Comment on “Pathogenesis-Guided Rational Engineering of Nanotherapies for the Targeted Treatment of Abdominal Aortic Aneurysm by Inhibiting Neutrophilic Inflammation”

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Learn More CiteCitationCitation and abstractCitation and referencesMore citation options ShareShare onFacebookX (Twitter)WeChatLinkedInRedditEmailJump toExpandCollapse Letter to the EditorJanuary 21, 2025Comment on "Pathogenesis-Guided Rational Engineering of Nanotherapies for the Targeted Treatment of Abdominal Aortic Aneurysm by Inhibiting Neutrophilic Inflammation"Click to copy article linkArticle link copied!Heng WangHeng WangCentre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales 2145, AustraliaMore by Heng Wanghttps://orcid.org/0000-0001-7408-0398Keyi FanKeyi FanDepartment of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, ChinaMore by Keyi FanXiaohua JiaXiaohua JiaKey Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, ChinaMore by Xiaohua JiaRuijing Zhang*Ruijing ZhangDepartment of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China*Email: [email protected]More by Ruijing ZhangHonglin Dong*Honglin DongDepartment of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China*Email: [email protected]More by Honglin DongGuoping Zheng*Guoping ZhengCentre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales 2145, Australia*Email: [email protected]More by Guoping ZhengOpen PDFACS NanoCite this: ACS Nano 2025, 19, 2, 1861–1864Click to copy citationCitation copied!https://pubs.acs.org/doi/10.1021/acsnano.4c12263https://doi.org/10.1021/acsnano.4c12263Published January 21, 2025 Publication History Received 2 September 2024Accepted 2 January 2025Revised 22 November 2024Published online 21 January 2025Published in issue 21 January 2025letterCopyright © Published 2025 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissionsThis publication is licensed for personal use by The American Chemical Society. ACS PublicationsCopyright © Published 2025 by American Chemical SocietySubjectswhat are subjectsArticle subjects are automatically applied from the ACS Subject Taxonomy and describe the scientific concepts and themes of the article.CellsImmunologyInflammationNanoparticlesRodent modelsRecently, Hu et al. (1) designed a nanotherapy targeting aortic abdominal aneurysm (AAA) by inhibiting neutrophil inflammation. This approach is based on lumino-conjugated α-cyclodextrin materials (LaCD), from which anti-inflammatory nanoparticles (LaCD NPs) were synthesized. The targeting capability of this nanoprobe for neutrophils was also demonstrated in their previous study. (2) Additionally, by modifying LaCD NPs with alendronate sodium, nanoparticles (AlaCD NPs) were obtained, which significantly enhanced their ability to target calcification within the aortic aneurysm. This modification thereby inhibits neutrophil-mediated inflammatory responses within the aortic aneurysm, particularly the proinflammatory effects of neutrophil extracellular traps (NETs), extracellular matrix degradation, and the promotion of vascular smooth muscle cell apoptosis.A Brief Overview of Nanotherapeutics for AAAClick to copy section linkSection link copied!Nanotherapeutics for AAA represent an emerging trend in the treatment of human disease. Nanomaterials possess unique properties such as high surface area, small size effects, and surface modification potential, making them suitable for drug delivery, (3) imaging guidance, (4) and tissue repair. These properties help to achieve therapeutic drug concentrations at the lesion sites, that are difficult to achieve by conventional methods. Various nanomedicines have shown potential in animal models for AAA treatment (Table 1).Table 1. Examples of Nanomedicine Delivery for the Treatment of AAADiseaseNanoparticlesTargetsEffectsAAA, Rats (5)Rapamycin-loaded PEG-b-PBLGBeing endocytosed by macrophagesThe inflammatory level was inhibitedAAA, Rats (6)Cation functionalized PLGA-PANPFibrin clot of intraluminal thrombusThe intracavitary thrombus was dissolvedAAA, Mice (3)EVMS@RGD-HBc NCMacrophages and vascular smooth muscle cells with high expression of αvβ3Inhibition of macrophage polarization and smooth muscle cell phenotypic switchingAAA, Rats (7)EL-BSA-NP-PGGDamaged elastinInhibition of macrophage recruitmentAAA, Mice (8)Nanoparticles of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC)Immune cellsReduced aortic inflammation and macrophage activationAAA, Rats (20)Supramolecular nanofibers using peptide amphiphile moleculesFragmented elastin, matrix metalloproteinase 2 (MMP-2), and membrane type 1 matrix metalloproteinaseOnly targeted localizationAAA, Mice (21)TPN-siRNA, formed through the oxidative polymerization and self-assembly of epigallocatechin gallateMacrophages and vascular smooth muscle cellsA siRNA was released to silence MMP-2 and MMP-9, promote M1 to M2 repolarization of macrophages, and inhibit cell calcification and apoptosisAAA, Rats (22)A rapamycin-loaded oxidation-responsive β-cyclodextrin materialIntegrins and macrophage membranesIt attenuated the infiltration of CD68 macrophages in the outer membrane and rupture media of rat AAA, reduced calcification, and inhibited elastin degradationNanomedicine can be passively targeted to the extracellular matrix of lesions or taken up by specific cells, leveraging the properties of nanoparticles and the structure of the injured artery. For example, PEG-b-PBLG loaded with rapamycin can accumulate in microdefects of the AAA, reducing inflammation by being endocytosed by macrophages. (5) Another example is PLGA-PANP, which targets fibrin clots, helping to reduce arterial injury. (6)Active targeting involves conjugating specific ligands or attaching drug-loaded nanoparticles to cells. Fandi Mo et al. developed EVMS@RGD-HBc NC viral nanoparticles that actively target macrophages and vascular smooth muscle cells with high expression of αvβ3 in AAA, thereby coordinating the anti-inflammatory microenvironment. (3) Nasim Nosoudi et al. constructed EL-BSA-NP-PGG using nanoframe carriers of damaged elastin-targeting particles to reduce macrophage recruitment in AAA tissues of calcium chloride rats. (7)Nanoparticles can also be internalized by cells through the hitchhiking effect, responding to signals from lesion sites for targeted drug delivery. For example, Michael Spinosa et al. discovered that nanoparticles derived from mesenchymal stem cell (MSC) -derived extracellular vesicles (EVs) could modulate the inflammatory response and aneurysm progression in AAA via miR-147. (8)Several studies highlight the advantages of drug-loaded nanoparticles, such as sustained release and targeted effects at lower drug concentrations. These nanoparticles demonstrate efficacy in reducing inflammation and protecting elastic fibers, though further research is needed to clarify their immunogenicity, stability, and bioavailability for clinical translation. Additionally, while nanomaterial-based photothermal therapy is used in cancer treatment, it remains unexplored in AAA.Limitations of the StudyClick to copy section linkSection link copied!To our knowledge, this is the first study to address aortic aneurysm treatment through targeted neutrophil therapy, thereby paving the way for precision treatment of aortic aneurysm and other inflammatory vascular diseases. The study has the following limitations that require further clarification.1.Myeloperoxidase (MPO) is not a sufficiently precise marker for neutrophils. MPO is an inflammatory protein that is believed to be secreted by both neutrophils and macrophages in vascular inflammatory diseases, such as atherosclerosis, and is positively correlated with plaque vulnerability. (9,10) To a certain extent, it is reasonable to choose MPO as a marker of inflammatory state to reflect the activity of neutrophils. However, the legend in Figure S1B is not accurate, and neutrophils would be more rigorously represented by specific markers such as Ly6G.2.Improving the probe's capability for in vivo imaging. Hu et al. noted that "due to the deep location of the abdominal aorta in the abdomen and the low accumulation of Cy5/LaCD NPs in aortas relative to major organs.″ Consequently, in subsequent studies, they abandoned in vivo imaging in favor of ex vivo fluorescence imaging (see original Figure S5, Figure 2F). Observation of in vivo fluorescence imaging can not only visualize the targeting and distribution characteristics of nanomaterials but also reveal the changes in their accumulation or metabolism. Using different strategies to improve the physical and chemical properties of fluorescent probes can help to understand different physiological processes and improve the diagnosis, treatment, and prognosis of diseases. We suggest that using near-infrared fluorescence dyes such as Cy7 or IRDye 800CW could enhance fluorescence penetration. (11,12) Additionally, coupling Fe3O4 nanoparticles with LaCD NPs for magnetic resonance imaging or magnetic nanoparticle imaging could overcome the depth limitations of fluorescence imaging. (13) Additionally, it may be worthwhile to explore using mice, dorsal imaging, and fasting or dehydration protocols. (14) Developing an integrated diagnostic and therapeutic platform for in vivo imaging could have significant clinical implications.3.The fate of LaCD NPs is internalized by neutrophils and monocytes in peripheral blood. Hu et al. proposed that "LaCD NPs can be internalized by neutrophils and monocytes in the bloodstream, followed by a hitchhiking-effect-mediated translocation to the aneurysmal sites due to the infiltration of inflammatory cells." However, Figures 5F-J and S18 indicate that neutrophils and macrophages exhibit decreased migratory capacity, reduced inflammatory factor release, and diminished ability to recruit other inflammatory cells following LaCD NPs treatment. Therefore, after intravenous injection, LaCD NPs that are internalized by immune cells may be metabolized and degraded, resulting in a limited quantity of nanoparticles reaching the aortic aneurysm site. In future studies, the authors may attempt to elucidate the interaction between LaCD NPs and carrier cells. On one hand, neutrophils and macrophages were cultured in vitro and their viability and migration ability after engulfing NPs were examined in relation to the dose and time of LaCD NPs administration. The carrier cells were then infused back into mice or rat for further in vivo, real-time elucidation and quantification of vector-cell viability. On the other hand, neutrophils and macrophages were isolated from the animals, and the aggregation signals of residual LaCD NPs in the carrier cells should be detected in vitro after different times of administration. We expect the authors to confirm this in future studies, which will be critical for clinical translation.4.Hu et al. conducted RNA sequencing on aneurysm tissues and suggested a close relationship between MPO and neutrophil activation. However, this sequencing technique cannot ascertain the cellular origin of MPO. Performing single-cell sequencing on aortic aneurysm tissues or RNA sequencing on purified neutrophils may yield more precise results.5.Utilize more common aortic aneurysm models. Among existing aortic aneurysm animal models, mice are more widely used. (15) Methods such as adventitial application of porcine pancreatic elastase, CaCl2 solution infusion, or angiotensin II slow-release pump implantation are commonly used. (16−18) We agree with the authors in choosing the rat as the experimental model; larger animal models are essential for the transition to humans, especially in the context of potential applications of new technologies, including drug-loaded nanoparticles. However, no single modeling method can fully represent the true complexity of human AAA. Employing multiple models to explore the therapeutic effects of LaCD NPs on acute and chronic aneurysms would provide a more accurate representation of the various clinical scenarios of aneurysm pathogenesis. It will be closer to the pathological state of clinical AAA, which is crucial for the mechanism study of aneurysm pathophysiology and the identification of potential therapeutic targets. We look forward to further validation of the excellent performance of LaCD NPs in future studies.6.Additionally, there are some minor errors in the study. In Figures 3F and 3G, the vascular intimal integrity and elastin content stained with EVG in the 50 mg/kg LaCD NPs treatment group do not appear to show improvement. In Figure S9, the fluorescence dye should be Cy5 rather than Cy3. In Figure S11, the 50 mg/kg LaCD NPs treatment group appears to exhibit more calcium deposition as indicated by alizarin red staining and shows insufficient structural integrity. Quantitative analysis would objectively and clearly support the experimental results. In addition, we suggest that the authors replace more representative images, which will help readers understand the effect of LaCD NPs on aortic aneurysm more intuitively.The purpose of this letter is to offer relevant knowledge and suggestions for improvement, which do not affect the results and conclusions of Hu et al.'s study. We hope that more researchers will explore additional diagnostic and therapeutic approaches for aortic aneurysm, a vascular disease with high mortality following rupture. Currently, preoperative detection of aortic aneurysm in clinical practice primarily relies on morphological imaging techniques such as computed tomography angiography (CTA) and ultrasound imaging. (19) Hu et al.'s study presented a precision-targeted therapeutic strategy for aortic aneurysm and other vascular inflammatory diseases from an inflammatory and immunological perspective, offering significant clinical translational potential.Finally, we would like to acknowledge the authors for their extensive work and thank them for designing the first nanoparticle delivery system aimed at improving aortic aneurysm progression through targeted neutrophil therapy.Author InformationClick to copy section linkSection link copied!Corresponding AuthorsRuijing Zhang - Department of Nephrology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China; Email: [email protected]Honglin Dong - Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China; Email: [email protected]Guoping Zheng - Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales 2145, Australia; Email: [email protected]AuthorsHeng Wang - Centre for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Sydney, New South Wales 2145, Australia; https://orcid.org/0000-0001-7408-0398Keyi Fan - Department of Vascular Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, ChinaXiaohua Jia - Key Laboratory of Molecular Imaging of Chinese Academy of Sciences, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, ChinaAuthor ContributionsThe manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.FundingThis work was supported by the NHMRC Ideas grant 2027965 and the Translational Medicine Engineering Research Center for Vascular Diseases of Shanxi Province, China (Grant No. 2022017).AbbreviationsClick to copy section linkSection link copied!AAAaortic abdominal aneurysmLaCD NPslumino-conjugated α-cyclodextrin materials nanoparticlesNETsneutrophil extracellular trapsMSCmesenchymal stem cellEVsextracellular vesiclesMPOmyeloperoxidaseCTAcomputed tomography angiographyReferencesClick to copy section linkSection link copied! This article references 22 other publications. 1Hu, K.; Zhong, L.; Lin, W.; Zhao, G.; Pu, W.; Feng, Z.; Zhou, M.; Ding, J.; Zhang, J. Pathogenesis-Guided Rational Engineering of Nanotherapies for the Targeted Treatment of Abdominal Aortic Aneurysm by Inhibiting Neutrophilic Inflammation. ACS Nano 2024, 18 (8), 6650– 6672, DOI: 10.1021/acsnano.4c00120 Google ScholarThere is no corresponding record for this reference.2Tao, H.; Guo, J.; Ma, Y.; Zhao, Y.; Jin, T.; Gu, L.; Dou, Y.; Liu, J.; Hu, H.; Xiong, X.; Zhang, J. Luminescence Imaging of Acute Liver Injury by Biodegradable and Biocompatible Nanoprobes. ACS Nano 2020, 14 (9), 11083– 11099, DOI: 10.1021/acsnano.0c00539 Google Scholar2Luminescence Imaging of Acute Liver Injury by Biodegradable and Biocompatible NanoprobesTao, Hui; Guo, Jiawei; Ma, Yongchang; Zhao, Yang; Jin, Taotao; Gu, Lijuan; Dou, Yin; Liu, Jinyi; Hu, Houyuan; Xiong, Xiaoxing; Zhang, JianxiangACS Nano (2020), 14 (9), 11083-11099CODEN: ANCAC3; ISSN:1936-0851. (American Chemical Society) Liver injury can result in different hepatic diseases such as fatty liver, liver fibrosis, hepatitis, and liver failure, which are mainly responsible for global mortality and morbidity. Early diagnosis is crit. for the treatment of liver diseases. Herein the authors report luminescence imaging of neutrophil-mediated acute liver injury, including alc. liver injury (ALI) and acute liver failure (ALF). To this purpose, a biodegradable luminescent material was developed by chem. functionalization of a cyclic oligosaccharide, which can be produced into nanoprobes (defined as LaCD NPs). Luminescence of LaCD NPs was dependent on the level of reactive oxygen species and myeloperoxidase (MPO). Correspondingly, activated neutrophils could be specifically imaged by LaCD NPs, and the luminescent signal was pos. assocd. with the neutrophil count. In mouse models of ALI and ALF, LaCD NPs enabled precise quantification and tracking of neutrophils in livers. In both cases, changes in the luminescence intensity are consistent with time-dependent profiles of neutrophils, MPO, and other parameters relevant to the pathogenesis of liver injury. Moreover, the luminescence imaging capacity of LaCD NPs can be addnl. improved by surface functionalization with a neutrophil-targeting peptide. In addn., preliminary in vitro and in vivo studies demonstrated good safety of LaCD NPs. Consequently, LaCD NPs can be further developed as an effective and biocompatible luminescent nanoprobe for in vivo dynamic detection of the development of neutrophil-mediated acute liver injury. It is also promising for diagnosis of other neutrophil-assocd. liver diseases. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsFOisb%252FN&md5=46acf3fc91a4bf907428cfae74a9f1fa3Mo, F.; Wang, C.; Li, S.; Li, Z.; Xiao, C.; Zhang, Y.; Hu, C.; Wang, E.; Lin, P.; Yuan, T.; Zuo, Z.; Fu, W.; Chen, X.; Ren, L.; Wang, L. A Dual-Targeting, Multi-Faceted Biocompatible Nanodrug Optimizes the Microenvironment to Ameliorate Abdominal Aortic Aneurysm. Advanced materials (Deerfield Beach, Fla.) 2024, 36 (33), e2405761 DOI: 10.1002/adma.202405761 Google ScholarThere is no corresponding record for this reference.4Wang, H.; Zhang, R.; Jia, X.; Gao, S.; Gao, T.; Fan, K.; Li, Y.; Wang, S.; Qiao, M.; Yan, S.; Hui, H.; Dong, H. Highly sensitive magnetic particle imaging of abdominal aortic aneurysm NETosis with anti-Ly6G iron oxide nanoparticles. Cell death discovery 2024, 10 (1), 395, DOI: 10.1038/s41420-024-02156-3 Google ScholarThere is no corresponding record for this reference.5Shirasu, T.; Koyama, H.; Miura, Y.; Hoshina, K.; Kataoka, K.; Watanabe, T. Nanoparticles Effectively Target Rapamycin Delivery to Sites of Experimental Aortic Aneurysm in Rats. PloS one 2016, 11 (6), e0157813 DOI: 10.1371/journal.pone.0157813 Google ScholarThere is no corresponding record for this reference.6Sivaraman, B.; Sylvester, A.; Ramamurthi, A. Fibrinolytic PLGA nanoparticles for slow clot lysis within abdominal aortic aneurysms attenuate proteolytic loss of vascular elastic matrix. Materials science & engineering. C, Materials for biological applications 2016, 59, 145– 156, DOI: 10.1016/j.msec.2015.09.056 Google ScholarThere is no corresponding record for this reference.7Nosoudi, N.; Chowdhury, A.; Siclari, S.; Parasaram, V.; Karamched, S.; Vyavahare, N. Systemic Delivery of Nanoparticles Loaded with Pentagalloyl Glucose Protects Elastic Lamina and Prevents Abdominal Aortic Aneurysm in Rats. Journal of cardiovascular translational research 2016, 9 (5–6), 445– 455, DOI: 10.1007/s12265-016-9709-x Google ScholarThere is no corresponding record for this reference.8Spinosa, M.; Lu, G.; Su, G.; Bontha, S. V.; Gehrau, R.; Salmon, M. D.; Smith, J. R.; Weiss, M. L.; Mas, V. R.; Upchurch, G. R., Jr.; Sharma, A. K. Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 2018, 32 (11), 6038 DOI: 10.1096/fj.201701138RR Google ScholarThere is no corresponding record for this reference.9Rashid, I.; Maghzal, G. J.; Chen, Y. C.; Cheng, D.; Talib, J.; Newington, D.; Ren, M.; Vajandar, S. K.; Searle, A.; Maluenda, A.; Lindstedt, E. L.; Jabbour, A.; Kettle, A. J.; Bongers, A.; Power, C.; Michaelsson, E.; Peter, K.; Stocker, R. Myeloperoxidase is a potential molecular imaging and therapeutic target for the identification and stabilization of high-risk atherosclerotic plaque. Eur. Heart J. 2018, 39 (35), 3301– 3310, DOI: 10.1093/eurheartj/ehy419 Google Scholar9Myeloperoxidase is a potential molecular imaging and therapeutic target for the identification and stabilization of high-risk atherosclerotic plaqueRashid, Imran; Maghzal, Ghassan J.; Chen, Yung-Chih; Cheng, David; Talib, Jihan; Newington, Darren; Ren, Minqin; Vajandar, Saumitra K.; Searle, Amy; Maluenda, Ana; Lindstedt, Eva-Lotte; Jabbour, Andrew; Kettle, Antony J.; Bongers, Andre; Power, Carl; Michaelsson, Erik; Peter, Karlheinz; Stocker, RolandEuropean Heart Journal (2018), 39 (35), 3301-3310CODEN: EHJODF; ISSN:1522-9645. (Oxford University Press) As the inflammatory enzyme myeloperoxidase (MPO) is abundant in ruptured human atherosclerotic plaques, we aimed to investigate the role of MPO as a potential diagnostic and therapeutic target for high-risk plaque. We employed the tandem stenosis model of atherosclerotic plaque instability in apolipoprotein E gene knockout (Apoe-/-) mice. To test the role of MPO, we used Mpo-/-Apoe-/- mice and the 2-thioxanthine MPO inhibitor AZM198. In vivo MPO activity was assessed by liq. chromatog.-tandem mass spectrometry detection of 2-chloroethidium generation from hydroethidine and by bis-5HT-DTPA-Gd (MPO-Gd) mol. magnetic resonance imaging (MRI), while plaque phenotype was verified histol. Myeloperoxidase activity was two-fold greater in plaque with unstable compared with stable phenotype. Genetic deletion of MPO significantly increased fibrous cap thickness, and decreased plaque fibrin and haemosiderin content in plaque with unstable phenotype. AZM198 inhibited MPO activity and it also increased fibrous cap thickness and decreased fibrin and haemosiderin in plaque with unstable phenotype, without affecting lesion monocytes and red blood cell markers or circulating leukocytes and lipids. MPO-Gd MRI demonstrated sustained enhancement of plaque with unstable phenotype on T1-weighted imaging that was two-fold greater than stable plaque and was significantly attenuated by both AZM198 treatment and deletion of the Mpo gene. Our data implicate MPO in atherosclerotic plaque instability and suggest that non-invasive imaging and pharmacol. inhibition of plaque MPO activity hold promise for clin. translation in the management of high-risk coronary artery disease. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtlKju7bK&md5=287250d7c0704abde344944ca95d2ac110Sugiyama, S.; Okada, Y.; Sukhova, G. K.; Virmani, R.; Heinecke, J. W.; Libby, P. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am. J. Pathol. 2001, 158 (3), 879– 91, DOI: 10.1016/S0002-9440(10)64036-9 Google Scholar10Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromesSugiyama, Seigo; Okada, Yoshikatsu; Sukhova, Galina K.; Virmani, Renu; Heinecke, Jay W.; Libby, PeterAmerican Journal of Pathology (2001), 158 (3), 879-891CODEN: AJPAA4; ISSN:0002-9440. (American Society for Investigative Pathology) Inflammation and oxidative stress contribute to the pathogenesis of many human diseases including atherosclerosis. Advanced human atheroma contains high levels of the enzyme myeloperoxidase that produces the pro-oxidant species, hypochlorous acid (HOCl). This study documents increased nos. of myeloperoxidase-expressing macrophages in eroded or ruptured plaques causing acute coronary syndromes. In contrast, macrophages in human fatty streaks contain little or no myeloperoxidase. Granulocyte macrophage colony-stimulating factor, but not macrophage colony-stimulating factor, selectively regulates the ability of macrophages to express myeloperoxidase and produce HOCl in vitro. Moreover, myeloperoxidase-pos. macrophages in plaques co-localized with granulocyte macrophage colony-stimulating factor. Pro-inflammatory stimuli known to be present in human atherosclerotic plaque, including CD40 ligand, lysophosphatidylcholine, or cholesterol crystals, could induce release of myeloperoxidase from HOCl prodn. by macrophages in vitro. HOCl-modified proteins accumulated at ruptured or eroded sites of human coronary atheroma. These results identify granulocyte macrophage colony-stimulating factor as an endogenous regulator of macrophage myeloperoxidase expression in human atherosclerosis and support a particular role for the myeloperoxidase-expressing macrophages in atheroma complication and the acute coronary syndromes. >> More from SciFinder ®https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXitlOnurY%253D&md5=ef265d90189152083a67c4a96cb6be9f11Tong, W.; Hui, H.; Shang, W.; Zhang, Y.; Tian, F.; Ma, Q.; Yang, X.; Tian, J.; Chen, Y. Highly sensitive magnetic particle imaging of vulnerable atherosclerotic plaque with active myeloperoxidase-targeted nanoparticles. Theranostics 2021, 11 (2), 506– 521, DOI: 10.7150/thno.49812 Google ScholarThere is no corresponding record for this reference.12Zhang, W.; Liang, X.; Zhu, L.; Zhang, X.; Jin, Z.; Du, Y.; Tian, J.; Xue, H. Optical magnetic multimodality imaging of plectin-1-targeted imaging agent for the precise detection of orthotopic pancreatic ductal adenocarcinoma in mice. EBioMedicine 2022, 80, 104040 DOI: 10.1016/j.ebiom.2022.104040 Google Scholar12Optical magnetic multimodality imaging of plectin-1-targeted imaging agent for the precise detection of orthotopic pancreatic ductal adenocarcinoma in miceZhang, Wenjia; Liang, Xiaolong; Zhu, Liang; Zhang, Xinyu; Jin, Zhengyu; Du, Yang; Tian, Jie; Xue, HuadanEBioMedicine (2022), 80 (), 104040CODEN: EBIOAX; ISSN:2352-3964. (Elsevier B.V.) Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy worldwide, and the precise detection is challenging currently. Magnetic particle imaging (MPI) is suitable for imaging deep and internal PDAC tumors because of its high sensitivity and unlimited imaging depth. The purpose of this study was to utilize the MPI, in combination with fluorescence mol. imaging (FMI) and magnetic resonance imaging (MRI), to advance the in vivo precise detection of PDAC xenografts. The PDAC targeted plectin-1 peptide and IRDye800CW were conjugated to the superparamagnetic iron oxide nanoparticles (PTP-Fe3O4-IRDye800CW) for the PDAC-targeting triple-modality imaging. S.c. and orthotopic PDAC mouse models were established. FMI, MPI, and MRI were performed for dynamic and quant. observation of PDAC tumors. Histol. staining analyses were used for ex vivo validation. PTP-Fe3O4-IRDye800CW nanoparticles possessed great triple-modality imaging performance and specific targeting to plectin-1 expressed on PDAC cells. For in vivo multi-modality imaging of orthotopic PDAC models, the PTP-Fe3O4-IRDye800CW nanoparticles demonstrated higher specificity, even distribution, and longer retention effects in tumors for over 7 d compared with Con-Fe3O4-IRDye800CW nanoparticles. (MPI, 2d post-injection: PTP-Fe3O4-IRDye800CW: 85.72% ± 1.53% vs. Con-Fe3O4-IRDye800CW: 74.41% ± 1.91%, **P < 0.01 (Student's t test)). Ex vivo histol. and Prussian blue stainings were performed to validate the distribution of probes. These data demonst