Acta Pharmaceutica Sinica. B最新文献_第2页

Cyclometalated iridium(III) complex based on isoquinoline alkaloid synergistically elicits the ICD response and IDO inhibition via autophagy-dependent ferroptosis 基于异喹啉生物碱的环甲基化铱（III）复合物通过自噬依赖性铁变态反应协同激发 ICD 反应和 IDO 抑制作用

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.06.017

Yuan Lu , Shan-Shan Wang , Meng-Ya Li , Rong Liu , Meng-Fan Zhu , Liang-Mei Yang , Feng-Yang Wang , Ke-Bin Huang , Hong Liang

The development of anticancer drugs to treat triple-negative breast cancer (TNBC) is an ongoing challenge. Immunogenic cell death (ICD) has garnered considerable interest worldwide as a promising synergistic modality for cancer chemoimmunotherapy. However, only few drugs or treatment modalities can trigger an ICD response and none of them exert a considerable clinical effect against TNBC. Therefore, new agents with potentially effective chemoimmunotherapeutic response are required. In this study, five new cyclometalated Ir(III) complexes containing isoquinoline alkaloid CˆN ligands were designed and synthesized. Among them, Ir-1 exhibited the highest in vitro cytotoxicity. Mechanistically, Ir-1 could trigger autophagy-dependent ferroptosis and a subsequent ferroptosis-dependent ICD response as well as indoleamine 2,3-dioxygenase (IDO) inhibition via reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress in MDA-MB-231 cells. When immunocompetent BALB/c mice were vaccinated with Ir-1-treated dying TNBC cells, antitumor CD8⁺ T-cell response and Foxp3⁺ T-cell depletion were induced, resulting in long-lasting antitumor immunity in TNBC cells. Moreover, combination therapy with Ir-1 and anti-PD1 could substantially augment in vivo therapeutic effects. Based on these results, Ir-1 is a promising candidate for chemoimmunotherapy against TNBC and its effects are mediated synergistically via ICD induction and IDO blockage.

开发治疗三阴性乳腺癌（TNBC）的抗癌药物是一项持续的挑战。免疫性细胞死亡（ICD）作为一种很有前景的癌症化学免疫治疗协同模式，在全球范围内引起了广泛关注。然而，只有少数药物或治疗方式能引发 ICD 反应，而且没有一种能对 TNBC 产生显著的临床效果。因此，需要具有潜在有效化学免疫治疗反应的新药物。本研究设计并合成了五种含有异喹啉生物碱 CˆN 配体的新型环金属化 Ir(III) 复合物。其中，Ir(III)复合物的细胞毒性最高。从机理上讲，它能引发 MDA-MB-231 细胞的自噬依赖性铁变态反应和随后的铁变态依赖性 ICD 反应，以及吲哚胺 2,3- 二氧化酶（IDO）抑制活性氧（ROS）介导的内质网（ER）应激。当免疫功能正常的 BALB/c 小鼠接种经-处理的濒死 TNBC 细胞时，可诱导 CD8 T 细胞抗肿瘤反应和 Foxp3 T 细胞耗竭，从而对 TNBC 细胞产生持久的抗肿瘤免疫力。此外，与抗-PD1联合治疗可大大增强疗效。基于这些结果，ICD诱导和IDO阻断有望成为TNBC化学免疫疗法的候选药物。

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引用次数: 0

Caffeic acid-vanadium nanozymes treat skin flap ischemia-reperfusion injury through macrophage reprogramming and the upregulation of X-linked inhibitors of apoptotic proteins 咖啡酸钒纳米酶通过巨噬细胞重编程和上调X连锁凋亡蛋白抑制因子治疗皮瓣缺血再灌注损伤

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.08.022

Xinyu Zhao , Jie Shan , Hanying Qian , Xu Jin , Yiwei Sun , Jianghao Xing , Qingrong Li , Xu-Lin Chen , Xianwen Wang

Ischemia-reperfusion (I/R) injury following skin flap transplantation is a critical factor leading to flap necrosis and transplant failure. Antagonizing inflammatory responses and oxidative stress are regarded as crucial targets for mitigating reperfusion injury and enhancing flap survival. In this study, caffeic acid-vanadium metal polyphenol nanoparticles (CA-V NPs) were prepared for the treatment of skin flap ischemia and reperfusion. This study was conducted using a one-step method to prepare new types of CA-V NPs with uniform sizes and stable structures. In vitro, the CA-V NPs exhibited CAT-like and SOD-like activities and could effectively scavenge ROS, generate oxygen, and alleviate oxidative stress. In the H₂O₂-induced cellular oxidative stress model, CA-V NPs effectively reduced ROS levels and inhibited apoptosis through the XIAP/Caspase-3 pathway. In the cellular inflammation model induced by LPS combined with IFN-γ, CA-V NPs reprogrammed macrophage polarization toward the M2 phenotype and reduced inflammatory responses by reducing the expression of the chemokines CCL4 and CXCL2. In addition, animal experiments have shown that CA-V NPs can alleviate oxidative stress in skin flap tissues, inhibit apoptosis, promote angiogenesis, and ultimately improve the survival rate of skin flaps. CA-V NPs provide a new target and strategy for the treatment of flap I/R injury.

皮瓣移植后的缺血再灌注（I/R）损伤是导致皮瓣坏死和移植失败的关键因素。拮抗炎症反应和氧化应激被认为是减轻再灌注损伤和提高皮瓣存活率的关键目标。本研究制备了咖啡酸-钒金属多酚纳米颗粒（CA-V NPs），用于治疗皮瓣缺血和再灌注。该研究采用一步法制备了大小均匀、结构稳定的新型CA-V NPs。结果表明，CA-V NPs具有类似CAT和SOD的活性，能有效清除ROS、产生氧气并缓解氧化应激。在 HO 诱导的细胞氧化应激模型中，CA-V NPs 能有效降低 ROS 水平，并通过 XIAP/Caspase-3 途径抑制细胞凋亡。在 LPS 与 IFN- 共同诱导的细胞炎症模型中，CA-V NPs 可使巨噬细胞向 M2 表型极化重编程，并通过减少趋化因子 CCL4 和 CXCL2 的表达来减轻炎症反应。此外，动物实验表明，CA-V NPs 能减轻皮瓣组织的氧化应激，抑制细胞凋亡，促进血管生成，最终提高皮瓣的存活率。CA-V NPs为治疗皮瓣I/R损伤提供了新的靶点和策略。

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引用次数: 0

Unlocking the role of wound microbiome in diabetic, burn, and germ-free wound repair treated by natural and synthetic scaffolds 揭示伤口微生物群在天然和合成支架处理的糖尿病、烧伤和无菌伤口修复中的作用

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.08.024

Zeyu Xu , Lixiang Zhang , Qinghan Tang , Chenxi Yang , Xiaotong Ding , Ziyu Wang , Rizhong Huang , Ruihan Jiang , Joannake Maitz , Huaikai Shi , Xin Yan , Mei Dong , Jun Chen , Yiwei Wang

In current clinical practice, various dermal templates and skin substitutes are used to enhance wound healing. However, the role of wound commensal microbiome in regulating scaffold performance and the healing process remains unclear. In this study, we investigated the influence of both natural and synthetic scaffolds on the wound commensal microbiome and wound repair in three distinct models including diabetic wounds, burn injuries, and germ-free (GF) wounds. Remarkably, synthetic electrospun polycaprolactone (PCL) scaffolds were observed to positively promote microbiome diversity, leading to enhanced diabetic wound healing compared to the natural scaffolds Integra® (INT) and MatriDerm® (MAD). In contrast, both natural and synthetic scaffolds exhibited comparable effects on the diversity of the microbiome and the healing of burn injuries. In GF wounds with no detectable microorganisms, a reversed healing rate was noted showing natural scaffold (MAD) accelerated wound repair compared to the open or the synthetic scaffold (PCL) treatment. Furthermore, the response of the wound commensal microbiome to PCL scaffolds appears pivotal in promoting anti-inflammatory factors during diabetic wound healing. Our results emphasize that the wound commensal microbiome, mediated by different scaffolds plays an important role in the wound healing process.

在目前的临床实践中，各种真皮模板和皮肤替代品被用于促进伤口愈合。然而，伤口共生微生物群在调节支架性能和愈合过程中的作用仍不清楚。在这项研究中，我们在糖尿病伤口、烧伤和无菌（GF）伤口等三种不同的模型中研究了天然和合成支架对伤口共生微生物群和伤口修复的影响。值得注意的是，与天然支架 Integra® (INT) 和 MatriDerm® (MAD) 相比，合成电纺聚己内酯（PCL）支架能积极促进微生物群的多样性，从而增强糖尿病伤口的愈合。相比之下，天然支架和合成支架对微生物群多样性和烧伤愈合的影响相当。在未检测到微生物的 GF 伤口中，愈合率出现了逆转，显示天然支架（MAD）与开放式或合成支架（PCL）相比加速了伤口修复。此外，伤口共生微生物群对 PCL 支架的反应似乎对促进糖尿病伤口愈合过程中的抗炎因子至关重要。我们的研究结果表明，不同支架介导的伤口共生微生物群在伤口愈合过程中发挥着重要作用。

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引用次数: 0

Cerebral endothelial 3-mercaptopyruvate sulfurtransferase improves ischemia-induced cognitive impairment via interacting with protein phosphatase 2A

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.015

Li Zhu , Yi Huang , Jing Jin , Rongjun Zou , Rui Zuo , Yong Luo , Ziqing Song , Linfeng Dai , Minyi Zhang , Qiuhe Chen , Yunting Wang , Wei Wang , Rongrong He , Yang Chen

The catalytic activity of 3-mercaptopyruvate (3MP) sulfurtransferase (MPST) converts 3MP to hydrogen sulfide (H₂S). However, the regulatory mechanisms governing MPST and its impact on the brain remain largely unexplored. Our study reveals the neuroprotective role of endothelial MPST-generated H₂S, regulated by protein phosphatase 2A (PP2A). Bioinformatics analysis and RNA sequencing demonstrated that endothelial PP2A is associated with neurodegenerative disease pathways. Cerebral ischemic mice exhibited significant inactivation of endothelial PP2A, evidenced by the reduction of PP2Acα in the brain endothelium. Mice with endothelium-specific null PP2A (PP2A^EC-cKO) exhibited neuronal loss, cognitive dysfunction, and long-term potentiation deficits. Postnatal inactivation of endothelial PP2A also contributes to cognitive dysfunction and neuronal loss. However, regaining endothelial PP2A activity by overexpressing Ppp2ca rescued neuronal dysfunction. Mechanistically, PP2A deficiency is intricately linked to the MPST–H₂S signaling pathway. A robust reduction in endothelial MPST-dependent H₂S production followed PP2A deficiency. Exogenous H₂S treatment and AAV-mediated overexpression of MPST in brain endothelial cells significantly mitigated neuronal dysfunction in PP2A^EC-cKO mice. Furthermore, PP2A deficiency promotes an increase in calcium influx and calpain2 phosphorylation, subsequently leading to MPST degradation. The PP2A activator (FTY720) and MPST activator (3MP sodium) both remarkably restored endothelial MPST-dependent H₂S production, subsequently rescuing ischemia-induced neurological deficits. In conclusion, our study demonstrates that endothelial PP2A deficiency leads to MPST degradation by activating calpain2, thus damaging neuronal function.

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引用次数: 0

Real-time platelet P2Y12 receptor occupancy as a promising pharmacodynamics biomarker for bridging the gap between PK/PD of clopidogrel therapy 实时血小板 P2Y12 受体占据率是一种很有前景的药效学生物标记物，可弥合氯吡格雷治疗的 PK/PD 差距

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.08.008

Haipeng Li , Yueming Gu , Yumeng Zhao , Aiyun Xu , Dong Sun , Jingkai Gu

Clopidogrel effectively inhibits platelet aggregation in response to ADP by irreversibly binding to the platelet P2Y₁₂ receptor through its active metabolite. However, the observed discrepancies between the pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel present substantial challenges in individualizing of antiplatelet therapy. To address these challenges, a robust liquid chromatography–tandem mass spectrometry method has been developed to facilitate the real-time assessment of platelet P2Y₁₂ receptor occupancy. This method has been validated in animal models, providing a reliable link between individual PK profiles and PD effects. Target receptor occupancy offers a comprehensive overview of interindividual variations in clopidogrel metabolism, regulation of P2Y₁₂ receptor expression, and platelet turnover. Moreover, it directly correlates with the inhibitory effect on platelet aggregation. The levels of platelet P2Y₁₂ occupancy accurately reflect the extent of clinical factors influencing the PD of clopidogrel, including dosage, drug–drug interactions (DDI), and type 2 diabetes mellitus (T2DM). As a normalized metric, platelet P2Y₁₂ occupancy not only serves potential as a diagnostic tool for personalized clopidogrel therapy but also aids in elucidating the role of the P2Y₁₂ signaling pathway in cases of abnormal on-treatment platelet reactivity.

氯吡格雷通过其活性代谢物与血小板 P2Y 受体不可逆地结合，从而有效抑制血小板对 ADP 的聚集反应。然而，观察到的氯吡格雷药代动力学（PK）和药效学（PD）之间的差异给抗血小板治疗的个体化带来了巨大挑战。为了应对这些挑战，我们开发了一种可靠的液相色谱-串联质谱方法，以方便实时评估血小板 P2Y 受体的占有率。该方法已在动物模型中得到验证，为个体 PK 特征和 PD 效果之间提供了可靠的联系。目标受体占据率能全面反映氯吡格雷代谢、P2Y 受体表达调控和血小板周转的个体差异。此外，它还与对血小板聚集的抑制作用直接相关。血小板 P2Y 占位水平能准确反映影响氯吡格雷 PD 的临床因素的程度，包括剂量、药物相互作用（DDI）和 2 型糖尿病（T2DM）。作为一种规范化指标，血小板 P2Y 占位率不仅可作为个性化氯吡格雷治疗的诊断工具，还有助于阐明 P2Y 信号通路在治疗中血小板反应性异常病例中的作用。

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引用次数: 0

Nanoengineered cargo with targeted in vivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.12.008

Manyu Chen , Yuan Liu , Quanying Liu , Siyan Deng , Yuhan Liu , Jiehao Chen , Yaojia Zhou , Xiaolin Cui , Jie Liang , Xingdong Zhang , Yujiang Fan , Qiguang Wang , Bin Shen

Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis (OA), but directly modulating mitochondria in vivo remains a significant challenge. This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the FOXO3 gene in the cartilage of OA patients, highlighting the potential for regulating mitophagy via FOXO3 gene modulation to alleviate OA. Consequently, we developed a chondrocyte-targeting CRISPR/Cas9-based FOXO3 gene-editing tool (FoxO3) and integrated it within a nanoengineered ‘truck’ (NETT, FoxO3-NETT). This was further encapsulated in injectable hydrogel microspheres (FoxO3-NETT@SMs) to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes. Collectively, these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the Foxo3 gene-modulated PINK1/Parkin pathway. As a result, FoxO3-NETT@SMs stimulate chondrocytes proliferation, migration, and ECM production in vitro, and effectively alleviate OA progression in vivo, demonstrating significant potential for clinical applications.

{"title":"Nanoengineered cargo with targeted in vivo Foxo3 gene editing modulated mitophagy of chondrocytes to alleviate osteoarthritis","authors":"Manyu Chen , Yuan Liu , Quanying Liu , Siyan Deng , Yuhan Liu , Jiehao Chen , Yaojia Zhou , Xiaolin Cui , Jie Liang , Xingdong Zhang , Yujiang Fan , Qiguang Wang , Bin Shen","doi":"10.1016/j.apsb.2024.12.008","DOIUrl":"10.1016/j.apsb.2024.12.008","url":null,"abstract":"<div><div>Mitochondrial dysfunction in chondrocytes is a key pathogenic factor in osteoarthritis (OA), but directly modulating mitochondria <em>in vivo</em> remains a significant challenge. This study is the first to verify a correlation between mitochondrial dysfunction and the downregulation of the <em>FOXO3</em> gene in the cartilage of OA patients, highlighting the potential for regulating mitophagy <em>via FOXO3</em> gene modulation to alleviate OA. Consequently, we developed a chondrocyte-targeting CRISPR/Cas9-based <em>FOXO3</em> gene-editing tool (FoxO3) and integrated it within a nanoengineered ‘truck’ (NETT, FoxO3-NETT). This was further encapsulated in injectable hydrogel microspheres (FoxO3-NETT@SMs) to harness the antioxidant properties of sodium alginate and the enhanced lubrication of hybrid exosomes. Collectively, these FoxO3-NETT@SMs successfully activate mitophagy and rebalance mitochondrial function in OA chondrocytes through the <em>Foxo3</em> gene-modulated PINK1/Parkin pathway. As a result, FoxO3-NETT@SMs stimulate chondrocytes proliferation, migration, and ECM production <em>in vitro</em>, and effectively alleviate OA progression <em>in vivo</em>, demonstrating significant potential for clinical applications.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 571-591"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

“Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.023

Jiayu Lu , Zhaomin Xia , Yongjing Zhang , He Wang , Wen Yang , Siqi Wang , Nan Wang , Yun Liu , Huaizhen He , Cheng Wang , Langchong He

MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis, atopic dermatitis, and chronic urticaria. Previously, we identified a class of diaryl urea (DPU) MRGPRX2 antagonists with sub-micromolar IC₅₀ values in vitro. However, the structure–activity relationship remains unclear. Herein, we adopted a “relative symmetry with electronegativity of different key-groups” strategy for further modification of DPUs to achieve a promising MRGPRX2 antagonist with higher activity and safety. Electrostatic potential energy analysis and biological evaluation revealed that B-1023 and B-5023, that possess relatively symmetric electron-withdrawing substituents, remarkable inhibited mast cell degranulation at a sub-micromolar IC₅₀ in vitro and alleviated anaphylactic symptoms. Furthermore, B-1023, mitigated antigen-induced pulmonary inflammation (AIPI) in mice and competitively bonded to MRGPRX2. In summary, the “relative symmetry with electronegativity of different key-groups” strategy provided a drug design pattern for MRGPRX2 antagonists and identified promising antiallergic precursors for AIPI treatment.

{"title":"“Relative symmetry with electronegativity of different key-groups” strategy for MRGPRX2 antagonist design and its effect on antigen-induced pulmonary inflammation","authors":"Jiayu Lu , Zhaomin Xia , Yongjing Zhang , He Wang , Wen Yang , Siqi Wang , Nan Wang , Yun Liu , Huaizhen He , Cheng Wang , Langchong He","doi":"10.1016/j.apsb.2024.11.023","DOIUrl":"10.1016/j.apsb.2024.11.023","url":null,"abstract":"<div><div>MRGPRX2 antagonists possess the potential for the treatment of allergic rhinitis, atopic dermatitis, and chronic urticaria. Previously, we identified a class of diaryl urea (DPU) MRGPRX2 antagonists with sub-micromolar IC<sub>50</sub> values <em>in vitro</em>. However, the structure–activity relationship remains unclear. Herein, we adopted a “relative symmetry with electronegativity of different key-groups” strategy for further modification of DPUs to achieve a promising MRGPRX2 antagonist with higher activity and safety. Electrostatic potential energy analysis and biological evaluation revealed that B-1023 and B-5023, that possess relatively symmetric electron-withdrawing substituents, remarkable inhibited mast cell degranulation at a sub-micromolar IC<sub>50</sub> <em>in vitro</em> and alleviated anaphylactic symptoms. Furthermore, B-1023, mitigated antigen-induced pulmonary inflammation (AIPI) in mice and competitively bonded to MRGPRX2. In summary, the “relative symmetry with electronegativity of different key-groups” strategy provided a drug design pattern for MRGPRX2 antagonists and identified promising antiallergic precursors for AIPI treatment.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 494-507"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

DiPTAC: A degradation platform via directly targeting proteasome DiPTAC：直接靶向蛋白酶体的降解平台

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.09.003

Yutong Tu , Qian Yu , Mengna Li , Lixin Gao , Jialuo Mao , Jingkun Ma , Xiaowu Dong , Jinxin Che , Chong Zhang , Linghui Zeng , Huajian Zhu , Jiaan Shao , Jingli Hou , Liming Hu , Bingbing Wan , Jia Li , Yubo Zhou , Jiankang Zhang

引用次数: 0

In situ tumor cell engineering reverses immune escape to enhance immunotherapy effect 原位肿瘤细胞工程逆转免疫逃逸，增强免疫疗法效果

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.08.028

Shujun Liu , Shijun Yuan , Meichen Liu , Jinhu Liu , Shunli Fu , Tong Gao , Shuang Liang , Xinyan Huang , Xinke Zhang , Yongjun Liu , Zipeng Zhang , Na Zhang

The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an in situ tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL⁺ B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual–conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL⁺ B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of αPD-1 and CAR-T therapies. The application of this in situ tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.

现有免疫疗法反应率低的根本原因是肿瘤细胞通过表面抗原缺乏和诱导肿瘤免疫抑制微环境（TIME）主导了肿瘤免疫逃逸。在此，我们提出了一种肿瘤细胞工程策略，通过恢复肿瘤细胞MHC-I/肿瘤特异性抗原复合物（MHC-I/TSA）表达以促进T细胞识别，以及沉默肿瘤细胞CD55以增加ICOSL B细胞比例并逆转TIME，从根本上破坏肿瘤免疫逃逸。研究人员制备了具有肿瘤靶向和电荷/大小双转换特性的多柔比星（DOX）和双基因质粒（MAC pDNA，同时编码MHC-I/ASMTNMELM和CD55-shRNA）共载给药系统（LCPN@ACD）。LCPN@ACD诱导的ICD促进了DC的成熟，增强了T细胞的活化和浸润。LCPN@ACD能使肿瘤细胞上的MHC-I/TSA有效表达，从而提高识别和杀伤肿瘤细胞的能力。LCPN@ACD 下调了肿瘤细胞 CD55 的表达，增加了 ICOSL B 细胞和 CTL 的比例，逆转了 TIME，从而大大提高了 PD-1 和 CAR-T 疗法的疗效。这种肿瘤细胞工程策略的应用消除了肿瘤免疫逃逸的源头，为解决临床免疫治疗难题提供了新思路。

{"title":"In situ tumor cell engineering reverses immune escape to enhance immunotherapy effect","authors":"Shujun Liu , Shijun Yuan , Meichen Liu , Jinhu Liu , Shunli Fu , Tong Gao , Shuang Liang , Xinyan Huang , Xinke Zhang , Yongjun Liu , Zipeng Zhang , Na Zhang","doi":"10.1016/j.apsb.2024.08.028","DOIUrl":"10.1016/j.apsb.2024.08.028","url":null,"abstract":"<div><div>The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an <em>in situ</em> tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL<sup>+</sup> B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual–conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL<sup>+</sup> B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of <em>α</em>PD-1 and CAR-T therapies. The application of this <em>in situ</em> tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 627-641"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The applications and advances of artificial intelligence in drug regulation: A global perspective

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B

Pub Date : 2025-01-01 DOI: 10.1016/j.apsb.2024.11.006

Lixia Fu , Guoshu Jia , Zhenming Liu , Xiaocong Pang , Yimin Cui

Artificial intelligence (AI) has emerged as a transformative force in healthcare, with applications spanning diagnostics to drug development. However, its integration into drug regulation remains nascent, with varying degrees of adoption and implementation across different regulatory bodies worldwide. This review aims to provide a comprehensive overview of the current state of AI in drug regulation, encapsulating AI-related policies, initiatives, and its practical application in regulatory agencies globally. It further discusses the challenges and future prospects of AI in this field. The findings reveal that numerous agencies have launched action plans and initiatives to incorporate AI, aiming to streamline regulatory processes and enhance data-driven regulatory decision-making. Moreover, AI's deployment in safety surveillance, workflow optimization, and regulatory science research is expanding, highlighting its increasing impact on drug regulation. Nonetheless, key challenges persist, such as data quality and reliability, technical limitations, talent shortage and the absence of standards. The review concludes that interdisciplinary collaboration is crucial to harness AI's full potential in drug regulation and overcoming its current limitations. In the future, AI may become a pivotal catalyst in drug regulation, promising a new era of enhanced scrutiny, efficiency, and innovation that will benefit public health on a global scale.

{"title":"The applications and advances of artificial intelligence in drug regulation: A global perspective","authors":"Lixia Fu , Guoshu Jia , Zhenming Liu , Xiaocong Pang , Yimin Cui","doi":"10.1016/j.apsb.2024.11.006","DOIUrl":"10.1016/j.apsb.2024.11.006","url":null,"abstract":"<div><div>Artificial intelligence (AI) has emerged as a transformative force in healthcare, with applications spanning diagnostics to drug development. However, its integration into drug regulation remains nascent, with varying degrees of adoption and implementation across different regulatory bodies worldwide. This review aims to provide a comprehensive overview of the current state of AI in drug regulation, encapsulating AI-related policies, initiatives, and its practical application in regulatory agencies globally. It further discusses the challenges and future prospects of AI in this field. The findings reveal that numerous agencies have launched action plans and initiatives to incorporate AI, aiming to streamline regulatory processes and enhance data-driven regulatory decision-making. Moreover, AI's deployment in safety surveillance, workflow optimization, and regulatory science research is expanding, highlighting its increasing impact on drug regulation. Nonetheless, key challenges persist, such as data quality and reliability, technical limitations, talent shortage and the absence of standards. The review concludes that interdisciplinary collaboration is crucial to harness AI's full potential in drug regulation and overcoming its current limitations. In the future, AI may become a pivotal catalyst in drug regulation, promising a new era of enhanced scrutiny, efficiency, and innovation that will benefit public health on a global scale.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"15 1","pages":"Pages 1-14"},"PeriodicalIF":14.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0