Ultra-Low Background NIR Fluorophores for In Vivo Imaging and Image-Guided Surger

用于体内成像和图像引导手术的超低背景近红外荧光团

• 批准号: 8889834
• 负责人: John V Frangioni
• 金额: $ 37.15万
• 依托单位: CURADEL, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889834
• 关键词: Ultra; Low; Background; NIR; Fluorophores

DESCRIPTION (provided by applicant): Near-infrared (NIR) fluorescence has the potential to revolutionize image-guided surgery. However, ideal fluorophores for in vivo, and eventually clinical, use have not yet been described. Under an NIH Bioengineering Research Partnership (BRP) grant, the PI's laboratory has developed a surgical imaging system that simultaneously, and in real-time, acquires two independent wavelengths of NIR fluorescence emission images along with color video images. The imaging system has already been translated to the clinic, and is being formally evaluated in three NIH-funded clinical trials. Nevertheless, the fundamental limitation to the future success of this technology is the development of NIR fluorophores that perform optimally in the body, and which can be made widely available to other academic researchers. To be clinically viable, the ideal NIR fluorophore requires certain optical properties, including excitation and emission H800 nm, and both a high extinction coefficient (5) and quantum yield (QY) in serum. However, the reason why existing NIR fluorophores perform so poorly in vivo has more to do with biodistribution and clearance. After IV injection, the ideal NIR fluorophore would rapidly equilibrate between the intravascular and extra vascular spaces and would be cleared efficiently via renal filtration. To date, every NIR fluorophore described in the literature suffers from two fundamental flaws: 1) hepatic clearance, which results in NIR fluorescence signal throughout the GI tract that persists for hours, and/or 2) non-specific background uptake in normal tissues, which typically persists for hours and results in a low signal-to-background ratio (SBR). This grant builds upon an observation we made two years ago using NIR fluorescent quantum dots (Choi et al., Nature Biotechnol. 2007; 25: 1165-70). Unexpectedly, and for reasons only partially understood, zwitterionic organic coatings resulted in extremely low non-specific tissue uptake, rapid renal clearance, and no serum protein binding. However, purely anionic or cationic coatings gave the opposite results. Based on these data, we began collaborating with Drs. Patonay and Strekowski at Georgia State University, leaders in the field of NIR fluorophore chemistry, to synthesize zwitterionic heptamethine indocyanine NIR fluorophores. The preliminary results, described herein, demonstrate that both non-targeted and tumor-targeted zwitterionic NIR fluorophores have remarkable optical and in vivo properties, including 800 nm fluorescence, high 5 and QY, rapid renal clearance, absence of protein binding, and ultra-low non-specific tissue uptake (i.e., background). The specific aims of this grant are focused on the synthesis of optimized zwitterionic NIR fluorophores for in vivo and surgical imaging, on validating their use as targeted diagnostic agents for prostate cancer, and for scale-up from analytical to preparative production. Completion of these aims will lay the foundation for future clinical testing during image-guided surgery. Importantly, we also present an intellectual property strategy that will permit free sharing of optimized NIR fluorophores within the academic community.

描述（由申请人提供）：近红外（NIR）荧光有可能改变图像引导手术。但是，尚未描述用于体内和最终临床的理想荧光团使用。在NIH生物工程研究合作伙伴关系（BRP）拨款下，PI的实验室开发了一种手术成像系统，该系统同时并实时地获取了两个独立的NIR荧光发射图像和彩色视频图像的独立波长。成像系统已经转化为诊所，并在三项由NIH资助的临床试验中进行了正式评估。然而，这项技术未来成功的基本局限性是在体内发挥最佳性能的NIR荧光团的发展，并且可以向其他学术研究人员广泛使用。 为了在临床上可行，理想的NIR荧光团需要某些光学特性，包括激发和发射H800 nm，以及血清中高灭绝系数（5）和量子产率（QY）。但是，现有的NIR荧光团在体内表现较差的原因与生物分布和清除率有关。注射静脉注射后，理想的NIR荧光团将在血管内和血管外空间之间迅速平衡，并通过肾脏过滤有效清除。迄今为止，文献中描述的每个NIR荧光团都有两个基本缺陷：1）肝清除率，这会导致整个GI范围内持续数小时的NIR荧光信号，并且/或2）正常组织中的非特异性背景吸收，通常在数小时和低信号到基信号群中持续下来，并在低信号到后群（SBR）中（SBR）。 这笔赠款建立在我们两年前使用NIR荧光量子点进行的观察基础上（Choi等，NatureBiotechnol。2007; 25：1165-70）。出乎意料的是，出于部分原因，Zwitterionic有机涂层导致了极低的非特异性组织摄取，快速肾脏清除率和无血清蛋白结合。但是，纯粹的阴离子或阳离子涂层给出了相反的结果。基于这些数据，我们开始与DRS合作。佐治亚州立大学的Patonay和Strekowski是NIR荧光团化学领域的领导者，以合成二翼特氨基氨基氨基氨基氨基氨基氨基NIR荧光团。本文描述的初步结果表明，非靶标和靶向肿瘤的Zwitterionic NIR荧光团具有出色的光学和体内特性，包括800 nm荧光，高5和QY，QY，快速肾脏清除率，蛋白质结合的缺乏，蛋白质结合和超高非特定的非特异性组织Uptake（I.E.E.E.E.E.E.E.E.E.E.E.E.E.E.E.E.E.E.E）。 该赠款的具体目的集中在于为体内和手术成像的优化Zwitterionic NIR荧光团综合，以验证其作为前列腺癌的靶向诊断剂的使用，并从分析到制备生产。这些目标的完成将为图像引导手术期间的未来临床测试奠定基础。重要的是，我们还提出了一项知识产权战略，该战略将允许在学术界免费共享优化的NIR荧光团。

项目成果

Nanoparticle assembly: building blocks for tumour delivery.

• DOI: 10.1038/nnano.2014.7
• 发表时间: 2014-02
• 期刊: Nature nanotechnology
• 影响因子: 38.3

Central C-C Bonding Increases Optical and Chemical Stability of NIR Fluorophores.

• DOI: 10.1039/c4ra11225c
• 发表时间: 2014-01-01
• 期刊: RSC advances
• 影响因子: 3.9
• 作者: Hyun H;Owens EA;Narayana L;Wada H;Gravier J;Bao K;Frangioni JV;Choi HS;Henary M
• 通讯作者: Henary M

Cartilage-Specific Near-Infrared Fluorophores for Biomedical Imaging.

• DOI: 10.1002/anie.201502287
• 发表时间: 2015-07-20
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Hyun H;Owens EA;Wada H;Levitz A;Park G;Park MH;Frangioni JV;Henary M;Choi HS
• 通讯作者: Choi HS

uPAR-targeted multimodal tracer for pre- and intraoperative imaging in cancer surgery.

• DOI: 10.18632/oncotarget.3680
• 发表时间: 2015-06-10
• 期刊: Oncotarget
• 作者: Boonstra MC;van Driel PB;van Willigen DM;Stammes MA;Prevoo HA;Tummers QR;Mazar AP;Beekman FJ;Kuppen PJ;van de Velde CJ;Löwik CW;Frangioni JV;van Leeuwen FW;Sier CF;Vahrmeijer AL
• 通讯作者: Vahrmeijer AL

Sentinel Lymph Node Mapping of Liver.

• DOI: 10.1245/s10434-015-4601-5
• 发表时间: 2015-12
• 期刊: Annals of surgical oncology
• 影响因子: 3.7
• 作者: Wada H;Hyun H;Vargas C;Genega EM;Gravier J;Gioux S;Frangioni JV;Choi HS
• 通讯作者: Choi HS