Pharmacological research最新文献_第6页

Plasma miR-150–5p as a biomarker for immunosuppressive therapy response in acetylcholine receptor positive myasthenia gravis: a long-term prospective longitudinal study 血浆miR-150-5p作为乙酰胆碱受体阳性重症肌无力免疫抑制治疗反应的生物标志物：一项长期前瞻性纵向研究

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108078

Nemanja Garai , Sanja Madic , Vukan Ivanovic , Aleksa Palibrk , Jovan Pesovic , Milos Brkusanin , Ivana Basta , Stojan Peric , Dusanka Savic-Pavicevic

Insufficient effectiveness and adverse effects of immunosuppressive therapy, seen in around 20 % of acetylcholine receptor (AChR) positive myasthenia gravis (MG) patients, highlight the need for new biomarkers. MicroRNAs (miRNAs), small regulatory non-coding RNAs with tissue-specific expression, have emerged as potential biomarkers due to their abundance and accessibility in body fluids. Several miRNAs involved in immune system and drug metabolism have been associated with improvement of neuromuscular status or response to immunosuppressive therapy in AChR-positive MG patients in cross-sectional studies. Here, we explored miRNAs as plasma biomarkers for immunosuppressive therapy response in a prospective longitudinal study of newly diagnosed, drug-naïve patients. Clinical examination and plasma sampling were performed at three time points: baseline (pre-treatment), 6-month, and 12-month follow-ups. MiRNA levels were quantified by qPCR. Three out of eight analyzed miRNAs (miR-150–5p, miR-27a–3p, and miR-21–5p) showed treatment-related changes. Among them, miR-150–5p level was negatively correlated with patient functionality (MG Activities of Daily Living score – MG-ADL; p = 0.007, ρ_s=−0.433), muscle strength and weakness (Quantitative MG score – QMG; p = 0.002, ρ_s=−0.355) and overall symptoms (MG Composite score – MGC; p = 7.814e-5, ρ_s=−0.457). Pre-treatment miR-150–5p levels showed excellent prognostic ability to discriminate responders from not-responders based on achieved minimal clinical expression (AUC=0.85, p = 0.0076) and MG-ADL (AUC=0.86, p = 0.016) at 12-month follow-up. Predictive performance was also acceptable based on QMG and MGC (AUC=0.74, p = 0.001 and AUC=0.73, p = 0.0002, respectively). Our findings imply plasma miR-150–5p as a potential biomarker for predicting immunosuppressive therapy response in AChR-positive MG, suggesting its further investigation for disease monitoring and a personalized medicine approach.

大约20%的乙酰胆碱受体（AChR）阳性重症肌无力（MG）患者存在免疫抑制治疗的有效性不足和不良反应，这突出了对新的生物标志物的需求。MicroRNAs （miRNAs）是具有组织特异性表达的小调节非编码rna，由于其在体液中的丰度和可及性，已成为潜在的生物标志物。在横断面研究中，一些参与免疫系统和药物代谢的mirna与achr阳性MG患者神经肌肉状态的改善或对免疫抑制治疗的反应有关。在这里，我们在一项新诊断的drug-naïve患者的前瞻性纵向研究中探索了miRNAs作为免疫抑制治疗反应的血浆生物标志物。临床检查和血浆采样在三个时间点进行：基线（治疗前），6个月和12个月的随访。qPCR检测miRNA水平。8个分析的mirna中有3个（miR-150-5p， miR-27a-3p和miR-21-5p）显示出与治疗相关的变化。其中，miR-150-5p水平与患者功能（MG日常生活活动评分- MG- adl， p=0.007, ρs=-0.433）、肌肉力量和无力（MG定量评分- QMG， p=0.002, ρs=-0.355）、整体症状（MG综合评分- MGC， p= 7.814e-5, ρs=-0.457）呈负相关。根据12个月随访时达到的最小临床表达（AUC=0.85, p=0.0076）和MG-ADL (AUC=0.86, p=0.016)，治疗前miR-150-5p水平显示出区分应答者和无应答者的良好预后能力。基于QMG和MGC的预测性能也可以接受（AUC分别=0.74,p=0.001和AUC=0.73, p=0.0002）。我们的研究结果表明，血浆miR-150-5p是预测achr阳性MG患者免疫抑制治疗反应的潜在生物标志物，建议进一步研究其用于疾病监测和个性化医疗方法。

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引用次数: 0

Corrigendum to “Epigenetic regulation in calcific aortic valve disease: Mechanisms and therapeutic potential” [Pharmacol. Res. (2025) 223 108073] “钙化主动脉瓣疾病的表观遗传调控：机制和治疗潜力”的勘误表[Pharmacol]。Res.(2025) 223 108073]。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108083

Hanshen Luo, Yuehang Yang, Chiyang Xie, Chuli Shi, Siyuan Liu, Jiawei Shi

引用次数: 0

Corrigendum to “Tagitinin F has anti-inflammatory, anti-nociceptive and anti-matrix metalloproteinase properties: An in silico, in vitro and in vivo study” [Pharmacol. Res. 164 (2021) 105303] “他吉宁F具有抗炎、抗伤害和抗基质金属蛋白酶特性：一项硅、体外和体内研究”的勘误表[Pharmacol]。Res. 164(2021)[105303]。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-01 DOI: 10.1016/j.phrs.2025.108070

Laíla Pereira Silva , Eliziária Cardoso Santos , Bruno Arantes Borges , Marcia Paranho Veloso , Daniela Aparecida Chagas-Paula , Reggiani Vilela Gonçalves , Rômulo Dias Novaes

引用次数: 0

Mitochondrial pyruvate dehydrogenase kinase 1 drives bevacizumab resistance and malignant phenotype of TNBC by enhancing mitophagy 线粒体丙酮酸脱氢酶激酶1通过增强线粒体自噬驱动TNBC的贝伐单抗耐药和恶性表型。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-31 DOI: 10.1016/j.phrs.2025.108081

Yan Ye , Qian Zeng , Zuli Ou , Xiaoqian Ju , Qingyu Liao , Canling Li , Dian Zhang , Yu Wei , Xiang Zhang , Kejia Wu , Tingmei Chen

Bevacizumab is an anti-angiogenic agent widely used in neoadjuvant chemotherapy for advanced triple-negative breast cancer (TNBC). TNBC patients frequently acquire resistance to bevacizumab due to the hypoxic tumor microenvironment, yet the underlying molecular mechanism remains unclear. Here, we demonstrate that mitochondrial reprogramming under hypoxia is crucial for resistance to bevacizumab. Mechanically, prolonged hypoxia causes the glycolytic pathway enzyme PDK1 to accumulate inside mitochondria. In mitochondria, PDK1 exerts its non-canonical function to phosphorylate mitochondrial protein Prohibitin 2 (PHB2) at Ser190. Phosphorylation at Ser190 stabilizes PHB2 and enhances its binding with LC3, thereby initiating mitophagy. Functionally, mitochondrial PDK1 (mito-PDK1) initiates mitophagy in response to hypoxia-induced mitochondrial damage and promotes the malignant phenotype of TNBC cells. In xenograft tumors, inhibiting the function of mito-PDK1 enhances the sensitivity to bevacizumab. Collectively, our findings identify the crucial function and mechanism of mito-PDK1 in TNBC. Targeting mito-PDK1 function may emerge as a novel therapeutic strategy to address acquired resistance to bevacizumab.

贝伐单抗是一种抗血管生成药物，广泛用于晚期三阴性乳腺癌（TNBC）的新辅助化疗。由于肿瘤微环境缺氧，TNBC患者经常获得对贝伐单抗的耐药，但其潜在的分子机制尚不清楚。在这里，我们证明了缺氧条件下线粒体重编程对贝伐单抗耐药性至关重要。机械上，长时间的缺氧导致糖酵解途径酶PDK1在线粒体内积聚。在线粒体中，PDK1发挥其非规范功能，使线粒体蛋白禁止蛋白2 （PHB2）在Ser190位点磷酸化。Ser190磷酸化稳定PHB2并增强其与LC3的结合，从而启动有丝分裂。在功能上，线粒体PDK1 （mito-PDK1）启动线粒体自噬以应对缺氧诱导的线粒体损伤，并促进TNBC细胞的恶性表型。在异种移植物肿瘤中，抑制mitto - pdk1的功能可增强对贝伐单抗的敏感性。总的来说，我们的研究结果确定了mito-PDK1在TNBC中的关键功能和机制。靶向mitto - pdk1功能可能成为解决贝伐单抗获得性耐药的新治疗策略。

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引用次数: 0

Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms 低剂量、非致幻剂裸盖菇素通过5-HT2B受体依赖机制作为MASLD、肥胖和2型糖尿病的新治疗方法。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-29 DOI: 10.1016/j.phrs.2025.108080

Martina Colognesi , Daniela Gabbia , Anna Signor , Miles Sarill , Lucia Centofanti , Andrea Rinaldi , Luciano Cascione , Sara Nunziata , Marco Banzato , Andrea Mattarei , Giovanna Finzi , Sonia Sonda , Diana Pendin , Ilaria Zanotto , Stefano Comai , Gianfranco Pasut , Abdullah Alajati , Miriam Saponaro , Loredana Bucciarelli , Maria Elena Lunati , Sara De Martin

The therapeutic potential of low, non-psychedelic doses of psilocybin, a fungal tryptamine alkaloid, was investigated in metabolic disorders including obesity, type 2 diabetes mellitus (T2DM), and liver steatosis. Mice fed a high-fat/high-fructose diet received chronic treatment with psilocybin (0.05 mg/kg) for 12 weeks. Body weight, liver histology, insulin sensitivity, and skeletal muscle function were assessed, and hepatic and muscle tissues underwent transcriptomic and lipidomic analyses. The role of three serotonin receptors (5-HT2A, 5-HT2B, and 5-HT2C) in psilocybin-induced metabolic effects was examined in human cell lines using pharmacological and CRISPR/Cas9-based genetic approaches. Low-dose psilocybin reduced body-weight gain, liver steatosis, hyperglycaemia, and insulin resistance without eliciting central nervous system effects. Multi-omics analyses revealed near-complete normalization of disrupted hepatic lipid and carbohydrate metabolism pathways. Psilocybin also improved muscle strength and function, potentially through restoration of leptin sensitivity. Mechanistic studies demonstrated that these metabolic benefits were independent of the canonical psychedelic target 5-HT2A and instead resulted from antagonism of the serotonin 5-HT2B receptor in the liver. Overall, chronic low-dose psilocybin exerts broad metabolic benefits via a hepatic 5-HT2B-dependent mechanism, distinct from its psychedelic effects, supporting its potential as a novel therapeutic strategy for liver steatosis, obesity, T2DM, and sarcopenia.

低剂量的非致幻剂裸盖菇素（一种真菌色胺生物碱）治疗代谢紊乱包括肥胖、2型糖尿病（T2DM）和肝脂肪变性的潜力进行了研究。饲喂高脂肪/高果糖饮食的小鼠给予裸盖菇素（0.05mg/kg）慢性治疗12周。评估体重、肝脏组织学、胰岛素敏感性和骨骼肌功能，并对肝脏和肌肉组织进行转录组学和脂质组学分析。在人类细胞系中，使用药理学和基于CRISPR/ cas9的遗传方法检测了三种5-羟色胺受体（5-HT2A、5-HT2B和5-HT2C）在裸盖菇素诱导的代谢效应中的作用。低剂量裸盖菇素可减少体重增加、肝脂肪变性、高血糖和胰岛素抵抗，而不会引起中枢神经系统的影响。多组学分析显示，肝脏脂质和碳水化合物代谢途径几乎完全正常化。裸盖菇素还能改善肌肉力量和功能，可能是通过恢复瘦素敏感性来实现的。机制研究表明，这些代谢益处与典型的迷幻靶点5-HT2A无关，而是由肝脏中5-HT2B受体的5-羟色胺的拮抗作用引起的。总的来说，慢性低剂量裸盖菇素通过肝脏5- ht2b依赖机制发挥广泛的代谢益处，不同于其迷幻作用，支持其作为肝脏脂肪变性、肥胖、2型糖尿病和肌肉减少症的新治疗策略的潜力。

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引用次数: 0

PHGDH as a therapeutic node: Natural modulators from TCM, degradation pathways, and emerging TPD strategies PHGDH作为治疗节点：来自中医的天然调节剂、降解途径和新兴的TPD策略。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-23 DOI: 10.1016/j.phrs.2025.108079

Song-Song Shi , Yu-Dan Du , Si-Yi Chen , Wen Zhang , Guo-Wu Rao , Quan Zheng

Phosphoglycerate dehydrogenase (PHGDH) has emerged as a promising therapeutic target due to its critical roles in the pathogenesis of cancer and neurological disorders. Targeting PHGDH holds significant theoretical and translational potential for cancer therapy and the amelioration of cognitive impairments. However, currently available PHGDH inhibitors are limited in number and primarily function through inhibition of the enzyme's catalytic activity. This review systematically summarizes PHGDH modulators identified from traditional Chinese medicine, including both inhibitors and activators, and presents a detailed analysis of their structure–activity relationships (SAR) and mechanisms of action. It also comprehensively outlines the signaling pathways that regulate PHGDH degradation through the ubiquitin–proteasome system and autophagy–lysosome pathway. Importantly, it also discusses emerging targeted protein degradation (TPD) technologies, including PROTACs, LYTACs, AUTACs, and ATTECs. The development of these frontier technologies has opened new pathways for mitigating the limitations of existing inhibitors.

磷酸甘油酸脱氢酶（Phosphoglycerate dehydrogenase， PHGDH）由于在癌症和神经系统疾病的发病机制中起着关键作用而成为一个有希望的治疗靶点。靶向PHGDH在癌症治疗和改善认知障碍方面具有重要的理论和转化潜力。然而，目前可用的PHGDH抑制剂数量有限，主要通过抑制酶的催化活性起作用。本文系统综述了中药中发现的PHGDH调节剂，包括抑制剂和激活剂，并详细分析了它们的构效关系（SAR）和作用机制。它还全面概述了通过泛素-蛋白酶体系统和自噬-溶酶体途径调节PHGDH降解的信号通路。重要的是，它还讨论了新兴的靶向蛋白降解（TPD）技术，包括PROTACs， lytac， autac和attec。这些前沿技术的发展为减轻现有抑制剂的局限性开辟了新的途径。

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引用次数: 0

Multi-target neuroprotective effects of notoginsenoside R1 in neurodegenerative diseases: From pharmacokinetics to translational prospects 三七皂苷R1在神经退行性疾病中的多靶点神经保护作用：从药代动力学到转化前景。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-18 DOI: 10.1016/j.phrs.2025.108074

Hao-wen Lin , Shi-pian Li , Jia-xin Wen , Jia-xuan Zhang , Bi-meng Zhang , Yong-jun Wang , Xue-jun Cui , Min Yao

Neurodegenerative diseases impose a heavy social and economic burden, and effective therapeutic strategies are essential for slowing disease progression and improving patient quality of life. Notoginsenoside R1 (NGR1), a key saponin derived from Panax notoginseng (Burk. F.H. Chen), has been widely studied in experimental models of neurodegenerative diseases, such as stroke and Alzheimer’s disease (AD). Based on a rigorous literature screening and a meta-analysis of animal studies, we confirmed that NGR1 significantly reduces infarct volumes in cerebral ischemia-reperfusion models and improves escape latency in AD mice. Mechanistically, NGR1 confers neuroprotection by attenuating oxidative stress, suppressing neuroinflammation, inhibiting apoptosis, and preserving the neurovascular unit. Furthermore, using network pharmacology, reverse virtual screening, and molecular docking, we preliminarily identified potential targets and signaling pathways, providing a theoretical basis for future studies. However, clinical translation of NGR1 remains limited due to poor oral bioavailability and restricted permeability across the blood-brain and blood-spinal cord barriers. To address these challenges, we summarized delivery strategies, including nanoparticle-based carriers, intranasal administration, and permeability enhancers, to facilitate NGR1 entry into the central nervous system. We also discussed additional potential approaches, such as structural modification and targeted delivery, analyzing their respective advantages and limitations. Collectively, these findings highlight NGR1 as a promising candidate for the prevention and treatment of neurodegenerative diseases.

神经退行性疾病造成沉重的社会和经济负担，有效的治疗策略对于减缓疾病进展和改善患者生活质量至关重要。三七皂苷R1 （NGR1）是一种从三七中提取的关键皂苷。在神经退行性疾病，如中风和阿尔茨海默病（AD）的实验模型中得到了广泛的研究。基于严格的文献筛选和动物研究的荟萃分析，我们证实NGR1显著减少脑缺血再灌注模型中的梗死体积，并改善AD小鼠的逃避潜伏期。从机制上讲，NGR1通过减轻氧化应激、抑制神经炎症、抑制细胞凋亡和保存神经血管单位来提供神经保护。通过网络药理学、反向虚拟筛选、分子对接等手段，初步确定了潜在靶点和信号通路，为后续研究提供理论基础。然而，由于口服生物利用度差以及血脑和血脊髓屏障的渗透性有限，NGR1的临床转化仍然有限。为了解决这些挑战，我们总结了递送策略，包括纳米颗粒载体、鼻内给药和渗透性增强剂，以促进NGR1进入中枢神经系统。我们还讨论了其他可能的方法，如结构改造和定向输送，分析了各自的优势和局限性。总的来说，这些发现突出了NGR1作为预防和治疗神经退行性疾病的有希望的候选者。

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引用次数: 0

Epigenetic Regulation in calcific aortic valve disease: Mechanisms and therapeutic potential 钙化主动脉瓣疾病的表观遗传调控：机制和治疗潜力

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-17 DOI: 10.1016/j.phrs.2025.108073

Hanshen Luo, Yuehang Yang, Chiyang Xie, Chuli Shi, Siyuan Liu, Jiawei Shi

Calcific aortic valve disease (CAVD) is a progressive cardiovascular disorder pathologically defined by valvular sclerosis, fibrosis, and ectopic mineralization, which constitutes a substantial and growing public health burden. Currently, surgical intervention represents the sole effective treatment, underscoring a critical unmet need for novel pharmacological strategies that can halt disease progression or provide early therapeutic intervention. Extensive research has established that the pathogenesis of CAVD is driven by a complex interplay of multiple mechanisms including inflammatory responses, oxidative stress, and metabolic dysregulation which are intricately modulated by epigenetic regulation, post-transcriptional modifications, and protein post-translational modifications. In recent years, the field of epigenetics has garnered considerable attention, particularly for its pivotal role in the pathogenesis of oncological and cardiovascular diseases and the subsequent development of targeted therapeutic strategies. Consequently, numerous investigations have been dedicated to elucidating the involvement of epigenetic mechanisms in CAVD, encompassing DNA methylation, histone modifications (including methylation and acetylation), and RNA methylation, with a pronounced emphasis on the regulatory functions of non-coding RNAs. This review synthesizes recent advances in our understanding of epigenetic mechanisms underlying CAVD, with a specific focus on the role of RNA N6-methyladenosine (m6A) methylation, and highlights the pivotal significance of epigenetic modulation in critical biological processes and CAVD pathogenesis. Collectively, these findings offer valuable mechanistic insights and may illuminate novel paths toward the clinical translation of epigenetically targeted therapies for CAVD.

钙化性主动脉瓣病（CAVD）是一种进行性心血管疾病，病理定义为瓣膜硬化、纤维化和异位矿化，构成了巨大且日益增长的公共卫生负担。目前，手术干预是唯一有效的治疗方法，强调了对能够阻止疾病进展或提供早期治疗干预的新型药理策略的关键未满足需求。大量研究表明，CAVD的发病机制是由多种机制的复杂相互作用驱动的，包括炎症反应、氧化应激和代谢失调，这些机制由表观遗传调控、转录后修饰和蛋白质翻译后修饰复杂地调节。近年来，表观遗传学领域获得了相当大的关注，特别是其在肿瘤和心血管疾病的发病机制以及随后的靶向治疗策略发展中的关键作用。因此，许多研究都致力于阐明CAVD的表观遗传机制，包括DNA甲基化，组蛋白修饰（包括甲基化和乙酰化）和RNA甲基化，并强调非编码RNA的调节功能。本文综述了近年来我们对CAVD的表观遗传机制的理解，特别关注RNA n6 -甲基腺苷（m6A）甲基化的作用，并强调了表观遗传调控在CAVD的关键生物学过程和发病机制中的关键意义。总的来说，这些发现提供了有价值的机制见解，并可能为CAVD的表观遗传靶向治疗的临床翻译照亮新的途径。

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引用次数: 0

Mast cells in digestive diseases: New insights to keep them under control 消化系统疾病中的肥大细胞：控制肥大细胞的新见解。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-14 DOI: 10.1016/j.phrs.2025.108069

Hayriye Akel Bilgic, Marie Bek, Mirelle Kleuskens, Frank Redegeld

The gut mucosa serves as an essential interface between the internal and external environment, providing a continuous barrier against possible harmful luminal content. The regulation of this protective function is controlled by immune-mediated and non-immune mechanisms, wherein mast cells (MCs) play a key role. These versatile immune cells are strategically located in the lining of the gastrointestinal (GI) tract, where they help maintain the integrity of the intestinal barrier, regulate blood flow, control the entry of immune cells into tissues, and participate in various physiological processes, such as wound healing and intestinal peristalsis. However, excessive MC activation may disturb the gut balance, which could cause a "leaky gut", where increased permeability of the intestinal lining allows substances to pass into the bloodstream, causing various health problems. Studies have confirmed an increased presence of MCs in the intestinal lining of individuals with compromised barriers, as seen in conditions like gastrointestinal diseases (GIDs). Hence, precise regulation of MC activity is essential for maintaining intestinal health and limiting disease progression. In this review, we aim to offer a comprehensive and current overview of the role of MCs in GIDs by delving into their origins, functions, and interactions in the GI environment. We explore the "leaky gut" concept, examining how MCs influence the intestinal barrier and its association with GIDs. Additionally, we describe the latest advancements in MC research, including targeted therapies and potential future directions.

肠道黏膜是内外环境之间的重要接口，为可能有害的肠道内容物提供了持续的屏障。这种保护功能的调节由免疫介导和非免疫机制控制，其中肥大细胞（MCs）起关键作用。这些多功能免疫细胞战略性地位于胃肠道的内壁，在那里它们帮助维持肠道屏障的完整性，调节血液流动，控制免疫细胞进入组织，并参与各种生理过程，如伤口愈合和肠道蠕动。然而，过度的MC激活可能会扰乱肠道平衡，从而导致“漏肠”，即肠道内膜通透性增加，使物质进入血液，导致各种健康问题。研究证实，屏障受损的个体肠道内壁中MCs的存在增加，如胃肠道疾病（gid）等疾病。因此，精确调节MC活性对于维持肠道健康和限制疾病进展至关重要。在这篇综述中，我们旨在通过深入研究MCs的起源、功能和在GI环境中的相互作用，对MCs在GI中的作用进行全面和最新的概述。我们探讨了“漏肠”的概念，研究了MCs如何影响肠屏障及其与gid的关联。此外，我们描述了MC研究的最新进展，包括靶向治疗和潜在的未来方向。

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引用次数: 0

Rapid 64Cu radiolabeling and in vivo evaluation of DSPE–NODAGA liposomes in a murine mammary tumor model DSPE-NODAGA脂质体在小鼠乳腺肿瘤模型中的快速64Cu放射性标记及体内评价

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2025-12-12 DOI: 10.1016/j.phrs.2025.108065

Elena Markova , Mathias Kranz , Morten Karlsen , Camilla Wolowczyk , Angel Moldes-Anaya , Nataša Škalko-Basnet , Rune Sundset , Alexandros Marios Sofias , Rodrigo Berzaghi , Montserrat Martin-Armas , Sjoerd Hak

Understanding the in vivo behavior of nanomedicines is critical for optimizing their therapeutic efficacy and facilitating personalized treatment strategies. In the quest to develop positron emission tomography (PET) methodology for liposome biodistribution studies, we systematically compared three liposome radiolabeling strategies - remote loading of ⁶⁴Cu into liposomes containing the hydrophilic chelator NOTA, membrane labeling using ATSM, and surface labeling with DSPE-NODAGA (phospholipid DSPE conjugated with chelator NODAGA) - to identify an effective method for liposome radiolabeling with ⁶⁴Cu. Our results demonstrated that DSPE-NODAGA incorporated in PEGylated liposomes allows for achieving 100 % radiochemical yield of ⁶⁴Cu at room temperature within just 5 min. Stability studies confirmed liposome integrity and minimal transchelation or dissociation in serum over 24 h, highlighting its suitability for in vivo applications. PET/MR imaging in healthy and tumor-bearing mice revealed prolonged circulation of ⁶⁴Cu-labeled PEGylated liposomes (PL-NODAGA) and significant tumor accumulation, validating DSPE-NODAGA’s potential for real-time tracking of liposome delivery. These findings establish the incorporation of DSPE-NODAGA as a robust and adaptable platform for PET-based monitoring of lipidic nanomedicine.

了解纳米药物的体内行为对于优化其治疗效果和促进个性化治疗策略至关重要。为了开发用于脂质体生物分布研究的正电子发射断层扫描（PET）方法，我们系统地比较了三种脂质体放射性标记策略——将64Cu远程装载到含有亲水性螯合剂NOTA的脂质体中，使用ATSM进行膜标记，以及使用DSPE-NODAGA（磷脂DSPE与螯合剂NODAGA偶联）进行表面标记——以确定一种有效的64Cu脂质体放射性标记方法。我们的研究结果表明，加入聚乙二醇脂质体的DSPE-NODAGA可以在室温下仅5分钟内实现100%的64Cu放射化学产率。稳定性研究证实脂质体的完整性和最小的转移或解离在血清中超过24小时，强调其适合体内应用。健康小鼠和肿瘤小鼠的PET/MR成像显示64cu标记的聚乙二醇脂质体（PL-NODAGA）循环延长和显著的肿瘤堆积，验证了DSPE-NODAGA在实时跟踪脂质体递送方面的潜力。这些发现建立了DSPE-NODAGA作为基于pet的脂质纳米药物监测的强大且适应性强的平台。

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引用次数: 0