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
基本信息
- 批准号:8112741
- 负责人:
- 金额:$ 68.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-08-01 至 2014-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAminesAntigen TargetingBiodistributionBiomedical EngineeringBlood CirculationBlood VesselsCarboxylic AcidsChargeChemistryClinicClinicalClinical TrialsColorCommunitiesCountryDataDetectionDevelopmentDiagnosticDiseaseEnsureEquilibriumEstersExcisionExerciseExtinction (Psychology)EyeFamilyFamily suidaeFiltrationFluorescenceFluorescent DyesFoundationsFundingFutureGastrointestinal tract structureGlutamate Carboxypeptidase IIGoalsGrantHepaticHourHumanImageImage-Guided SurgeryInjection of therapeutic agentIntellectual PropertyKidneyLaboratoriesLifeLigandsLightLiteratureMalignant NeoplasmsMalignant neoplasm of prostateMetricNatureNormal tissue morphologyOperative Surgical ProceduresOpticsOrganOrganic SynthesisPerformanceProceduresProductionPropertyProtein BindingQuantum DotsRenal clearance functionReportingResearchResearch PersonnelResolutionSerumSerum ProteinsSignal TransductionSurgeonSystemTechnologyTimeTissuesTranslatingUnited States National Institutes of HealthUniversitiesbasecancer surgerydesignexperiencefluorescence imagingfluorophorein vivointravenous injectionpublic health relevancequantumresearch clinical testingscale upsmall moleculesuccesstumoruptake
项目摘要
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.
PUBLIC HEALTH RELEVANCE: Near-infrared light is invisible to the human eye, but penetrates relatively deeply into living tissue. It is therefore ideal for image-guided surgery, because it provides surgeons with high- sensitivity, high-resolution detection of diseases, such as cancer, without changing the look of the surgical field. Although hardware systems that use near-infrared fluorescent light for image-guided surgery are already available, optimized fluorophores, or "light bulbs" are not. The goal of this grant is to develop a new class of ideal near-infrared fluorophores that can be injected into the bloodstream. These fluorophores would "stick" to tumors and other diseased tissue, but not to normal tissue.
描述(由申请人提供):近红外(NIR)荧光具有彻底改变图像引导手术的潜力。然而,理想的荧光团在体内,并最终在临床上,使用尚未被描述。在美国国立卫生研究院生物工程研究伙伴关系(BRP)的资助下,PI的实验室开发了一种手术成像系统,该系统同时实时采集两种独立波长的NIR荧光发射图像沿着彩色视频图像。该成像系统已经被转移到临床,并正在NIH资助的三项临床试验中进行正式评估。然而,这项技术未来成功的根本限制是开发在体内表现最佳的近红外荧光团,并且可以广泛提供给其他学术研究人员。 为了在临床上可行,理想的NIR荧光团需要某些光学性质,包括激发和发射H800 nm,以及在血清中的高消光系数(δ)和量子产率(QY)。然而,现有的NIR荧光团在体内表现如此差的原因更多地与生物分布和清除有关。静脉注射后,理想的近红外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,文献中描述的每种NIR荧光团都存在两个基本缺陷:1)肝清除,这导致整个胃肠道的NIR荧光信号持续数小时,和/或2)正常组织中的非特异性背景摄取,这通常持续数小时并导致低信号背景比(SBR)。 这项资助建立在我们两年前使用近红外荧光量子点进行的观察的基础上(Choi等人,Nature Biotechnol. 2007; 25:1165-70)。出乎意料的是,并且由于仅部分理解的原因,两性离子有机涂层导致极低的非特异性组织摄取、快速肾清除和无血清蛋白结合。然而,纯阴离子或阳离子涂层给出相反的结果。基于这些数据,我们开始与格鲁吉亚州立大学的Patonay和Strekowski博士合作,合成两性离子七甲川吲哚菁NIR荧光团。本文所述的初步结果表明,非靶向和肿瘤靶向两性离子NIR荧光团都具有显著的光学和体内性质,包括800 nm荧光、高δ和QY、快速肾清除、不存在蛋白结合和超低非特异性组织摄取(即,背景)。 该资助的具体目标是合成用于体内和手术成像的优化两性离子近红外荧光团,验证其作为前列腺癌靶向诊断剂的用途,以及从分析生产扩大到制备生产。这些目标的完成将为未来图像引导手术的临床试验奠定基础。重要的是,我们还提出了一项知识产权战略,允许在学术界免费共享优化的近红外荧光团。
公共卫生相关性:近红外光对人眼是不可见的,但相对深入地穿透到活组织中。因此,它是图像引导手术的理想选择,因为它为外科医生提供了对疾病(例如癌症)的高灵敏度、高分辨率检测,而不改变手术野的外观。虽然使用近红外荧光进行图像引导手术的硬件系统已经可用,但优化的荧光团或“灯泡”还没有。这项资助的目标是开发一类新的理想的近红外荧光团,可以注射到血液中。这些荧光团会“粘”在肿瘤和其他病变组织上,但不会粘在正常组织上。
项目成果
期刊论文数量(0)
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Hak Soo Choi其他文献
Hak Soo Choi的其他文献
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