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Recent progress of ferroptosis in cancers and drug discovery 癌症和药物发现中的铁蛋白沉积的最新进展
IF 10.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-01 DOI: 10.1016/j.ajps.2024.100939

Ferroptosis is a nonapoptotic form of cell death characterized by iron dependence and lipid peroxidation. Ferroptosis is involved in a range of pathological processes, such as cancer. Many studies have confirmed that ferroptosis plays an essential role in inhibiting cancer cell proliferation. In addition, a series of small-molecule compounds have been developed, including erastin, RSL3, and FIN56, which can be used as ferroptosis inducers. The combination of ferroptosis inducers with anticancer drugs can produce a significant synergistic effect in cancer treatment, and patients treated with these combinations exhibit a better prognosis than patients receiving traditional therapy. Therefore, a thorough understanding of the roles of ferroptosis in cancer is of great significance for the treatment of cancer. This review mainly elaborates the molecular biological characteristics and mechanism of ferroptosis, summarizes the function of ferroptosis in cancer development and treatment,illustrates the application of ferroptosis in patient's prognosis prediction and drug discovery, and discusses the prospects of targeting ferroptosis.

铁凋亡是一种非凋亡性的细胞死亡形式,其特点是铁依赖性和脂质过氧化。铁凋亡参与了癌症等一系列病理过程。许多研究证实,铁凋亡在抑制癌细胞增殖方面起着至关重要的作用。此外,还开发了一系列小分子化合物,包括麦拉宁(erastin)、RSL3 和 FIN56,它们可用作铁氧化诱导剂。铁突变诱导剂与抗癌药物联合使用可在癌症治疗中产生显著的协同效应,与接受传统疗法的患者相比,接受这些联合疗法的患者表现出更好的预后。因此,深入了解铁蛋白在癌症中的作用对癌症治疗具有重要意义。这篇综述主要阐述了铁凋亡的分子生物学特征和机制,总结了铁凋亡在癌症发展和治疗中的作用,说明了铁凋亡在患者预后预测和药物研发中的应用,并探讨了靶向铁凋亡的前景。
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引用次数: 0
Recent advances in living cell nucleic acid probes based on nanomaterials for early cancer diagnosis 基于纳米材料的活细胞核酸探针用于早期癌症诊断的最新进展
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100910
Xuyao Liu , Qi Shi , Peng Qi , Ziming Wang , Tongyue Zhang , Sijia Zhang , Jiayan Wu , Zhaopei Guo , Jie Chen , Qiang Zhang

The early diagnosis of cancer is vital for effective treatment and improved prognosis. Tumor biomarkers, which can be used for the early diagnosis, treatment, and prognostic evaluation of cancer, have emerged as a topic of intense research interest in recent years. Nucleic acid, as a type of tumor biomarker, contains vital genetic information, which is of great significance for the occurrence and development of cancer. Currently, living cell nucleic acid probes, which enable the in situ imaging and dynamic monitoring of nucleic acids, have become a rapidly developing field. This review focuses on living cell nucleic acid probes that can be used for the early diagnosis of tumors. We describe the fundamental design of the probe in terms of three units and focus on the roles of different nanomaterials in probe delivery.

癌症的早期诊断对于有效治疗和改善预后至关重要。肿瘤生物标志物可用于癌症的早期诊断、治疗和预后评估,是近年来备受关注的研究课题。核酸作为肿瘤生物标志物的一种,含有重要的遗传信息,对癌症的发生和发展具有重要意义。目前,可对核酸进行成像和动态监测的活细胞核酸探针已成为一个快速发展的领域。本综述重点介绍可用于肿瘤早期诊断的活细胞核酸探针。我们从三个单元描述了探针的基本设计,并重点介绍了不同纳米材料在探针传输中的作用。
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引用次数: 0
A biomimetic spore nanoplatform for boosting chemodynamic therapy and bacteria-mediated antitumor immunity for synergistic cancer treatment 一种生物仿生孢子纳米平台,可增强化学动力疗法和细菌介导的抗肿瘤免疫力,从而实现癌症的协同治疗
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100912
Cuixia Zheng , Lingling Sun , Hongjuan Zhao , Mengya Niu , Dandan Zhang , Xinxin Liu , Qingling Song , Weijie Zhong , Baojin Wang , Yun Zhang , Lei Wang

Bacterial-based antitumor immunity has become a promising strategy to activate the immune system for fighting cancer. However, the potential application of bacterial therapy is hindered by the presence of instability and susceptibility to infections within bacterial populations. Furthermore, monotherapy is ineffective in completely eliminating complex cancer with multiple contributing factors. In this study, based on our discovery that spore shell (SS) of Bacillus coagulans exhibits excellent tumor-targeting ability and adjuvant activity, we develop a biomimetic spore nanoplatform to boost bacteria-mediated antitumor therapy, chemodynamic therapy and antitumor immunity for synergistic cancer treatment. In detail, SS is separated from probiotic spores and then attached to the surface of liposome (Lipo) that was loaded with hemoglobin (Hb), glucose oxidase (GOx) and JQ1 to construct SS@Lipo/Hb/GOx/JQ1. In tumor tissue, highly toxic hydroxyl radicals (•OH) are generated via sequential catalytic reactions: GOx catalyzing glucose into H2O2 and Fe2+ in Hb decomposing H2O2 into •OH. The combination of •OH and SS adjuvant can improve tumor immunogenicity and activate immune system. Meanwhile, JQ1-mediated down-regulation of PD-L1 and Hb-induced hypoxia alleviation synergistically reshape immunosuppressive tumor microenvironment and potentiate immune response. In this manner, SS@Lipo/Hb/GOx/JQ1 significantly suppresses tumor growth and metastasis. To summarize, the nanoplatform represents an optimum strategy to potentiate bacteria-based cancer immunotherapy.

以细菌为基础的抗肿瘤免疫已成为激活免疫系统抗击癌症的一种前景广阔的策略。然而,细菌群的不稳定性和易感染性阻碍了细菌疗法的潜在应用。此外,单一疗法无法彻底消除具有多种诱因的复杂癌症。在本研究中,我们发现凝结芽孢杆菌的孢子壳(SS)具有出色的肿瘤靶向能力和辅助活性,基于这一发现,我们开发了一种仿生孢子纳米平台,以促进细菌介导的抗肿瘤治疗、化学动力治疗和抗肿瘤免疫,从而实现协同癌症治疗。具体来说,将 SS 从益生菌孢子中分离出来,然后附着在装有血红蛋白(Hb)、葡萄糖氧化酶(GOx)和 JQ1 的脂质体(Lipo)表面,构建 SS@Lipo/Hb/GOx/JQ1。在肿瘤组织中,剧毒的羟自由基(-OH)通过连续的催化反应生成:GOx 将葡萄糖催化成 H2O2,Hb 中的 Fe2+ 将 H2O2 分解成 -OH。-OH与SS佐剂结合可提高肿瘤免疫原性,激活免疫系统。同时,JQ1 介导的 PD-L1 下调与 Hb 诱导的缺氧缓解协同重塑免疫抑制性肿瘤微环境,增强免疫反应。因此,SS@Lipo/Hb/GOx/JQ1 能显著抑制肿瘤的生长和转移。总之,该纳米平台是增强基于细菌的癌症免疫疗法的最佳策略。
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引用次数: 0
Charge adaptive phytochemical-based nanoparticles for eradication of methicillin-resistant staphylococcus aureus biofilms 用于消除耐甲氧西林金黄色葡萄球菌生物膜的电荷自适应植物化学纳米颗粒
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100923
Xilong Cui , Fanhui Liu , Shuang Cai , Tingting Wang , Sidi Zheng , Xinshu Zou , Linlin Wang , Siqi He , Yanhua Li , Zhiyun Zhang

The intrinsic resistance of MRSA coupled with biofilm antibiotic tolerance challenges the antibiotic treatment of MRSA biofilm infections. Phytochemical-based nanoplatform is a promising emerging approach for treatment of biofilm infection. However, their therapeutic efficacy was restricted by the low drug loading capacity and lack of selectivity. Herein, we constructed a surface charge adaptive phytochemical-based nanoparticle with high isoliquiritigenin (ISL) loading content for effective treatment of MRSA biofilm. A dimeric ISL prodrug (ISL-G2) bearing a lipase responsive ester bond was synthesized, and then encapsulated into the amphiphilic quaternized oligochitosan. The obtained ISL-G2 loaded NPs possessed positively charged surface, which allowed cis-aconityl-d-tyrosine (CA-Tyr) binding via electrostatic interaction to obtain ISL-G2@TMDCOS-Tyr NPs. The NPs maintained their negatively charged surface, thus prolonging the blood circulation time. In response to low pH in the biofilms, the fast removal of CA-Tyr led to a shift in their surface charge from negative to positive, which enhanced the accumulation and penetration of NPs in the biofilms. Sequentially, the pH-triggered release of d-tyrosine dispersed the biofilm and lipase-triggered released of ISL effectively kill biofilm MRSA. An in vivo study was performed on a MRSA biofilm infected wound model. This phytochemical-based system led to ∼2 log CFU (>99 %) reduction of biofilm MRSA as compared to untreated wound (P < 0.001) with negligible biotoxicity in mice. This phytochemical dimer nanoplatform shows great potential for long-term treatment of resistant bacterial infections.

MRSA 的内在耐药性和生物膜对抗生素的耐受性给 MRSA 生物膜感染的抗生素治疗带来了挑战。基于植物化学物质的纳米平台是治疗生物膜感染的一种前景广阔的新兴方法。然而,由于药物负载能力低且缺乏选择性,其疗效受到限制。在此,我们构建了一种表面电荷自适应的植物化学纳米粒子,该粒子具有较高的isisiquiritigenin(ISL)载药量,可有效治疗MRSA生物膜。该研究合成了一种带有脂肪酶响应酯键的二聚 ISL 原药(ISL-G2),然后将其包封在两亲性季铵化低聚壳聚糖中。获得的 ISL-G2 负载 NPs 表面带正电荷,可通过静电作用与顺式-乌头基-d-酪氨酸(CA-Tyr)结合,从而获得 ISL-G2@TMDCOS-Tyr NPs。这些 NPs 保持了带负电荷的表面,从而延长了血液循环时间。由于生物膜中的 pH 值较低,CA-Tyr 的快速脱落导致其表面电荷由负变正,从而增强了 NPs 在生物膜中的积累和渗透。随后,pH 触发释放的 d- 酪氨酸分散了生物膜,而脂肪酶触发释放的 ISL 则有效地杀死了生物膜上的 MRSA。在 MRSA 生物膜感染伤口模型上进行了体内研究。与未经处理的伤口相比,这种基于植物化学物质的系统可使生物膜 MRSA 减少 2 log CFU(99 %)(P <0.001),对小鼠的生物毒性可忽略不计。这种植物化学二聚体纳米平台显示出长期治疗耐药细菌感染的巨大潜力。
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引用次数: 0
Autophagy and mitophagy as potential therapeutic targets in diabetic heart condition: Harnessing the power of nanotheranostics 自噬和丝裂噬是糖尿病心脏疾病的潜在治疗靶点:利用纳米otheranostics的力量
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100927
Sagnik Nag , Oishi Mitra , Bhanu Maturi , Simran Preet Kaur , Ankita Saini , Muskan Nama , Soumik Roy , Souvik Samanta , Leena Chacko , Rohan Dutta , Suresh Babu Sayana , Vetriselvan Subramaniyan , Jasvinder Singh Bhatti , Ramesh Kandimalla

Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition (DHC), which encompasses a complex range of cardiovascular issues linked to diabetes and associated cardiomyopathies. Despite significant progress in reducing mortality rates from cardiovascular diseases (CVDs), heart failure remains a major cause of increased morbidity among diabetic patients. These cellular processes are essential for maintaining cellular balance and removing damaged or dysfunctional components, and their involvement in the development of diabetic heart disease makes them attractive targets for diagnosis and treatment. While a variety of conventional diagnostic and therapeutic strategies are available, DHC continues to present a significant challenge. Point-of-care diagnostics, supported by nanobiosensing techniques, offer a promising alternative for these complex scenarios. Although conventional medications have been widely used in DHC patients, they raise several concerns regarding various physiological aspects. Modern medicine places great emphasis on the application of nanotechnology to target autophagy and mitophagy in DHC, offering a promising approach to deliver drugs beyond the limitations of traditional therapies. This article aims to explore the potential connections between autophagy, mitophagy and DHC, while also discussing the promise of nanotechnology-based theranostic interventions that specifically target these molecular pathways.

自噬和噬丝分裂是了解糖尿病性心脏病(DHC)病理过程中尚未解决的难题,DHC 包括一系列与糖尿病和相关心肌病有关的复杂心血管问题。尽管在降低心血管疾病(CVDs)死亡率方面取得了重大进展,但心力衰竭仍然是糖尿病患者发病率增加的主要原因。这些细胞过程对于维持细胞平衡和清除受损或功能失调的成分至关重要,它们参与了糖尿病性心脏病的发病过程,因此成为极具吸引力的诊断和治疗目标。虽然已有多种常规诊断和治疗策略,但糖尿病性心脏病仍是一项重大挑战。在纳米生物传感技术的支持下,护理点诊断为这些复杂的情况提供了一种很有前景的替代方法。虽然传统药物已广泛应用于 DHC 患者,但它们在生理方面也引起了一些问题。现代医学非常重视纳米技术在 DHC 中针对自噬和有丝分裂的应用,这为超越传统疗法的局限性提供了一种前景广阔的给药方法。本文旨在探讨自噬、有丝分裂和 DHC 之间的潜在联系,同时还讨论了专门针对这些分子途径的基于纳米技术的治疗干预的前景。
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引用次数: 0
Immunotherapeutic hydrogel for co-delivery of STAT3 siRNA liposomes and lidocaine hydrochloride for postoperative comprehensive management of NSCLC in a single application 用于联合递送 STAT3 siRNA 脂质体和盐酸利多卡因的免疫治疗水凝胶,可一次性用于 NSCLC 术后综合治疗
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100925
Xianglei Fu , Yanbin Shi , Zili Gu , Hengchang Zang , Lian Li , Qingjie Wang , Yongjun Wang , Xiaogang Zhao , Hang Wu , Shengnan Qiu , Yankun Zhang , Jiamin Zhou , Xiangqin Chen , Hua Shen , Guimei Lin

Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.

尽管非小细胞肺癌(NSCLC)的标准治疗方法是手术切除,但癌症复发和并发症(如诱发恶性胸腔积液和明显的术后疼痛)通常会导致治疗失败。本研究开发了一种基于藻酸盐的混合水凝胶(SOG),可在手术中注入肺部切除面。简而言之,内质网修饰的脂质体(MSL)预载了信号转导子和转录激活子 3(STAT3)小干扰 RNA 和盐酸利多卡因,被包裹在 SOG 中。应用 MSLs 后,STAT3 在肿瘤微环境中的表达被强烈下调,导致肺癌细胞凋亡和肿瘤相关巨噬细胞向 M1 样表型极化。同时,盐酸利多卡因的释放有利于缓解疼痛和激活自然杀伤细胞。我们的数据表明,MSL@LID@SOG 不仅能有效抑制肿瘤生长,还能有效改善生活质量,包括减少 MPE 体积和缓解正位 NSCLC 小鼠模型的疼痛,即使单次给药也是如此。MSL@LID@SOG显示了在NSCLC肿瘤切除后进行综合临床治疗的潜力,并可能改变其他癌症的治疗模式。
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引用次数: 0
A PET probe targeting polyamine transport system for precise tumor diagnosis and therapy 用于肿瘤精确诊断和治疗的多胺转运系统正电子发射计算机断层显像探针
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100924
Ming Zhou , Xiaoqin Yin , Bei Chen , Shuo Hu , Wenhu Zhou

Polyamine metabolism dysregulation is a hallmark of many cancers, offering a promising avenue for early tumor theranostics. This study presents the development of a nuclear probe derived from spermidine (SPM) for dual-purpose tumor PET imaging and internal radiation therapy. The probe, radiolabeled with either [68Ga]Ga for diagnostic applications or [177Lu]Lu for therapeutic use, was synthesized with exceptional purity, stability, and specific activity. Extensive testing involving 12 different tumor cell lines revealed remarkable specificity towards B16 melanoma cells, showcasing outstanding tumor localization and target-to-non-target ratio. Mechanistic investigations employing polyamines, non-labeled precursor, and polyamine transport system (PTS) inhibitor, consistently affirmed the probeʼs targetability through recognition of the PTS. Notably, while previous reports indicated PTS upregulation in various tumor types for targeted therapy, this study observed no positive signals, highlighting a concentration-dependent discrepancy between targeting for therapy and diagnosis. Furthermore, when labeled with [177Lu], the probe demonstrated its therapeutic potential by effectively controlling tumor growth and extending mouse survival. Investigations into biodistribution, excretion, and biosafety in healthy humans laid a robust foundation for clinical translation. This study introduces a versatile SPM-based nuclear probe with applications in precise tumor theranostics, offering promising prospects for clinical implementation.

多胺代谢失调是许多癌症的特征之一,为早期肿瘤治疗提供了一个前景广阔的途径。本研究介绍了一种提取自精胺(SPM)的核探针的开发情况,该探针具有肿瘤 PET 成像和内放射治疗双重用途。该探针用[68Ga]Ga放射性标记,用于诊断;或用[177Lu]Lu放射性标记,用于治疗。对 12 种不同的肿瘤细胞系进行的广泛测试表明,它对 B16 黑色素瘤细胞具有显著的特异性,显示了出色的肿瘤定位能力和靶向-非靶向比率。利用多胺、非标记前体和多胺转运系统(PTS)抑制剂进行的机理研究证实,该探针通过识别 PTS 具有靶向性。值得注意的是,以前的报告显示,在各种肿瘤类型中,PTS 上调可用于靶向治疗,而本研究却没有观察到阳性信号,这凸显了靶向治疗和诊断之间存在浓度依赖性差异。此外,用[177Lu]标记后,该探针有效地控制了肿瘤的生长,延长了小鼠的存活时间,证明了其治疗潜力。对健康人体生物分布、排泄和生物安全性的研究为临床转化奠定了坚实的基础。本研究介绍了一种基于 SPM 的多功能核探针,它可应用于精确的肿瘤治疗,为临床应用提供了广阔的前景。
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引用次数: 0
Advancing ophthalmic delivery of flurbiprofen via synergistic chiral resolution and ion-pairing strategies 通过手性解析和离子配对协同策略推进氟比洛芬的眼科给药
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100928
Zhining Ma , Yuequan Wang , Huiyang He , Tong Liu , Qikun Jiang , Xiaohong Hou

Flurbiprofen (FB), a nonsteroidal anti-inflammatory drug, is widely employed in treating ocular inflammation owing to its remarkable anti-inflammatory effects. However, the racemic nature of its commercially available formulation (Ocufen®) limits the full potential of its therapeutic activity, as the (S)-enantiomer is responsible for the desired anti-inflammatory effects. Additionally, the limited corneal permeability of FB significantly restricts its bioavailability. In this study, we successfully separated the chiral isomers of FB to obtain the highly active (S)-FB. Subsequently, utilizing ion-pairing technology, we coupled (S)-FB with various counter-ions, such as sodium, diethylamine, trimethamine (TMA), and l-arginine, to enhance its ocular bioavailability. A comprehensive evaluation encompassed balanced solubility, octanol-water partition coefficient, corneal permeability, ocular pharmacokinetics, tissue distribution, and in vivo ocular anti-inflammatory activity of each chiral isomer salt. Among the various formulations, S-FBTMA exhibited superior water solubility (about 1–12 mg/ml), lipid solubility (1< lg Pow < 3) and corneal permeability. In comparison to Ocufen®, S-FBTMA demonstrated significantly higher in vivo anti-inflammatory activity and lower ocular irritability (such as conjunctival congestion and tingling). The findings from this research highlight the potential of chiral separation and ion-pair enhanced permeation techniques in providing pharmaceutical enterprises focused on drug development with a valuable avenue for improving therapeutic outcomes.

氟比洛芬(FB)是一种非甾体抗炎药,因其显著的抗炎效果而被广泛用于治疗眼部炎症。然而,其商业制剂(Ocufen®)的外消旋性质限制了其治疗活性的全部潜力,因为(S)-对映体负责产生所需的抗炎效果。此外,FB 的角膜渗透性有限,这也大大限制了其生物利用度。在这项研究中,我们成功分离了 FB 的手性异构体,得到了高活性的 (S)-FB。随后,我们利用离子配对技术,将(S)-FB 与各种反离子(如钠、二乙胺、三甲胺 (TMA) 和精氨酸)偶联,以提高其眼部生物利用度。对每种手性异构盐的平衡溶解度、辛醇-水分配系数、角膜渗透性、眼部药代动力学、组织分布和体内眼部抗炎活性进行了全面评估。在各种制剂中,S-FBTMA 的水溶性(约 1-12 mg/ml)、脂溶性(1< lg Pow <3)和角膜渗透性均优于 Ocufen®。与 Ocufen® 相比,S-FBTMA 的体内抗炎活性更高,眼部刺激性(如结膜充血和刺痛)更低。这项研究结果凸显了手性分离和离子对增强渗透技术的潜力,为专注于药物开发的制药企业提供了改善治疗效果的宝贵途径。
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引用次数: 0
Biomimetic Integrated Nanozyme for Flare and Recurrence of Gouty Arthritis 治疗痛风性关节炎发作和复发的生物仿生集成纳米酶
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100913
Rui Wang , Tongyao Liu , Xinhong Li , Enhao Lu , Yiting Chen , Kuankuan Luo , Tao Wang , Xueli Huang , Zhiwen Zhang , Shilin Du , Xianyi Sha

Flare and multiple recurrences pose significant challenges in gouty arthritis. Traditional treatments provide temporary relief from inflammation but fail to promptly alleviate patient pain or effectively prevent subsequent recurrences. It should also be noted that both anti-inflammation and metabolism of uric acid are necessary for gouty arthritis, calling for therapeutic systems to achieve these two goals simultaneously. In this study, we propose a biomimetic integrated nanozyme, HMPB-Pt@MM, comprising platinum nanozyme and hollow Prussian blue. It demonstrates anti-inflammatory properties by eliminating reactive oxygen species and reducing infiltration of inflammatory macrophages. Additionally, it rapidly targets inflamed ankles through the camouflage of macrophage membranes. Furthermore, HMPB-Pt@MM exhibits urate oxidase-like capabilities, continuously metabolizing locally elevated uric acid concentrations, ultimately inhibiting multiple recurrences of gouty arthritis. In summary, HMPB-Pt@MM integrates ROS clearance with uric acid metabolism, offering a promising platform for the treatment of gouty arthritis.

痛风性关节炎的发作和多次复发给患者带来了巨大的挑战。传统治疗方法能暂时缓解炎症,但无法及时减轻患者的痛苦,也无法有效预防后续复发。还需要注意的是,痛风性关节炎需要抗炎和尿酸代谢,这就要求治疗系统同时实现这两个目标。在这项研究中,我们提出了一种生物仿生集成纳米酶 HMPB-Pt@MM,由铂纳米酶和中空普鲁士蓝组成。它具有抗炎特性,能消除活性氧,减少炎性巨噬细胞的浸润。此外,它还能通过伪装巨噬细胞膜,迅速锁定发炎的脚踝。此外,HMPB-Pt@MM 还具有类似尿酸氧化酶的能力,可持续代谢局部升高的尿酸浓度,最终抑制痛风性关节炎的多次复发。总之,HMPB-Pt@MM 将清除 ROS 与尿酸代谢结合在一起,为痛风性关节炎的治疗提供了一个前景广阔的平台。
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引用次数: 0
Glucocorticoids-based prodrug design: Current strategies and research progress 基于糖皮质激素的原药设计:当前策略与研究进展
IF 10.2 1区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-06-01 DOI: 10.1016/j.ajps.2024.100922
Hongbing Liu , Muse Ji , Peifu Xiao , Jingxin Gou , Tian Yin , Haibing He , Xing Tang , Yu Zhang

Attributing to their broad pharmacological effects encompassing anti-inflammation, antitoxin, and immunosuppression, glucocorticoids (GCs) are extensively utilized in the clinic for the treatment of diverse diseases such as lupus erythematosus, nephritis, arthritis, ulcerative colitis, asthma, keratitis, macular edema, and leukemia. However, long-term use often causes undesirable side effects, including metabolic disorders-induced Cushing's syndrome (buffalo back, full moon face, hyperglycemia, etc.), osteoporosis, aggravated infection, psychosis, glaucoma, and cataract. These notorious side effects seriously compromise patients' quality of life, especially in patients with chronic diseases. Therefore, glucocorticoid-based advanced drug delivery systems for reducing adverse effects have received extensive attention. Among them, prodrugs have the advantages of low investment, low risk, and high success rate, making them a promising strategy. In this review, we propose the strategies for the design and summarize current research progress of glucocorticoid-based prodrugs in recent decades, including polymer-based prodrugs, dendrimer-based prodrugs, antibody-drug conjugates, peptide-drug conjugates, carbohydrate-based prodrugs, aliphatic acid-based prodrugs and so on. Besides, we also raise issues that need to be focused on during the development of glucocorticoid-based prodrugs. This review is expected to be helpful for the research and development of novel GCs and prodrugs.

糖皮质激素(GCs)具有抗炎、抗毒素和免疫抑制等广泛的药理作用,因此在临床上被广泛用于治疗红斑狼疮、肾炎、关节炎、溃疡性结肠炎、哮喘、角膜炎、黄斑水肿和白血病等多种疾病。然而,长期服用往往会引起不良副作用,包括代谢紊乱--诱发库欣综合征(水牛背、满月脸、高血糖等)、骨质疏松症、感染加重、精神病、青光眼和白内障。这些臭名昭著的副作用严重影响了患者的生活质量,尤其是慢性病患者。因此,以糖皮质激素为基础的减少不良反应的先进给药系统受到广泛关注。其中,原研药具有投资少、风险低、成功率高等优点,是一种前景广阔的策略。在这篇综述中,我们提出了基于糖皮质激素的原研药的设计策略,并总结了近几十年来糖皮质激素原研药的研究进展,包括聚合物基原研药、树枝状聚合物基原研药、抗体-药物共轭物、多肽-药物共轭物、碳水化合物基原研药、脂肪族酸基原研药等。此外,我们还提出了糖皮质激素类原药研发过程中需要关注的问题。希望这篇综述能对新型 GCs 和原药的研究与开发有所帮助。
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Asian Journal of Pharmaceutical Sciences
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