一种用于短波和近红外荧光成像的实体瘤筛查、切除和伤口监测的泛癌染料-动脉网

A pan-cancer dye for solid-tumour screening, resection and wound monitoring via short-wave and near-infrared fluorescence imaging

Nature 等信源发布 2024-09-09 19:35

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AbstractThe efficacy of fluorescence-guided surgery in facilitating the real-time delineation of tumours depends on the optical contrast of tumour tissue over healthy tissue. Here we show that CJ215—a commercially available, renally cleared carbocyanine dye sensitive to apoptosis, and with an absorption and emission spectra suitable for near-infrared fluorescence imaging (wavelengths of 650–900 nm) and shortwave infrared (SWIR) fluorescence imaging (900–1,700 nm)—can facilitate fluorescence-guided tumour screening, tumour resection and the assessment of wound healing.

摘要荧光引导手术在促进肿瘤实时描绘方面的功效取决于肿瘤组织与健康组织的光学对比度。在这里，我们显示CJ215-一种对细胞凋亡敏感的市售，肾清除的碳菁染料，其吸收和发射光谱适用于近红外荧光成像（波长650-900 nm）和短波红外（SWIR）荧光成像（900-1700 nm）-可以促进荧光引导的肿瘤筛查，肿瘤切除和伤口愈合评估。

In tumour models of either murine or human-derived breast, prostate and colon cancers and of fibrosarcoma, and in a model of intraperitoneal carcinomatosis, imaging of CJ215 with ambient light allowed for the delineation of nearly all tumours within 24 h after intravenous injection of the dye, which was minimally taken up by healthy organs.

在鼠源性或人源性乳腺癌，前列腺癌和结肠癌以及纤维肉瘤的肿瘤模型中，以及在腹膜内癌病模型中，用环境光对CJ215进行成像，可以在静脉注射染料后24小时内描绘几乎所有的肿瘤，这是健康器官摄取最少的。

At later timepoints, CJ215 provided tumour-to-muscle contrast ratios up to 100 and tumour-to-liver contrast ratios up to 18. SWIR fluorescence imaging with the dye also allowed for quantifiable non-contact wound monitoring through commercial bandages. CJ215 may be compatible with existing and emerging clinical solutions..

在后来的时间点，CJ215提供的肿瘤与肌肉的对比度高达100，肿瘤与肝脏的对比度高达18。使用染料的SWIR荧光成像还允许通过商业绷带进行可量化的非接触伤口监测。CJ215可能与现有和新兴的临床解决方案兼容。。

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Fig. 1: CJ215 spectral, in vitro and in vivo assessment.Fig. 2: Tumour resection using SWIRFI (>900 nm, sensor response) and CJ215.Fig. 3: Extended spectral emission (>1,100, >1,300 nm) assessment of CJ215 via SWIRFI.Fig. 4: NIRFI (745 nm excitation, 840 nm emission) necropsy biodistribution assessment of CJ215 in four tumour models.Fig.

图1:CJ215光谱，体外和体内评估。图2：使用SWIRFI（>900 nm，传感器响应）和CJ215进行肿瘤切除。图3：通过SWIRFI对CJ215进行扩展光谱发射（>1100，>1300 nm）评估。图4:CJ215在四种肿瘤模型中的NIRFI（745nm激发，840nm发射）尸检生物分布评估。图。

5: Necropsy and histological analysis of additional regions of interest during CT26 tumour resection.Fig. 6: SWIRFI (>900 nm) and CJ215 enable contrast-based image generation for binary tumour delineation.Fig. 7: CJ215 assessment in a colorectal peritoneal carcinomatosis model (SW1222).Fig. 8: Non-invasive, non-contact and ambient-light-resistant wound monitoring through commercially available bandages via SWIRFI (>1,300 nm) and CJ215..

5： CT26肿瘤切除过程中其他感兴趣区域的尸检和组织学分析。图6:SWIRFI（>900 nm）和CJ215能够基于对比度的图像生成用于二值肿瘤描绘。图7：结直肠癌腹膜癌病模型（SW1222）中的CJ215评估。图8：通过SWIRFI（>1300 nm）和CJ215通过市售绷带进行非侵入性，非接触性和环境耐光伤口监测。。

Data availability

数据可用性

The raw and analysed datasets generated during the study are available for research purposes from the corresponding author on reasonable request. Source data are provided with this paper.

研究期间生成的原始和分析数据集可根据合理要求从通讯作者处获得用于研究目的。本文提供了源数据。

Code availability

代码可用性

The code required to generate the CNR images via framewise or pixelwise methods is included in the Supplementary Information. All code to process the images in ImageJ is readily available via plugins.

补充信息中包含了通过逐帧或逐像素方法生成CNR图像所需的代码。ImageJ中处理图像的所有代码都可以通过插件轻松获得。

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Download referencesAcknowledgementsWe thank S. Urbain and F. Scherninski from Proimaging (Paris, France) along with J. Tran-Guyon and V. Guyon from Laboratoires Synth-Innove (Paris, France) for helpful advice, discussions and for providing CJ215 for this investigation (CJ215 was a gift from Proimaging which did not sponsor this research other than providing CJ215); the small-animal imaging core at MSKCC for assistance as well as RARC at MSKCC for advice on animal experiments and excellent animal assistance, especially A.

下载参考文献致谢我们感谢Proimaging（法国巴黎）的S.Urbain和F.Scherninski以及Laboratoires Synth Innove（法国巴黎）的J.Tran Guyon和V.Guyon提供了有益的建议，讨论并为本次调查提供了CJ215（CJ215是Proimaging的礼物，除了提供CJ215之外，没有赞助这项研究）；MSKCC的小动物成像核心提供帮助，MSKCC的RARC提供动物实验和优秀动物援助的建议，特别是A。

Ritter and E. Soto-Lemus; N. Fan, B. Shrestha and W. Kang of the Molecular Cytology Core Facility at MSKCC and I. Miranda of the Laboratory of Comparative Pathology at MSKCC; E. Chan, E. Rosiek and Y. Romin of the Molecular Cytology core at MSKCC for microscopy assistance. Support for this work was provided by the the National Science Foundation CAREER Award (1752506, D.A.H.), the NCI (R01-CA-257811, J.G., R01-CA215719, D.A.H.

Ritter和E.Soto Lemus；N、 MSKCC分子细胞学核心设施的Fan，B.Shrestha和W.Kang以及MSKCC比较病理学实验室的I.Miranda；E、 MSKCC分子细胞学核心的Chan，E。Rosiek和Y。Romin提供显微镜辅助。国家科学基金会职业奖（1752506，D.A.H.），NCI（R01-CA-257811，J.G.，R01-CA215719，D.A.H.）为这项工作提供了支持。

and Cancer Center Support Grant P30-CA008748, Selwyn Vickers/MSKCC), NIBIB (R56 EB030512, J.G., R01-EB033651, D.A.H.; R00-EB033580, M.K.), the Department of Defense Congressionally Directed Medical Research Program (W81XWH-22-1-0563, D.A.H.), the Ara Parseghian Medical Research Fund (D.A.H.), the American Cancer Society Research Scholar Grant (GC230452, D.A.H.), the Louis and Rachel Rudin Foundation (D.A.H.), MSK’s Cycle for Survival’s Equinox Innovation Award in Rare Cancers (D.A.H.), the Experimental Therapeutics Center of MSKCC (D.A.H.

和癌症中心支持拨款P30-CA008748，Selwyn Vickers/MSKCC），NIBIB（R56 EB030512，J.G.，R01-EB033651，D.A.H.；R00-EB033580，M.K.），国防部国会指导的医学研究计划（W81XWH-22-1-0563，D.A.H.），Ara Parseghian医学研究基金（D.A.H.），美国癌症协会研究学者拨款（GC230452，D.A.H.），路易斯和雷切尔·鲁丁基金会（D.A.H.），MSK的生存周期罕见癌症Equinox创新奖（D.A.H.），MSKCC实验治疗中心（D.A.H.）。

and J.G.), Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research (D.A.H.) and the Vince Lombardi Cancer Foundation (J.G.). This work was partially funded by Memorial Sloan Kettering Cancer Center’s Technology Development Funding Program,.

和J.G.），威廉·古德温先生和爱丽丝·古德温夫人以及英联邦癌症研究基金会（D.A.H.）和文斯·伦巴第癌症基金会（J.G.）。这项工作部分由纪念斯隆·凯特琳癌症中心的技术发展资助计划资助，。

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PubMed Google ScholarContributionsB.E.M.L conceived, designed and performed the experiments, and designed the analysis pipelines and CNR code. A.Y.S. designed and performed Sta and zVAD experiments. E.A. designed and performed in vivo experiments. B.E.M.L. and C.H. performed in vitro assessment and microscopy.

PubMed谷歌学术贡献b。E、 M.L构思，设计和执行了实验，并设计了分析管道和CNR代码。A、 Y.S.设计并进行了Sta和zVAD实验。E、 A.设计并进行体内实验。B、 E.M.L.和C.H.进行了体外评估和显微镜检查。

B.E.M.L., D.G. and M.K. performed spectral characterization. R.M.E. performed the in silico serum docking assessment. N.A. and D.V. generated and assisted with metastatic modelling. S.M. performed pathology analysis and staining. N.M., E.I., N.B.P. and M.S. generated various tumour models and performed experiments.

B、 E.M.L.，D.G.和M.K.进行了光谱表征。R、 M.E.进行了计算机血清对接评估。N、 A.和D.V.生成并协助进行转移建模。S、 M.进行病理分析和染色。N、 M.，E.I.，N.B.P.和M.S.生成了各种肿瘤模型并进行了实验。

A.O. and N.M. conducted in vivo experimental design and work. B.E.M.L., D.A.H. and J.G. designed experiments and supervised the study. All authors discussed the work, and edited and commented on the manuscript.Corresponding authorCorrespondence to.

A、 O.和N.M.进行了体内实验设计和工作。B.E.M.L.，D.A.H.和J.G.设计了实验并监督了研究。所有作者都讨论了这项工作，并对稿件进行了编辑和评论。对应作者对应。

Jan Grimm.Ethics declarations

简·格林。道德宣言

Competing interests

相互竞争的利益

D.A.H. is a co-founder with equity interest in Lime Therapeutics Inc., Selectin Therapeutics Inc., and Nine Diagnostics Inc.; is a member of the scientific advisory board of Concarlo Therapeutics Inc., Celine Therapeutics Inc., Nanorobotics Inc., and Mediphage Bioceuticals Inc.; and is a consultant for METiS Therapeutics Inc.

D、。；是Concarlo Therapeutics Inc.，Celine Therapeutics Inc.，Nanorobotics Inc.和Mediphage Bioceuticals Inc.科学顾问委员会的成员。；并且是METiS Therapeutics Inc.的顾问。

B.M.L., D.A.H. and J.G. have filed a provisional patent in relation to some of the work in this paper. The other authors declare no competing interests..

B、 M.L.，D.A.H.和J.G.已经就本文中的一些工作提交了临时专利。其他作者声明没有利益冲突。。

Peer review

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Peer review information

同行评审信息

Nature Biomedical Engineering thanks Jianmin Wu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Nature Biomedical Engineering感谢吴建民（Jianmin Wu）和另一位匿名审稿人对这项工作的同行评审所做的贡献。可以获得同行评审报告。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 In silico assessment of serum binding affinity of CJ215 and ICG to human serum albumin (HSA) and mouse serum albumin (MSA).A) Overview of ALIGN results between human and murine serum albumin revealed a sequence homology of 72.37 %.

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。扩展数据扩展数据图1计算机评估CJ215和ICG对人血清白蛋白（HSA）和小鼠血清白蛋白（MSA）的血清结合亲和力。A）人和鼠血清白蛋白之间比对结果的概述显示序列同源性为72.37%。

B) Predicted aligned error for murine albumin (AF-P07724-F1). C) Left, overview of CJ215 docking pose with HSA. Right, zoomed in portion of docking site. D) Residue interactions of HSA with CJ215. E) Left, overview of ICG binding with HSA. Right, zoomed in view of the binding site. F) Residue interactions of HSA with ICG.

B）鼠白蛋白（AF-P07724-F1）的预测比对误差。C）左，CJ215与HSA对接姿势概述。右，放大了对接站点的一部分。D） HSA与CJ215的残基相互作用。E）左，ICG与HSA结合的概述。。F） HSA与ICG的残基相互作用。

G) Left, overview of docking pose of CJ215 with MSA. Right, zoomed in view of the binding site. H) Residue interactions of CJ215 with MSA. J) Left, overview of ICG binding with MSA. Right, zoomed in view of the binding site. K) Residue interactions of ICG and MSA. For D, F, H, & K the non-covalent binding co-efficient (GlideScore) is shown in italics, where more negative binding correlates to a stronger binding and interaction.

G）左，CJ215与MSA对接姿势概述。。H） CJ215与MSA的残基相互作用。J）。。K） ICG和MSA的残基相互作用。对于D，F，H和K，非共价结合系数（GlideScore）以斜体显示，其中更多的负结合与更强的结合和相互作用相关。

In all cases CJ215 showed improved binding efficacy to albumin over ICG.Supplementary informationMain Supplementary InformationSupplementary figures and video captions.Reporting SummaryPeer Review FileVideo 1CJ215 uptake in single 4T1 cells.Video 2CJ215 uptake in 4T1 spheroids.Video 3SWIRFI CNR mode (pixel-based) of CJ215 uptake in various tumour models.Video 4SWIRFI CNR mode (pixel-based) of CJ215 uptake in wounds, without and with bandage application.Source dataSource Data for Figs.

在所有情况下，与ICG相比，CJ215对白蛋白的结合效力都有所提高。补充信息主要补充信息补充数字和视频字幕。报告总结同行评审文件视频1CJ215在单个4T1细胞中的摄取。视频2CJ215在4T1球体中的摄取。视频3SWIRFI CNR模式（基于像素）在各种肿瘤模型中摄取CJ215。视频4SWIRFI CNR模式（基于像素）在伤口中摄取CJ215，不使用和使用绷带应用。图的源数据源数据。

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Nat. Biomed. Eng (2024). https://doi.org/10.1038/s41551-024-01248-wDownload citationReceived: 19 January 2024Accepted: 21 July 2024Published: 09 September 2024DOI: https://doi.org/10.1038/s41551-024-01248-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

自然生物医学。Eng（2024年）。https://doi.org/10.1038/s41551-024-01248-wDownload引文接收日期：2024年1月19日接受日期：2024年7月21日发布日期：2024年9月9日OI：https://doi.org/10.1038/s41551-024-01248-wShare本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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