构

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-07 DOI: 10.1016/j.ejps.2026.107431

Zhuo Tao , Hongzhi Yu , Bin Xu , Xueming Wang , Junping Wu , Ying Wen , Tianjun Liu

Asthma, a common chronic inflammatory airway disease, affects 300 million people globally. Pathologically, it features Th2/Th17-driven airway inflammation and remodeling, which worsens disease and impairs lung function. Current therapies alleviate symptoms but cannot prevent irreversible airway structural changes, highlighting the need for targeted treatments. The TGF-β1/Smad axis is pivotal for epithelial‒mesenchymal transition (EMT) and airway fibrosis‒key features of asthmatic remodeling. This study aimed to explore the interaction between the TGF-β1/Smad pathway and EGR1 and evaluate the effect of LD4-based photodynamic therapy (LD4-PDT) as a potential anti-inflammatory agent on asthma by evaluating inflammatory cell infiltration, nitrosative and oxidative stress markers, and EMT-related substances in a rat model of asthma. Primarily, we evaluated the efficacy of LD4-PDT in ovalbumin (OVA)-induced asthmatic rats. Assessments included pulmonary function (FVC, MMF), airway histopathology, oxidative stress markers, and EMT-related proteins (TGF-β1, Smad, MMP-9). Transcriptomics identified key targets, molecular docking verified binding, and TGF-β1-stimulated BEAS-2B/16HBE cells validated mechanisms in vitro. LD4-PDT exerted dose-dependent effects: improved lung function (increased FVC/MMF), reduced inflammation (lower IgE/TNF-α), and attenuated remodeling (decreased collagen deposition and PAS+ cells). Mechanistically, it suppressed EMT by inhibiting EGR1-dependent TGF-β1/Smad signaling and modulating arachidonic acid metabolism. Transcriptomics confirmed EGR1 as a critical mediator, and molecular docking showed strong LD4-EGR1 binding—providing a molecular basis for LD4-PDT’s effects. LD4-PDT effectively targets EGR1-driven EMT, inflammation, and metabolic dysregulation, emerging as a novel therapeutic strategy for asthma.

哮喘是一种常见的慢性炎症性气道疾病，影响着全球3亿人。病理上，它以Th2/ th17驱动的气道炎症和重塑为特征，这使疾病恶化并损害肺功能。目前的治疗方法可以缓解症状，但不能防止不可逆的气道结构改变，因此需要有针对性的治疗。TGF-β1/Smad轴对上皮-间质转化（EMT）和气道纤维化至关重要，这是哮喘重塑的关键特征。本研究旨在通过评估哮喘大鼠模型中的炎症细胞浸润、亚硝酸盐和氧化应激标志物以及emt相关物质，探讨TGF-β1/Smad通路与EGR1的相互作用，并评价LD4-PDT作为一种潜在的抗炎药对哮喘的作用。首先，我们评估了LD4-PDT对卵清蛋白（OVA）诱导的哮喘大鼠的疗效。评估包括肺功能（FVC、MMF）、气道组织病理学、氧化应激标志物和emt相关蛋白（TGF-β1、Smad、MMP-9）。转录组学鉴定关键靶点，分子对接验证结合，TGF-β1刺激BEAS-2B/16HBE细胞体外机制验证。LD4-PDT发挥剂量依赖效应：改善肺功能（增加FVC/MMF），减轻炎症（降低IgE/TNF-α），减轻重塑（减少胶原沉积和PAS+细胞）。在机制上，它通过抑制egr1依赖性TGF-β1/Smad信号传导和调节花生四烯酸代谢来抑制EMT。转录组学证实了EGR1是关键的介质，分子对接显示了LD4-EGR1的强结合，为LD4-PDT的作用提供了分子基础。LD4-PDT有效靶向egr1驱动的EMT、炎症和代谢失调，成为治疗哮喘的新策略。

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引用次数: 0

Development and in vitro/in vivo evaluation of polymeric dissolving microneedle formulation for psoriasis treatment 银屑病聚合物溶解微针制剂的研制及体外/体内评价

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-06 DOI: 10.1016/j.ejps.2026.107429

Meryem Kaplan , Fatma Betül Arslan , Süleyman Can Öztürk , Sıla Ulutürk , Çisel Aydın Meriçöz , Güneş Esendağlı , Sema Çalış , Kıvılcım Öztürk

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 in vitro 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.

牛皮癣是一种炎症性自身免疫性皮肤病，严重影响生活质量。这种疾病的慢性和复发性可以持续一生。目前的常规治疗方案有几个缺点，包括不充分或短暂的疗效，耐受性和依从性问题，局部应用和光疗相关的实际限制，以及与全身治疗相关的重大安全性和成本问题。通常采用对症治疗，但很少能完全康复。研究人员正在探索替代治疗方法，例如基于生物学的治疗方法。这些疗法专门针对牛皮癣相关的免疫机制，与传统疗法相比，具有更可靠的疾病控制、患者生活质量的显著改善以及更有利的安全性等优势。目前正在研究的治疗牛皮癣的一种创新方法是使用微针作为经皮给药策略，该策略在研究中显示出有希望的结果。本研究采用微模塑法制备了透明质酸和蔗糖组成的生物相容性聚合物溶解微针制剂。微针上装载了secukinumab（一种针对IL-17A的人单克隆抗体）和Stattic（一种STAT3抑制剂），用于联合治疗。预计将微针直接应用于银屑病斑块会增加局部药物浓度。通过体外表征和细胞培养研究，建立了成年小鼠牛皮癣模型。将含有secukinumab和Stattic（单独和同时加载）的微针的治疗效果与对照组进行比较。治疗后观察病变进展并进行组织学检查。结果表明，负载secukinumab的微针在较低剂量下提供了更有效的治疗。

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引用次数: 0

Design and evaluation of dual-functional aptamer-peptide conjugates as a platform for targeted cancer therapy 双功能适配体-肽偶联物作为靶向癌症治疗平台的设计与评价。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-06 DOI: 10.1016/j.ejps.2026.107428

Simona Marzano , Maria Grazia Ferraro , Nicola Grasso , Rossella Buono , Valentina Arciuolo , Federica Iazzetti , Marialuisa Piccolo , Assunta Passarelli , Federica D’Aria , Francesco Merlino , Paolo Grieco , Antonio Randazzo , Bruno Pagano , Carlo Irace , Jussara Amato

AS1411 is a G-rich DNA aptamer that exhibits intrinsic antitumor activity through selective binding to nucleolin, a protein overexpressed in many cancers. Beyond its cytotoxic effects, AS1411 can also serve as an effective targeting ligand for the delivery of therapeutics with poor cellular uptake, including peptide-based drugs. One such candidate is the pro-apoptotic peptide KLA, which selectively disrupts mitochondrial membranes and induces apoptosis upon internalization. In this study, AS1411-KLA conjugates were designed and synthesized using strain-promoted azide-alkyne cycloaddition chemistry, incorporating protease-cleavable peptide linkers to enable intracellular release of both the aptamer and peptide as independent active units. Circular dichroism analysis showed that, in all constructs, the AS1411 domain preserved the characteristic G-quadruplex structural features, while surface plasmon resonance experiments revealed that all conjugates retained nucleolin binding. The biological activity of the conjugates was evaluated in MCF-7 breast cancer cells and in non-tumorigenic MCF-10A cells, and compared with that of the individual aptamer and peptide. One conjugate displayed an enhanced antiproliferative effect compared to the unconjugated components, underscoring the therapeutic potential of this modular design. Overall, this work demonstrates the potential of aptamer-peptide conjugates as a promising strategy for next-generation targeted cancer therapeutics, combining targeted delivery with synergistic therapeutic effects.

AS1411是一种富含g的DNA适体，通过选择性结合核蛋白（一种在许多癌症中过度表达的蛋白质），显示出内在的抗肿瘤活性。除了其细胞毒性作用外，AS1411还可以作为一种有效的靶向配体，用于递送细胞摄取不良的治疗药物，包括基于肽的药物。其中一个候选是促凋亡肽KLA，它选择性地破坏线粒体膜并在内化后诱导细胞凋亡。本研究采用菌株促进叠氮-炔环加成化学方法设计并合成AS1411-KLA偶联物，结合蛋白酶可切割肽连接物，使适体和肽作为独立的活性单元在细胞内释放。圆二色性分析表明，在所有构建体中，AS1411结构域都保留了典型的g -四重体结构特征，而表面等离子体共振实验显示，所有共轭物都保留了核蛋白结合。结合物在MCF-7乳腺癌细胞和非致瘤性MCF-10A细胞中的生物活性进行了评估，并与单个适配体和肽的生物活性进行了比较。与未偶联的组分相比，一种偶联物显示出增强的抗增殖作用，强调了这种模块化设计的治疗潜力。总的来说，这项工作证明了适体-肽缀合物作为下一代靶向癌症治疗的一种有前途的策略，结合靶向递送和协同治疗效果。

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引用次数: 0

Deconvoluting the in vitro to in vivo drug clearance gap: Questioning the predictive performance of traditional hepatic clearance models 解离体内药物清除差距：质疑传统肝脏清除模型的预测性能。

IF 4.7 3区医学 Q1 PHARMACOLOGY & PHARMACY

European Journal of Pharmaceutical Sciences

Pub Date : 2026-01-02 DOI: 10.1016/j.ejps.2026.107427

Sofie Heylen , Johan Nicolaï , Stijn Van Asten , Katie De Wagter , Andrea Treyer , Jan Snoeys , Raymond Evers , Stephanie Kourula , Pieter Annaert

In vitro to in vivo extrapolation (IVIVE) methods for hepatic clearance (CL_H) prediction often underpredict, partly due to reliance on mathematical liver disposition models such as the well-stirred model (WSM) or parallel tube model (PTM). The ex vivo isolated perfused rat liver (IPRL) model bridges in vitro and in vivo data, providing mechanistic insights into the predictive accuracy of IVIVE models. This study evaluates the IPRL model across a diverse selection of 16 compounds, and benchmarks results against in vitro and in vivo data to verify the predictive performance of the WSM and PTM. Results demonstrate that both the IPRL and in vivo clearance conflict with assumptions of the WSM (AAFE = 2.85) or PTM (AAFE = 1.74), which consider the liver outlet concentration as a driver for the hepatic elimination rate. However, except for terfenadine, IPRL clearance predictions were within two-fold (AAFE = 1.59) of in vivo clearance when the liver inlet concentration was utilized to calculate the CL_H. When employing the WSM or PTM for in vitro to ex vivo extrapolation, underpredictions were observed for compounds with high plasma protein binding and subject to sinusoidal hepatic uptake, reflecting model oversimplification compared to in vivo dynamics. Our findings experimentally challenge the theoretical assumptions underlying the use of the WSM and PTM in IVIVE methods. Unique insights from the IPRL model point to the next steps needed to advance IVIVE: refining current liver disposition models through enhanced and next-generation in vitro assays, capturing dynamic in vivo disposition mechanisms, and exploring complementary models.

体外到体内外推法（IVIVE）预测肝脏清除率（CLH）的方法往往预测不足，部分原因是依赖于数学肝脏配置模型，如搅拌良好模型（WSM）或平行管模型（PTM）。体外离体灌注大鼠肝脏（IPRL）模型连接了体外和体内数据，为IVIVE模型的预测准确性提供了机制见解。本研究对16种化合物的IPRL模型进行了评估，并对体外和体内数据进行了基准测试，以验证WSM和PTM的预测性能。结果表明，IPRL和体内清除率与WSM （AAFE = 2.85）或PTM （AAFE = 1.74）的假设相冲突，后者认为肝出口浓度是肝脏清除率的驱动因素。然而，除特非那定外，当使用肝脏进口浓度计算CLH时，IPRL清除率预测值在体内清除率的两倍之内（AAFE = 1.59）。当使用WSM或PTM进行体外离体外推时，对具有高血浆蛋白结合且受肝正弦摄取的化合物的预测不足，反映了与体内动力学相比模型过于简化。我们的研究结果在实验上挑战了在IVIVE方法中使用WSM和PTM的理论假设。来自IPRL模型的独特见解指出了推进IVIVE所需的下一步：通过增强和下一代体外分析来完善当前的肝脏处置模型，捕获动态体内处置机制，并探索互补模型。

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引用次数: 0