CN105143855A - 时间分辨激光诱导荧光光谱系统及其用途 - Google Patents
时间分辨激光诱导荧光光谱系统及其用途 Download PDFInfo
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Abstract
本发明提供了一种通过分析在激发时来自生物样本的荧光发射来表征生物样本的系统和使用所述系统的方法。所述系统包括激光源、采集光纤、多路分配器和光学延迟装置。本文引用的所有参考文献都如同充分阐述一般以引用方式整体并入。除非另外定义,否则本文使用的技术术语和科学术语具有与本发明所属领域中的普通技术人员通常所理解的相同的含义。
Description
政府权利
本发明在由国立神经疾病和中风研究所授予的NS060685号资助下由政府支持获得。政府对本发明享有某些权利。
技术领域
本发明通常涉及通过分析来自标记或未标记生物分子的激光诱导光发射来表征生物材料的技术。
背景技术
本文所引用的所有参考仿佛完全阐述一般以整体方式并入。除非另外定义,否则本文所使用的技术和科学术语具有与本发明所属领域的普通技术人员通常所了解的意义相同的意义。下述文献为本领域中技术人员提供用于本申请的许多术语的通用指导:Allen等人,《Remington:TheScienceandPracticeofPharmacy》第22版.,英国医药出版社(PharmaceuticalPress)(2012年9月15日);Hornyak等人,《IntroductiontoNanoscienceandNanotechnology》,CRC出版社(2008);Singleton和Sainsbury,《DictionaryofMicrobiologyandMolecularBiology》第3版.,修订版.,约翰.威利出版社(J.Wiley&Sons)(纽约,NY2006);Smith,《March’sAdvancedOrganicChemistryReactions,MechanismsandStructure》第7版.,约翰.威利出版社(纽约,NY2013);Singleton,《DictionaryofDNAandGenomeTechnology》第3版.,威立布莱克维尔出版社(Wiley-Blackwell)(2012年11月28日);以及Green和Sambrook,《MolecularCloning:ALaboratoryManual》第4版.,冷泉港出版社(ColdSpringHarborLaboratoryPress)(冷泉港,纽约2012)。关于如何制备抗体的参考,参见如下文献:Greenfield,《AntibodiesALaboratoryManual》第2版.,冷泉港出版社(冷泉港,纽约2013)(ColdSpringHarborNY,2013);和Milstein,《Derivationofspecificantibody-producingtissuecultureandtumorlinesbycellfusion》,欧洲免疫学杂志(Eur.J.Immunol.)1976年7月,6(7):511-9;Queen和Selick,《Humanizedimmunoglobulins》,美国专利号5,585,089(1996年12月);以及Riechmann等人,《Reshapinghumanantibodiesfortherapy》,自然(Nature)1988年3月24日,332(6162):323-7。
激光诱导荧光光谱(LIFS)已被广泛地应用于复杂的生物系统以诊断疾病,例如肿瘤或动脉粥样硬化斑块,以及分析有机物的化学或生物化学成分。LIFS的益处包括其在活体内获取定性和定量的生物系统信息的无创性途径(noninvasiveapproach)。LIFS的其他优势包括波长可调谐性、窄带激发、指向性和短脉冲激发。另外,LIFS能够选择性并有效地激发有机物中的荧光团并极大地提升荧光选择性和可检测性。
时间分辨技术使得激光诱导的发射的实时演化被直接地记录,短(纳秒)和极短(皮秒)脉冲激光的可用性以及高速电子设备的进展使得此直接记录过程成为可能。由于光发射过程发生在刺激事件后非常短的时间间隔内(例如,荧光衰减时间大约为几纳秒),时间分辨测量可提供关于样本的分子种类和蛋白质结构的信息。例如,时间分辨技术允许将测量数据中的“早期”过程(典型地为短期状态的直接激发或非常快速的后续反应)和“后期”过程(典型地为长期状态,由持续电子布居或由初始电子过程后的反应所导致的延迟激发)“分离”。
时间分辨测量仅从宽范围的波长中获取整体效应,并且可由激光诱导发射中的光谱信息补充,以揭示样本的额外特征。为了将激光诱导发射分解成组分波长,同时仍然能够执行时间分辨测量,一些现有的LIFS技术使用扫描单色仪从宽频发射中选择波长,每次一个波长,并且将选择的波长组分导向光电探测器。然而,当调谐单色仪以选择新波长的时候,为了从发射光谱中分解另一个波长,样本需要再次激发以产生另一个再发射。
此类现有的技术会耗费大量的时间以从宽带光发射中分辨出多个光谱组分。尽管每个波长组分都可被实时记录,但是使用单色仪选择另一个波长的转换时间可花费数秒,这在执行实时测量中成为限制因素。另外,如果需要测量样本上的大量刺激位置,总体测量会花费大量时间。因此,需要促进来自单次样本激发引起的光发射的时间分辨和波长分辨信息的接近实时记录的系统和方法。
发明概述
本发明提供了一种通过分析来自生物样本的光发射来表征生物样本的系统,其中,生物样本对激发信号进行响应而产生所述光发射。系统首先用激光脉冲辐射生物样本以促使生物样本产生响应光发射。系统随后使用波长分割装置将响应光发射分割成不同中心波长的光谱带组。随后向光谱带组应用时间延迟,使得每个光谱带在不同时间到达光学检测器,从而使光学检测器分别瞬时分辨每个光谱带的响应光发射。延迟的光谱带随后由系统在光学检测器的单个检测窗口中捕获。随后处理捕获的光谱带。
附图说明
图1根据本发明的不同实施方案描述了,(A)多点激发时间分辨激光诱导荧光光谱的原理图。BS:分光镜;FB:光纤束;OD:光密度;LPFW:长通道滤光轮;ExF:激发光纤;CF:收集光纤;PMT:光电倍增管。(B)触发同步。
图2根据本发明的多个实施方案描述了示例性多路分配器设计的原理图。
图3根据本发明的多个实施方案描述了探测器的原理图。
图4根据本发明的多个实施方案描述了多个示例性生物分子的荧光发射。
图5根据本发明的多个实施方案描述了显示离体脑样本中持续NADH监测的使用的原理图。
图6根据本发明的多个实施方案描述了这样的数据:该数据展示了TRLIFS装置在细胞暴露于鱼藤酮(一种干扰NADH-依赖性ATP产生的化合物)中时持续监测NADH水平的能力。
图7根据本发明的多个实施方案描述了,(A)由TRLIFS系统观测到的区域;(B)来自于(A)的样本在用TTC处理后被覆盖;以及(C)为每个区域(点)标绘的荧光强度。
图8根据本发明的多个实施方案描述了具有不同浓度甲氨蝶呤的琼脂/凝胶。
图9根据本发明的多个实施方案描述了,(A)在暴露于具有350nm波长的光20分钟之后不同浓度的MTX的荧光,以及(B)在20分钟内的荧光时间进程的曲线图,其指示由于形成活性荧光形式而导致MTX的荧光增加。
发明详述
本文引用的所有参考文献都如同充分阐述一般以引用方式整体并入。除非另外定义,否则本文使用的技术术语和科学术语具有与本发明所属领域中的普通技术人员通常所理解的相同的含义。下述文献为本领域中的技术人员提供用于本申请中的许多术语的通用指导:Allen等人,《Remington:TheScienceandPracticeofPharmacy》第22版.,英国医药出版社(2012年9月15日);Hornyak等人,IntroductiontoNanoscienceandNanotechnology,CRC出版社(2008);Singleton和Sainsbury,《DictionaryofMicrobiologyandMolecularBiology》第3版.,修订版,约翰.威利出版社(纽约,NY2006);Smith,《March’sAdvancedOrganicChemistryReactions,MechanismsandStructure》第7版.,约翰.威利出版社(纽约,NY2013);Singleton,《DictionaryofDNAandGenomeTechnology》第3版,威立布莱克维尔出版社(2012年11月28日);以及Green和Sambrook,《MolecularCloning:ALaboratoryManual》第4版,冷泉港出版社(冷泉港,纽约2012)。关于如何制备抗体的参考,见于下述文献:Greenfield,《AntibodiesALaboratoryManual》第2版,冷泉港出版社(冷泉港,纽约2013);和Milstein,《Derivationofspecificantibody-producingtissuecultureandtumorlinesbycellfusion》,欧洲免疫学杂志1976年7月,6(7):511-9;Queen和Selick,《Humanizedimmunoglobulins》,美国专利号5,585,089(1996年12月);以及Riechmann等人,《Reshapinghumanantibodiesfortherapy》,自然1988年3月24日,332(6162):323-7。
提供以下描述以使得本领域的任何技术人员能够制造和使用本发明,并在特定申请和其需求的背景下提供。本领域的技术人员将容易明白对这些实施方案的各种修改,并且本文定义的一般原则可以应用于其他实施方案而不背离本发明的精神和范围。因此,本发明不局限于所示的实施方案,而是根据与权利要求一致的最宽广的范围。
本发明涉及通过分析来自(标记或未标记的)生物分子的激光诱导光发射来表征生物材料的技术。更具体地说,本发明涉及通过对来自生物材料的激光诱导的荧光发射执行时间分辨分析和波长分辨分析来表征生物材料的方法和装置。
本文所描述的系统可被用于表征多种生理状态和疾病状态,包括但不限于,评估损伤后组织活力、检测肿瘤和癌旁组织、持续监测细胞新陈代谢、监视血浆以便优化药物治疗。系统可根据被分析的底物/标记而适用于不同的应用/用途。
系统
激发源为脉冲激光器100。来自脉冲激光器的输出脉冲以适合用于激发生物样本101而不对样本造成伤害的预定波长和功率电平(powerlevel)辐射在生物样本上。脉冲激光器由内部或外部脉冲控制器装置或数字延迟装置或触发装置102控制,其为每个激光脉冲输出提供精确的时间。此精确的时间在每个脉冲中用光电二极管检查并用模数转换器装置如NIPCIe-6220更新。在一个实施方案中,脉冲激光器发射紫外(UV)光脉冲以激发生物样本。在另一个实施方案中,脉冲激光器发射可见光脉冲或近红外光脉冲以激发生物样本。
脉冲激光器发射的激光可被连接/聚焦进光纤中,并通过光纤103(图3)或透镜系统被引导到生物样本中的特定位置。激光脉冲激发促使生物样本产生响应光发射,例如荧光发射,其典型地具有包括多个波长的宽光谱。激光诱导光发射随后被一个或多个光采集光纤或透镜所采集。在本发明的一个实施方案中,光采集光纤为一束多模式光纤103。在另一个实施方案中,光采集使用物镜完成。
随后,光采集光纤将宽带发射光导入到波长分离装置104(图2)中,其可包括一个或多个波长分离阶段。宽带发射光经历一系列波长分离处理,使得宽带信号能被分解成多个窄光谱带,其中每个窄光谱带都具有不同的中心波长。波长分辨光谱带被连接至相应的延迟装置105,其在每个光谱带朝光电探测器106行进时对每个光谱带应用预定的时间延迟。离开延迟装置的时间延迟光谱带被布置在快速响应光电倍增管上,使得包括激光的每个波长分辨的光谱带的荧光衰减曲线都能够被独立记录并瞬间分辨。应用于这些光谱带的延迟使得每个光学信号在不同时间到达多通道光电倍增管(MCP-PMT),这使得每个光谱带的衰减曲线都可与激光一起被MCP-PMT分别检测到。在一个实施方案中,来自MCP-PMT的输出可用高速数字化仪107记录并显示。在另一个实施方案中,来自MCP-PMT的输出可用示波器记录并显示。在一个实施方案中,MCP-PMT是由门控电路控制的门控MCP-PMT,使得MCP-PMT仅在MCP-PMT打开时的窄检测窗口中响应于光信号。在一个实施方案中,门控电路和脉冲控制同步,使得所有与单个激光诱导激发相关的荧光衰减曲线可在单个MCP-PMT检测窗口中记录。在一个实施方案中,通过使用基于先前延迟的校正改变激光触发和MCP-PMT门之间的延迟,从而使MCP-PMT门打开的时间与激光脉冲同步。激光器中的触发延迟(触发信号和激光的实际启动之间的延迟)用光电二极管记录。测量过的触发延迟被用来校正激光触发和MCP-PMT门之间的同步。包括但不限于雪崩光电二极管(APD)、硅PMT的其他光电探测器可被用来代替或附加于MCP-PMT。MCP-PMT的增益可自动控制。在本发明的一个实施方案中,MCP-PMT电压可基于荧光信号而不断改变。在本发明的一个实施方案中,电压改变通过分析荧光信号并在记录信号前确定改变的量来确定。
脉冲激光器103具有在元件已被外部触发后产生激光的固有延迟。在示例性实施方案中,在外部延迟后产生激光的延迟可达到但不限于85毫秒。此后以“触发延迟”提到的触发信号中的延迟可在激光的每个脉冲之间变化。为了将激光与PMT门的打开同步,发明者使用了光电二极管来检测激光脉冲的时间,将它与外部触发比较并且随后基于上一次触发延迟校正下一次触发的时间(图1B)。在图1B中,t0是当激光被触发时,t1是当激光启动时,t2是当PMT被触发时,以及t3是当PMT门打开时。通过实现此基于反馈的触发同步t2被动态地设定以保证MCP-PMT上的电压增益在荧光信号到达MCP-PMT时“启始”。使用第二光电二极管触发启动数字化仪以保证更小的数据大小。
TRLIFS系统的原理图解描绘于图1中。在不同的实施方案中,系统包括:(i)激发光纤(ExF);(ii)采集光纤(CF);(iii)多路分配器(demultiplexer)(多路分配器(demuxer)),一种波长分割装置,其提供对荧光信号的生命期的微小测量,(例如荧光信号的衰减指数);(iv)光电倍增管(例如MCP-PMT,高增益(106)、低噪音且快上升时间检测器(~80ps)如Photek210);(v)可选的前置放大器,其在信号数字转换之前在光电倍增管之后提供额外增益;(vi)数字化仪,用以将从光电倍增管接收的信号数字化,(例如,以6.4G样本/秒),从而执行数据分析(例如SP装置:108ADQTiger);以及(vii)处理和显示信号的计算机系统。
基于生物系统中的荧光团,来自生物组织的荧光信号可能非常高或者低。荧光团基于量子效能和/或激发光的吸收发出荧光发射强度,激发光的吸收可能由于特定条件如样本类型(例如,组织、血液、血浆)而受阻。为了正确记录荧光光谱,PMT增益需要被调整,使得增加的荧光发射不引起信号的饱和并且低荧光发射不导致非常低的信噪比。这可通过基于之前记录的数据迅速改变穿过MCP-PMT的电压来完成。在一个实施方案中,来自激光器的两个脉冲的荧光被(例如,使用软件)平均并分析以确定荧光信号是否太高或太低,之后穿过(负责控制PMT的增益)MCP-PMT的电压通过在高电压电源供给和计算机之间的连通来改变。假如荧光发射太高,就将电压降低,并且反之亦然,反复直到达到正确量的信噪比。只有在达到正确SNR后,真实信号才被保存并分析。
在一些实施方案中,激发光纤(例如,具有0.12NA的600微米直径的UV等级的二氧化硅芯光纤)将激光源连接到样本,以便在需要的波长下激发样本。采集光纤(例如,12条具有0.22NA的200微米直径的UV等级二氧化硅芯光纤)被封装成单个束;此束导向多路分配器(图3)。采用将多模光纤组合成单个光纤的技术将这12条光纤组合成单个光纤。(http://www.ofsoptics.com/)。在用预定波长的激光器对样本激发后,采集光纤从样本采集荧光信号,并且向多路分配器传播信号。多路分配器中的多个波长分割滤波器基于光束分割装置的波长分割传入的信号,光束分割装置包括但不限于滤波器或棱镜等。(脉冲激发后的)荧光信号脉冲通过光电倍增管、前置放大器和数字化仪传播到计算机系统,其中荧光衰减通过去卷积(之前记录的)来自记录的荧光脉冲的激光脉冲来计算。
波长分割装置
图2示出了波长分割装置(多路分配器(demultiplexer)、多路分配器(demuxer))的原理图。来自生物样本的激光诱导光发射信号(包含宽范围的波长)由光采集光纤采集,其朝波长分割装置传递发射的信号。
在本发明的一个示例性实施方案中,生物样本以大约337-350nm的波长激发。在一个实施方案中,图1和2中描述的波长分割装置(多路分配器)分割传入的信号,其波长为:小于365nm(激发波长)、365-410nm、410-450nm、450-480nm、500-550nm、550-600nm和大于600nm。如图1所示,传入的光信号被引导到波长分割装置的第一光束分割装置上,波长分割装置将传入的信号分割为波长大于约495nm和小于约495nm。在穿过第一光束分割装置后,波长大于495nm的信号用60mm焦距的双面凹透镜聚焦,并且随后穿过信号分割波长为500-560nm以及大于560nm的第二光束分割装置,最终第三光束分割器将光分割为波长为560-600nm和大于600nm的光。具有小于495nm的波长的信号还穿过60mm焦距的双面凹透镜并在通过将495nm光信号分割成波长约为410-480nm和小于410nm的第四光束分割装置前被聚焦。具有410-450nm的波长的光信号穿过将信号分割成波长约为415-450nm和450-495nm的第五光束分割装置。波长小于410nm的光信号穿过第六光束分割器并被分割成波长365-410nm和小于365nm的波长,其包含激光激发信号。通过同时记录激光和荧光,可保证精确的去卷积(deconvolution)。此多路分配器设计能够对传入的生物分子的信号进行检测,所述生物分子包括但不限于,黄素单核苷酸(FMN)核黄素、黄素腺嘌呤二核苷酸(FAD)核黄素、脂色素、内生卟啉以及如NADH和PLP-GAD的荧光分子。本文所描述的光束分割装置可以是但不限于二向色性滤光器、棱镜以及衍射光栅。
在本发明的另一个示例性实施方案中,生物样本以大约337-350nm的波长激发。在此实施方案中,波长分割装置分割传入信号,其波长为:小于400nm、415-450nm、455-480nm、400-600nm和大于500nm。在离开光采集光纤时和进入波长分割装置前,发射的光首先用准直透镜照准(collimated)。准直透镜可包括但不限于,梯度指数(GRIN)透镜或非球面透镜。照准的光束被导向到波长分割装置的第一光束分割装置上,其以波长大于约400nm和小于约400nm将传入信号分割。在穿过第一光束分割装置后,具有大于400nm波长的信号穿过第二光束分割装置,其以400-500nm和大于500nm的波长将信号分割。具有在400-500nm范围内的波长的信号穿过第三光束分割装置,其将光信号分割成波长大于450nm和小于450nm。在不同的实施方案中,波长小于450nm的信号针对生物分子的活动来被分析。这些波长对于测量生物分子而言是重要的,所述生物分子包括但不限于游离形式(或称为自由形式)和结合形式的NADH、PLP-GAD或其组合。
通过改变光束分割装置的配置,可检测多个波长的光谱带。其他波长带可用不同组的滤波器完成,这对于本领域的技术人员是显而易见的。
时间延迟光学装置
如图1中所示,来自波长分割装置的每个分解的波长组分都可以连接到相应的延迟装置并且随后在相应的延迟装置中经受预定量的延迟。在不同的实施方案中,延迟装置为具有不同长度L1、L2、L3、L4等等的光纤。在特定实施方案中,光纤的长度可为约5英尺(ft)、55英尺、115英尺、165英尺、215英尺、265英尺以及315英尺。其他长度的光纤可基于所需延迟选择,这对本领域的技术人员来说是显而易见的。为了在同一个光学检测器上从时间上分开每一个波长组分,每一个波长组分穿过不同长度的光纤,从而经历不同量的延迟。最终,每一个波长组分在不同时间到达光学检测器,这使得每个组分能被分别检测到。
除了光纤(fiber)的长度之外,光纤的其他物理性质,包括但不限于光纤的折射率,也被用于确定光纤的长度以获得特定量的延迟。因为在时域中,每个光谱组分具有持续特定时间量(例如几十纳秒)的衰减曲线,所以两个邻近的光谱组分之间的时间延迟可被设计成充分长以在时间上分开两个衰减曲线。
在本发明的一个实施方案中,光学检测器为带门控的MCP-MCP-PMT,其仅在由门控电路控制的短检测窗口中对传入光信号作出响应。带门控的窗口可被设计成足够长使得所有分解的和时间分开的波长组分将在带门控的窗口中到达MCP-PMT。因此,带门控的MCP-PMT能够捕获所有波长组分,这些波长组分是由一个检测窗口内的单个激光诱导发射引起的。被用来在时间上分开分解的光谱带的延迟装置不限于光纤,并且任何延迟装置通常都能使用。
在不同的实施方案中,样本为固体、半固体或液体生物样本。在不同的实施方案中,样本是如下物质中任意一种或多种:血液、血浆、尿液、组织、微生物、寄生虫、唾液、呕吐物、脑脊液或任何其他能够从中检测到化学标记的生物样本。
在不同的实施方案中,组织可为前列腺、肺、肾、脑、黏膜、皮肤、肝脏、肠胃道、结肠、膀胱、肌肉、乳房和/或子宫颈中的任何一个或多个。
本文所述的系统可被用来检测任何具有可检测(例如,发射的)属性的分子。在一些实施方案中,发射的属性是荧光发射。在一些实施方案中,属性是荧光发射衰减。
本文所述的多路分配器设计允许检测例如治疗试剂(标记的或未标记的)、抗体(标记的或未标记的)、毒素(标记的或未标记的)、内毒素(标记的或未标记的)、外毒素(标记的或未标记的)、肿瘤标记和/或它们的组合。在不同的实施方案中,未标记的生物分子具有固有的荧光。
本文所述的系统可以检测传入信号中生物分子,包括但不限于,黄素单核苷酸(FMN)核黄素、黄素腺嘌呤二核苷酸(FAD)核黄素、脂色素、内生卟啉以及如NADH和PLP-GAD的荧光分子。
在不同的实施方案中,治疗试剂包括化疗药剂。化疗药剂的实例包括但不限于白蛋白结合紫杉醇(nab-紫杉醇)、放线菌素(Actinomycin)、阿利类视色素(Alitretinoin)、全反式维甲酸(All-transretinoicacid)、阿扎胞苷(Azacitidine)、硫唑嘌呤(Azathioprine)、贝伐珠单抗(Bevacizumab)、贝沙罗汀(Bexatotene)、博莱霉素(Bleomycin)、硼替佐米(Bortezomib)、卡铂(Carboplatin)、卡培他滨(Capecitabine)、西妥昔单抗(Cetuximab)、顺铂(Cisplatin)、苯丁酸氮芥(Chlorambucil)、环磷酰胺、阿糖胞苷、柔红霉素、多西他赛(Docetaxel)、去氧氟尿苷、阿霉素(Doxorubicin)、表柔比星(Epirubicin)、埃博霉素(Epothilone)、埃罗替尼(Erlotinib)、依托泊苷(Etoposide)、氟尿嘧啶、吉非替尼(Gefitinib)、吉西他滨(Gemcitabine)、羟基脲、伊达比星(Idarubicin)、伊马替尼(Imatinib)、易普利单抗(Ipilimumab)、伊立替康(Irinotecan)、氮芥、美法仑(Melphalan)、巯嘌呤、甲氨蝶呤、米托蒽醌(Mitoxantrone)、阿仑单抗(Ocrelizumab)、奥法木单抗(Ofatumumab)、奥沙利铂(Oxaliplatin)、紫杉醇、帕尼妥单抗(Panitumab)、培美曲塞(Pemetrexed)、利妥昔单抗(Rituximab)、他氟泊苷(Tafluposide)、替尼泊苷(Teniposide)、硫鸟嘌呤(Tioguanine)、拓扑替康(Topotecan)、类视色素、戊柔比星(Valrubicin)、威罗菲尼(Vemurafenib)、长春碱(Vinblastine)、长春新碱(Vincristine)、长春地辛(Vindesine)、长春瑞滨(Vinorelbine)、伏立诺他(Vorinostat)、罗米地辛(Romidepsin)、5-氟尿嘧啶(5-FU)、6-巯基嘌呤(6-MP)、克拉屈滨(Cladribine)、氯法拉滨(Clofarabine)、氟尿苷(Floxuridine)、氟达拉滨(Fludarabine)、喷司他丁(Pentostatin)、丝裂霉素、伊沙匹隆(ixabepilone)、雌莫司汀(Estramustine)或它们的组合。如本文所述,化疗药剂是标记的或未标记的(例如,具有固有荧光性的试剂)。在一些实施方案中,标记是荧光标记。可与本文所述的系统、装置和方法一起使用以标记治疗试剂的荧光标记的实例包括但不限于吲哚菁绿(ICG)、姜黄素、若丹明(例如若丹明B、若丹明123、若丹明6G或其变体)、绿色荧光蛋白(GFP)、萤光素、荧光黄、量子点或它们的组合。
在不同的实施方案中,包括治疗抗体的抗体,包括但不限于3F8、8H9、阿巴伏单抗(Abagovomab)、阿昔单抗(Abciximab)、阿克托克单抗(Actoxumab)、阿达木单抗(Adalimumab)、阿德木单抗(Adecatumumab)、阿杜卡尼单抗(Aducanumab)、阿非莫单抗(Afelimomab)、阿夫土珠(Afutuzumab)、培化阿珠单抗(Alacizumabpegol)、ALD518、阿仑单抗(Alemtuzumab)、阿力罗克单抗(Alirocumab)、喷替酸阿妥莫单抗(Altumomabpentetate)、阿姆土西单抗(Amatuximab)、麻安莫单抗(Anatumomabmafenatox)、阿尼富路单抗(Anifrolumab)、安芦珠单抗(Anrukinzumab)、阿泊珠单抗(Apolizumab)、阿西莫单抗(Arcitumomab)、阿塞珠单抗(Aselizumab)、阿缇努单抗(Atinumab)、阿特立单抗(Atlizumab)、阿托木单抗(Atorolimumab)、巴匹珠单抗(Bapineuzumab)、巴利昔单抗(Basiliximab)、巴土昔单抗(Bavituximab)、贝妥莫单抗(Bectumomab)、贝利木单抗(Belimumab)、Benralizumab、柏替莫单抗(Bertilimumab)、贝索单抗(Besilesomab)、贝伐单抗(Bevacizumab)、贝茨罗特斯单抗(Bezlotoxumab)、比西单抗(Biciromab)、比玛格鲁单抗(Bimagrumab)、比伐单抗(Bivatuzumabmertansine)、兰妥莫单抗(Blinatumomab)、布鲁宗津单抗(Blosozumab)、布妥昔单抗(Brentuximabvedotin)、贝伐珠单抗(Briakinumab)、布达路单抗(Brodalumab)、卡那单抗(Canakinumab)、美坎珠单抗(Cantuzumabmertansine)、莫坎妥珠单抗(Cantuzumabravtansine)、卡普兰珠单抗(Caplacizumab)、卡罗单抗喷地妆(Capromabpendetide)、卡鲁单抗(Carlumab)、卡妥索单抗(Catumaxomab)、cBR96-多柔比星免疫偶联物(doxorubicinimmunoconjugate)、西利珠单抗(Cedelizumab)、培舍珠单抗(Certolizumabpegol)、西妥昔单抗(Cetuximab)、泊西他珠单抗(Citatuzumabbogatox)、西妥木单抗(Cixutumumab)、克莱赞珠单抗(Clazakizumab)、克立昔单抗(Clenoliximab)、克莱维足单抗(Clivatuzumabtetraxetan)、可那木单抗(Conatumumab)、可那足单抗(Concizumab)、克雷内治单抗(Crenezumab)、达西珠单抗(Dacetuzumab)、达克珠单抗(Daclizumab)、达罗土珠单抗(Dalotuzumab)、达拉土姆单抗(Daratumumab)、地莫米佐单抗(Demcizumab)、地舒单抗(Denosumab)、地莫单抗(Detumomab)、阿托度单抗(Dorlimomabaritox)、德罗图单抗(Drozitumab)、杜力戈图单抗(Duligotumab)、杜丕璐单抗(Dupilumab)、杜氏图单抗(Dusigitumab)、依美昔单抗(Ecromeximab)、依库珠单抗(Eculizumab)、埃巴单抗(Edobacomab)、依决洛单抗(Edrecolomab)、依法珠单抗(Efalizumab)、依夫单抗(Efungumab)、依德鲁单抗(Eldelumab)、埃罗妥珠单抗(Elotuzumab)、艾西莫单抗(Elsilimomab)、埃文单抗(Enavatuzumab)、培戈赖莫单抗(Enlimomabpegol)、艾诺克单抗(Enokizumab)、艾诺提克单抗(Enoticumab)、埃斯托西单抗(Ensituximab)、西依匹莫单抗(Epitumomabcituxetan)、依帕珠单抗(Epratuzumab)、厄利珠单抗(Erlizumab)、厄马索单抗(Ertumaxomab)、埃达珠单抗(Etaracizumab)、埃图力珠单抗(Etrolizumab)、艾沃单抗(Evolocumab)、艾韦单抗(Exbivirumab)、法索单抗(Fanolesomab)、法拉莫单抗(Faralimomab)、法拉图组单抗(Farletuzumab)、法希姆单抗(Fasinumab)、FBTA05、非维珠单抗(Felvizumab)、非扎奴单抗(Fezakinumab)、费希腊妥单抗(Ficlatuzumab)、芬妥木单抗(Figitumumab)、弗兰托单抗(Flanvotumab)、芳妥珠单抗(Fontolizumab)、弗罗鲁单抗(Foralumab)、福拉韦单抗(Foravirumab)、夫苏木单抗(Fresolimumab)、弗兰单抗(Fulranumab)、弗图希单抗(Futuximab)、加利昔单抗(Galiximab)、盖尼塔单抗(Ganitumab)、盖坦德单抗(Gantenerumab)、加维莫单抗(Gavilimomab)、吉妥珠单抗奥佐米星(Gemtuzumabozogamicin)、加沃坦珠单抗(Gevokizumab)、吉仁土希单抗(Girentuximab)、维德汀单抗(Glembatumumabvedotin)、戈利木单抗(Golimumab)、戈利昔单抗(Gomiliximab)、古谢夫单抗(Guselkumab)、替伊立珠单抗(Ibalizumab)、替伊莫单抗(Ibritumomabtiuxetan)、依库单抗(Icrucumab)、伊戈伏单抗(Igovomab)、IMAB362、英西单抗(Imciromab)、英戈土珠单抗(Imgatuzumab)、英克拉库单抗(Inclacumab)、依坦希单抗(Indatuximabravtansine)、英利昔单抗(Infliximab)、伊诺莫单抗(Inolimomab)、伊珠单抗奥佐米星(Inotuzumabozogamicin)、英妥木单抗(Intetumumab)、英妥木单抗(Ipilimumab)、英妥木单抗(Iratumumab)、依拓珠单抗(Itolizumab)、希凯珠单抗(Ixekizumab)、凯利昔单抗(Keliximab)、拉贝珠单抗(Labetuzumab)、拉姆布罗力珠单抗(Lambrolizumab)、拉姆帕力珠单抗(Lampalizumab)、来金珠单抗(Lebrikizumab)、来马索单抗(Lemalesomab)、乐地单抗(Lerdelimumab)、来沙木单抗(Lexatumumab)、利韦单抗(Libivirumab)、Ligelizumab、林妥珠单抗(Lintuzumab)、立鲁单抗(Lirilumab)、罗德希珠单抗(Lodelcizumab)、劳乌土珠单抗(Lorvotuzumabmertansine)、鲁卡木单抗(Lucatumumab)、鲁昔单抗(Lumiliximab)、马帕木单抗(Mapatumumab)、马格土希单抗(Margetuximab)、马司莫单抗(Maslimomab)、马妥珠单抗(Matuzumab)、美力姆单抗(Mavrilimumab)、美泊利单抗(Mepolizumab)、美替木单抗(Metelimumab)、米拉珠单抗(Milatuzumab)、明瑞莫单抗(Minretumomab)、米妥莫单抗(Mitumomab)、莫格穆里单抗(Mogamulizumab)、莫罗木单抗(Morolimumab)、莫他珠单抗(Motavizumab)、莫希土姆单抗(Moxetumomabpasudotox)、莫罗单抗-CD3(Muromonab-CD3)、他那可单抗(Nacolomabtafenatox)、纳米路单抗(Namilumab)、他那莫单抗(Naptumomabestafenatox)、纳瑞特单抗(Narnatumab)、那他珠单抗(Natalizumab)、奈巴库单抗(Nebacumab)、奈昔木单抗(Necitumumab)、奈瑞莫单抗(Nerelimomab)、耐西维单抗(Nesvacumab)、尼妥珠单抗(Nimotuzumab)、妮威禄单抗(Nivolumab)、巯诺莫单抗(Nofetumomabmerpentan)、奥卡土珠单抗(Ocaratuzumab)、奥瑞珠单抗(Ocrelizumab)、奥度莫单抗(Odulimomab)、奥法木单抗(Ofatumumab)、奥拉图单抗(Olaratumab)、奥鲁凯珠单抗(Olokizumab)、奥马珠单抗(Omalizumab)、欧那土珠单抗(Onartuzumab)、欧土希珠单抗(Ontuxizumab)、莫奥珠单抗(Oportuzumabmonatox)、奥戈伏单抗(Oregovomab)、奥泰单抗(Orticumab)、奥昔珠单抗(Otelixizumab)、奥特乐土珠单抗(Otlertuzumab)、欧西鲁单抗(Oxelumab)、欧赞尼珠单抗(Ozanezumab)、欧咗立珠单抗(Ozoralizumab)、帕昔单抗(Pagibaximab)、帕利珠单抗(Palivizumab)、帕利珠单抗(Panitumumab)、帕尼库单抗(Pankomab)、帕诺库单抗(Panobacumab)、帕萨土珠单抗(Parsatuzumab)、帕考珠单抗(Pascolizumab)、帕特立珠单抗(Pateclizumab)、帕图单抗(Patritumab)、帕尼单抗(Pemtumomab)、培拉凯珠单抗(Perakizumab)、培妥珠单抗(Pertuzumab)、培克珠单抗(Pexelizumab)、皮地利珠单抗(Pidilizumab)、平尼土珠单抗(Pinatuzumabvedotin)、平妥莫单抗(Pintumomab)、普拉库鲁单抗(Placulumab)、普拉土珠单抗(Polatuzumabvedotin)、珀珠单抗(Ponezumab)、普立昔单抗(Priliximab)、普陀希单抗(Pritoxaximab)、普立木单抗(Pritumumab)、PRO140、坤立珠单抗(Quilizumab)、雷库图单抗(Racotumomab)、雷德图单抗(Radretumab)、雷韦单抗(Rafivirumab)、雷莫芦单抗(Ramucirumab)、雷珠单抗(Ranibizumab)、雷昔库单抗(Raxibacumab)、瑞加韦单抗(Regavirumab)、瑞利珠单抗(Reslizumab)、利妥木单抗(Rilotumumab)、利妥昔单抗(Rituximab)、罗妥木单抗(Robatumumab)、罗勒杜单抗(Roledumab)、罗姆苏珠单抗(Romosozumab)、罗利珠单抗(Rontalizumab)、罗维珠单抗(Rovelizumab)、鲁利珠单抗(Ruplizumab)、沙玛立珠单抗(Samalizumab)、沙鲁单抗(Sarilumab)、沙妥莫单抗(Satumomabpendetide)、司库钦单抗(Secukinumab)、司瑞斑图单抗(Seribantumab)、斯图希单抗(Setoxaximab)、司韦单抗(Sevirumab)、SGN-CD19A、SGN-CD33A、西罗珠单抗(Sibrotuzumab)、西法木单抗(Sifalimumab)、西图希单抗(Siltuximab)、西姆土珠单抗(Simtuzumab)、西利珠单抗(Siplizumab)、希瑞库单抗(Sirukumab)、苏兰珠单抗(Solanezumab)、苏力图单抗(Solitomab)、松普希珠单抗(Sonepcizumab)、松妥珠单抗(Sontuzumab)、司他芦单抗(Stamulumab)、硫索单抗(Sulesomab)、索维单抗(Suvizumab)、他贝鲁单抗(Tabalumab)、他珠单抗(Tacatuzumabtetraxetan)、他度珠单抗(Tadocizumab)、他利珠单抗(Talizumab)、他尼珠单抗(Tanezumab)、帕他莫单抗(Taplitumomabpaptox)、替非珠单抗(Tefibazumab)、阿替莫单抗(Telimomabaritox)、替妥莫单抗(Tenatumomab)、替奈昔单抗(Teneliximab)、替利珠单抗(Teplizumab)、替普单抗(Teprotumumab)、TGN1412、替西木单抗(Ticilimumab)(曲美木单抗(tremelimumab))、替加珠单抗(TigatuzumabTildrakizumab)、TNX-650、托珠单抗(Tocilizumab)(atlizumab)、托利珠单抗(Toralizumab)、托西莫单抗(Tositumomab)、托维图单抗(Tovetumab)、曲洛青木单抗(Tralokinumab)、曲妥珠单抗(Trastuzumab)、TRBS07、曲加立珠(Tregalizumab)、曲美木单抗(Tremelimumab)、西莫白介素单抗(Tucotuzumabcelmoleukin)、妥韦单抗(Tuvirumab)、乌波利土西单抗(Ublituximab)、乌瑞鲁单抗(Urelumab)、乌珠单抗(Urtoxazumab)、优特克单抗(Ustekinumab)、伐提克图单抗(Vantictumab)、伐利昔单抗(Vapaliximab)、维特立珠单抗(Vatelizumab)、维多珠单抗(Vedolizumab)、维妥珠单抗(Veltuzumab)、维帕莫单抗(Vepalimomab)、维西库单抗(Vesencumab)、维西珠单抗(Visilizumab)、伏洛昔单抗(Volociximab)、伏妥土珠单抗(Vorsetuzumabmafodotin)、伏妥昔单抗(Votumumab)、扎芦木单抗(Zalutumumab)、扎木单抗(Zanolimumab)、扎土希单抗(Zatuximab)、齐拉木单抗(Ziralimumab)、阿佐莫单抗(Zolimomabaritox)。如本文所述,抗体可标记或未标记。在一些实施方案中,标记是荧光标记。可与本文所述的系统、装置和方法一起使用以标记治疗试剂的荧光标记的实例包括但不限于吲哚菁绿(ICG)、姜黄素、若丹明(例如,若丹明B、若丹明123、若丹明6G或其变体)、绿色荧光蛋白(GFP)、萤光素、荧光黄、量子点或其组合。
在不同的实施方案中,毒素包括但不限于阿尔法毒素、炭疽毒素、细菌毒素、白喉毒素、外毒素、百日咳毒素、志贺毒素、类志贺毒素、耐热肠毒素、通道形成毒素、霉菌毒素、霍乱毒素、蝎子毒液、氯毒素和/或破伤风毒素。如本文所述,抗体可标记或未标记。在一些实施方案中,标记是荧光标记。可与本文所述的系统、装置和方法一起使用以标记治疗试剂的荧光标记的实例包括但不限于吲哚菁绿(ICG)、姜黄素、若丹明(例如,若丹明B、若丹明123、若丹明6G或其变体)、绿色荧光蛋白(GFP)、萤光素、荧光黄、量子点或其组合。
在一些实施方案中,蛋白质(例如,细胞表面蛋白)可用本文所述的系统检测到。在一些实施方案中,蛋白质可用结合到细胞表面标记的抗体(例如,标记的或未标记的抗体)检测。在一些实施方案中,蛋白质可用结合到目标蛋白质的siRNA(例如,标记的或未标记的siRNA)检测。可用本文所述的系统检测到的蛋白质的实例包括但不限于4-1BB、5T4、腺癌抗原、甲胎蛋白、膜联蛋白(例如,膜联蛋白A1、A2、A5)、BAFF、B型淋巴瘤细胞、C242抗原、CA-125、碳酸酐酶9(CA-IX)、C-MET、CCR4、CD152、CD19、CD20、CD200、CD22、CD221、CD23(IgE受体)、CD28、CD30(TNFRSF8)、CD33、CD4、CD40、CD44v6、CD51、CD52、CD56、CD74、CD80、CEA、CNTO888、CTLA-4、DR5、EGFR、EpCAM、CD3、FAP、纤连蛋白外结构域B、叶酸受体1、GD2、GD3神经节苷脂、糖蛋白75、GPNMB、HER2/neu、HGF、人类传播因子受体激酶、IGF-1受体、IGF-I、IgG1、L1-CAM、IL-13、IL-6、类胰岛素生长因子I受体、整合蛋白α5β1、整合蛋白αvβ3、MORAb-009、MS4A1、MUC1、黏蛋白CanAg、N-羟乙酰神经氨酸、NPC-1C、PDGF-Rα、PDL192、磷脂酰丝氨酸、前列腺癌细胞、RANKL、RON、ROR1、SCH900105、SDC1、SLAMF7、TAG-72、腱生蛋白C、TGFβ2、TGF-β、TRAIL-R1、TRAIL-R2、肿瘤抗原CTAA16.88、VEGF-A、VEGFR-1、VEGFR2或波形蛋白。其他的实例包括但不限于AOC3(VAP-1)、CAM-3001、CCL11(嗜酸细胞激活趋化因子-1)、CD125、CD147(基础免疫球蛋白)、CD154(CD40L)、CD2、CD20、CD23(IgE受体)、CD25(IL-2型受体的α链)、CD3、CD4、CD5、IFN-α、IFN-γ、IgE、IgEFc区域、IL-1、IL-12、IL-23、IL-13、IL-17、IL-17A、IL-22、IL-4、IL-5、IL-5、IL-6、IL-6受体,整合蛋白α4、整合蛋白α4β7,大羊驼、LFA-1(CD11a)、MEDI-528、肌生成抑制蛋白、OX-40、rhuMAbβ7、硬化蛋白(scleroscin)、SOST、TGFβ1、TNF-α、VEGF-A、β淀粉样蛋白、MABT5102A、L-1β、CD3、C5、心肌肌球蛋白、CD41(整合素α-IIb)、血纤维蛋白II、β链、ITGB2(CD18)、鞘氨醇-1-磷酸、炭疽毒素、CCR5、CD4、聚集因子A、巨细胞病毒、巨细胞病毒糖蛋白B、内毒素、大肠杆菌蛋白、乙肝表面抗原、乙肝病毒、HIV-1、Hsp90、流感A血凝素、脂磷壁酸、绿脓杆菌、狂犬病毒糖蛋白、呼吸道合胞病毒、TNF-α、路易斯Y和CEA抗原、Tag72、叶酸结合蛋白或其组合。在一些实施方案中,蛋白质是标记的。在一些实施方案中,标记是荧光标记。可与本文所述的系统、装置和方法一起使用以标记治疗试剂的荧光标记的实例包括但不限于吲哚菁绿(ICG)、姜黄素、若丹明(像若丹明B、若丹明123、若丹明6G或其变体)、绿色荧光蛋白(GFP)、萤光素、荧光黄、量子点或其组合。
方法
基于激发波长的组合以及多路分配器中光束分割装置的波长分割,不同分子的荧光性可以被分析(图4)。例如,通过样本在350nm波长下的激发和多路分配器中适当分割波长的光束分割装置,可以对如下生物分子的荧光性进行分析:包括但不限于,PLG-GAD(吡哆醛-5’-磷酸盐(PLP)谷氨酸脱羧酶(GAD))、结合的NADH和游离的NADH。或者,基于440nm波长处对样本的激发和多路分配器中适当分割波长的光束分割装置,可以对例如FAD(黄素腺嘌呤二核苷酸)、FMN(黄素单核苷酸)和卟啉的生物分子的荧光性进行分析。
本发明提供了采用本文所述的TRLIFS系统对有需要的受试者在受伤后的组织活力进行测定的方法。所述方法包括:使用本文所述系统测量从生物分子(例如NADH氧化还原状态)发射的荧光,其中荧光信号的变化表示组织活力。在一些实施方案中,生物分子的荧光信号的变化是相对于对照(正常)受试者,受试者的生物分子的荧光信号的增加。在一些实施方案中,生物分子的荧光信号的变化是相对于对照(正常)受试者,受试者的生物分子的荧光信号的减少。在一种实施方案中,NADH氧化还原状态的变化表示组织活力。在一种实施方案中,受试者的NADH荧光性的增加表示NADH积累和较差组织活力。
本发明还提供了使用本文所述系统对有需要的受试者的细胞新陈代谢进行监测的方法。所述方法包括:使用本文所述TRLIFS系统测量从生物分子(例如NADH氧化还原状态)发射的荧光,其中荧光信号的变化指示细胞新陈代谢。在一些实施方案中,生物分子的荧光信号的变化是相对于对照(正常)受试者,受试者的生物分子的荧光信号的增加。在一些实施方案中,生物分子的荧光信号的变化是相对于对照(正常)受试者,受试者的生物分子的荧光信号的减少。在一种实施方案中,NADH荧光可被用于监测细胞新陈代谢。细胞新陈代谢可被持续或定期监视。在不同的实施方案中,例如,对细胞新陈代谢的持续监测可以评估细胞在缺血条件下的活力以及易损性,药物(例如,在药物研发或对治疗窗口进行优化期间)对于细胞新陈代谢的效果以及/或者同时监视pH值和氧气水平以确定细胞的新陈代谢状态。
如本文所述,本发明还提供了使用本文所述的TRLIFS系统检测肿瘤的方法。
实施例
实施例1
细胞新陈代谢的持续监测
本文所述的系统允许以极微小尺度持续监视NADH水平变化以测定新陈代谢状态的变化,从而对氧气消耗、神经保护药物效果等作出响应(图1和5)。
烟酰胺腺嘌呤二核苷酸(NADH)与在有氧呼吸中的用于ATP产生的氧化还原反应有关。NADH在糖酵解和柠檬酸(TCA)循环中在线粒体中产生。NADH在线粒体膜上被氧化为NAD+,在此过程中产生ATP。此过程在包括但不限于由于中风的局部缺血的条件下被中断。在低氧条件下,NADH在细胞中积聚,并且持续的缺氧会引起细胞死亡,导致NADH的完全崩溃。NADH水平的这些变化允许评估细胞在局部缺血条件下的活力和易损性。通过测量来自NADH的荧光发射可以对NADH水平的波动进行评估。NAD+和NADH都对UV光谱具有强吸收性,但是它们的荧光特性不同。依赖于NADH的结合(与细胞色素)状态而非游离状态,NADH展示在紫/蓝带约440/460nm的波长上的强荧光性。荧光性的实时测量允许监测NADH水平的变化,评估NADH的新陈代谢状态,从而监测细胞新陈代谢。
为了激发组织,具有Q开关的以350nm的波长发射的Nd:YaG激光器被使用,以1KHz随着400ps的脉冲宽度(FWHM)运行(型号为TeemPhotonicsPNVM02510的激光器)。每个脉冲的总能量不超过5μJ,这防止NADH的光致漂白。激发光用定制的三叉光探针传递到组织。探针包括用来传递激发光的中心600微米光纤,其被十二根用来采集荧光的200微米光纤环绕(图3)。来自12条采集光纤中的每个其他光纤都被结合到一起形成两个通道。一个采集通道/束连接到分光仪(由美国OceanOptics公司制造,型号是Maya),其每100ms测量荧光光谱,而另一个通道/束连接到光束分割器(多路分配器)。光束分割器以452nm的波长分开有效的游离和结合荧光,其都被MCP-PMT和分光仪记录下来。
在OR中处死动物后,兔脑被移除,并在富含冷氧的K氏液中运输到实验室。皮质被分离并放在K氏液中,其具有95%氧气和5%二氧化碳的混合物的持续鼓泡以使组织存活。探针被调整到组织上以便记录图5中示出的荧光。基线NADH(结合和游离)被记录直到来自组织的荧光平衡且稳定。在接近30分钟后,添加测量剂量的50nM鱼藤酮,其在线粒体中阻断NADH与细胞色素的结合。额外浓度的鱼藤酮每10分钟添加。
不同浓度的鱼藤酮对于兔脑组织的影响被记录(图6)。结果显示,游离NADH和结合NADH的浓度都能实时(每~100ms)绘制并且对外部刺激的响应被记录下来。图6示出NADH荧光水平在超过2小时时期内的连续曲线。在添加50nM浓度的鱼藤酮到溶液中时,由于NADH的消耗和随后的积聚被阻断,NADH水平的增加被预料地观察到。随着鱼藤酮的浓度增加,NADH荧光如预料地增加。在80分钟时,持续穿过液体鼓泡的气体被停止,并且随后氧气供给一旦恢复,重新开始允许评估缺氧对于组织中NADH积聚以及其随后消耗的影响。这展示了本文所述的TRLIFS系统实时监测新陈代谢状态的能力。
实施例2
确定组织损伤后的生存能力
在局部缺血性发作之后,记录脑中一大片区域的NADH水平允许对可成活细胞数量进行评估,可成活细胞可能由于缺氧处于休克中但可能没有经历细胞凋亡而因此可以救活。这些细胞形成熟知为半影的大块区域,并且中风治疗的重要目标是在救活尽可能多的神经元的过程中减少半影尺寸。监测整个半影区域的NADH允许评估具有上述治疗设计目的的不同干预的效果。
为了激发组织,具有Q开关的以350nm的波长发射的Nd:YaG激光器被使用,以1KHz随着400ps的脉冲宽度(FWHM)运行(TeemPhotonicsPNVM02510)。每个脉冲的总能量不超过5μJ,这防止NADH的光致漂白。激发光用定制的三叉光探针传递到组织。探针包括用来传递激发光的中心600微米光纤,其被十二根用来采集荧光的200微米光纤环绕。来自12条采集光纤中的每个其他光纤都被结合到一起形成两个通道。一个采集通道/束连接到分光仪(OceanOptics,Maya),其每100ms测量荧光光谱,而另一个通道/束连接到光束分割器(多路分配器)。
兔脑中风模型被使用,其中兔脑中的中风通过在大脑动脉注射凝块引起。兔子在测试神经学损伤之后被处死。大脑被移除并在冷氧气饱和的K氏液中被运输到实验室中。在实验室中,梗塞的皮质与大脑的其他部分分离,并被放置在K氏液(Kreb-Ringersolution)中,伴随着95%氧气和5%二氧化碳混合物的鼓泡。单个读数被从皮质边缘记录并且探针被移过皮质的表面,如图7中所示。从组织样本中记录荧光强度。组织样本浸没于TTC(2,3,5-氯化三苯基四氮唑)的溶液中,所述溶液当被可成活细胞吸收时使细胞变红。TTC是目前用于测试可成活细胞的黄金标准。将TTC染色组织与记录的荧光强度比较。
可以观察到NADH自发荧光的从健康组织(图7中染红区域)到死亡组织(图7中未染色区域)的平滑的梯度。我们还注意到,并非如TTC染色所见的从可成活到死亡组织的突然改变,荧光强度(图7)逐渐改变,这暗示了在指示死亡的区域存在可成活细胞。
实施例3
使用荧光来测定血浆中的药物/代谢物水平
一些抗癌药物在高剂量是有毒的,而在低剂量又会失去其功效。由于身高、体重、新陈代谢和种族的不同,药物最有效的最理想的药物血浆浓度(治疗窗口)在患者之中变化。尽管有这些不同,如今的药物剂量是基于患者的体重和标准药代动力学曲线计算的。测定血浆药物水平的快速廉价的方法可以优化用于单个患者的剂量。血浆的药物水平可用荧光光谱学检测。众所周知,一些抗癌药物如甲氨蝶呤具有荧光属性。本申请人证明使用本文所述的TRLIFS系统,改变甲氨蝶呤(MTX)在琼脂中的浓度(图8),导致MTX的荧光性的相应变化。
为了激发琼脂凝胶,具有Q开关的以350nm的波长发射的Nd:YaG激光器被使用,以1KHz随着400ps的脉冲宽度(FWHM)运行(TeemPhotonicsPNVM02510)。每个脉冲的总能量不超过5μJ,这防止NADH的光致漂白。激发光用定制的三叉光探针传递到凝胶。探针包括用来传递激发光的中心的600微米光纤,其被十二根用来采集荧光的200微米光纤环绕。来自12条采集光纤中的每个其他光纤都被结合到一起形成两个通道。一个采集通道/束移动到分光仪(OceanOptics,Maya),其每100ms测量荧光光谱,而另一个通道/束连接到光束分割器(多路分配器)。
MTX的连续稀释液(25μg/ml至25ng/ml)在琼脂凝胶中制备。当曝露于紫外光时,MTX改变成更加具有荧光性的形式。在曝露于紫外光时,荧光形式积聚。为了检测荧光形式,允许从低荧光到荧光形式的变化发生直到达到饱和水平。最终荧光强度被记录并与浓度比较。在20分钟的紫外光曝露后的MTX的荧光强度良好指示MTX在琼脂凝胶中的浓度,如图9中所示。
实施例4
肿瘤检测
激光诱导荧光光谱(LIFS)代表用于活体内诊断中有前途的新的附加技术。荧光光谱涉及激发组织中的内在荧光团(无标记)和记录发射。可以以两种方式应用荧光光谱,稳定状态或时间分辨荧光光谱。时间分辨测量将荧光强度衰减按照生命周期分解,并因此提供关于荧光强度衰减的潜在动力学的附加信息。时间分辨测量还独立于如下因素:例如被组织固有荧光团(例如,血液)吸收,光漂白或任何其他可能影响荧光强度的条件。通过测量荧光衰减特征,这反映了不同荧光分子的弛豫动力学(relaxationdynamics)中的不同,时间分辨测量能够分解重叠光谱以及提升荧光测量的特异性。
申请人证明在患者中,本文所述的TR-LIFS系统能够在手术中将胶质肿瘤(重度和轻度)与周围正常脑组织区分开。此研究可确立TR-LIFS增强神经外科医生-神经病理学家团队在手术中迅速辨别肿瘤和正常脑的能力的可能性。
使用仪器:实验通过允许以光谱分辨方式进行荧光寿命测量的仪器设置来执行。在图1中示出了本装置的光学和电子布局的原理图。简略地,其包括:a)脉冲的具有Q开关的Nd:YaG激光器(TeemPhotonics,型号TeemPhotonicsPNVM02510,λ=350nm,脉冲宽度=400psFWHM,脉冲速率=1KHz),其被用作激发源;b)定制的可灭菌的三叉光纤探针(美国Fiberguide公司,新泽西州(NJ));c)带门控的多通道板光电倍增管(MCP-PMTPhotek公司,英国,型号210,上升时间=80ps),其具有可选的快速前置放大器(Photek公司,英国,型号PA200-10,2GHz);e)数字化仪(型号是ADQ-108,SPDevices公司,斯维登,7千兆样本/秒)(ADQ-108,SPDevices,Sveden,7Gsamples/sec);以及f)笔记本电脑;g)定制的多路分配器,如图1中所示,以及外围的电子设备。当仪器被包含在局部改造以适应个别装置的标准内窥镜匣(70×70×150cm3)中时,其允许可移动性。为了保证来自所用的电子设备的低噪音水平,如高电压电源和前置放大器电源,所有仪器都用医疗等级的隔离变压器(ISB-170A)与电力网供电屏蔽开。
递送导管:用定制的二叉可灭菌探针实施光递送和采集。探针包括0.11数值孔径(NA)未曝光过度的二氧化硅/二氧化硅步进指数纤维(Fiberguide公司,新泽西,NJ)。其具有600μm核心直径的中心激发光纤,由十二根200μm核心直径的光纤的采集环包围。所有采集光纤都被结合到一起并组成单个600微米光纤。激发光纤和采集光纤之间中心到中心的分隔为480μm。除了7cm的末端部分是刚性不锈钢管的,探针在其整个长度(3米)上是柔性的。这有利于了探针的装备和显微操作。在对立面具有两个裂缝的垫片被添加在探针的远侧端部的前方。这允许探针在与组织保持固定距离时与组织接触。垫片上的两个裂缝使得外科医师能够采用抽滤管来维持清晰视野。当采集通道的远侧端部形成直线以便促进连接到光谱仪时,用标准SMA连接器将激光连接进探针的照明通道。在组织激发后,发射的荧光被束一采集并导入到多路分配器的入口裂缝并且通过束二导入到分光仪。信号随后被MCP-PMT检测到,由快速前置放大器放大,并最后被数字示波器以8位分辨率数字化。系统的总时间分辨率为大约150ps。
光纤探针在垫片的帮助下被定位在暴露的脑组织样本上方3mm,以优化探针光采集效率(如之前所报告的)并在组织上方使探针稳定。每个样本的时间分辨发射都被记录在七个分别的波长带(355(<365nm))、365-410nm、415-450nm、450-490nm、500-560nm、560-600nm和>600nm)光谱范围里。用于样本激发的激光的能量输出(在光纤的尖端)被调整到5.0μJ/脉冲。在光谱学分析后,组织在精确的位置被活组织切片检查并送到病理学研究。
每个切片样本都被固定在10%缓冲福尔马林中。组织样本被固定在载玻片上并被H&E染色。所有切片样本都被病理学家研究并与初始荧光光谱测量结果相关联。组织结构上,基于WHO分级,胶质瘤被分类为低等级:少突神经胶质瘤(Oligodendroglioma)、混合型少突星形细胞瘤(oligodendroastrocytoma)、扩散星形细胞瘤(diffuseastrocytoma)(WHO等级II);中间等级:间变型星形细胞瘤(anaplasticastrocytoma)(WHO等级III);以及高等级:间变型少突神经胶质瘤(anaplasticoligodendroglioma)、间变型少突星形细胞瘤(anaplasticoligodendroglioma)和多形性成胶质细胞瘤(glioblastomamultiforme)(等级III-IV)。出于在此研究中光谱分类的目标,神经胶质瘤被分类为低等级神经胶质瘤(LGG)(等级I和II)和高级神经胶质瘤(HGG)(等级III和IV)。
TR-LIFS数据分析:在TR-LIFS的背景下,固有荧光脉冲响应函数(IRF),h(n),描述荧光衰减的实际动力学。IRF由测量的输入激光脉冲从测量的荧光响应暂态的数值去卷积获得。拉盖尔展开技术(Laguerreexpansiontechnique)被用于去卷积。出于一组理由,优于更常规多项指数曲线拟合来选择拉盖尔展开技术。它允许荧光IR的更快去卷积。由于拉盖尔基础是标准正交的,它提供衰减函数的唯一和完整的展开。此技术也是无参数的,因此不需要衰减函数形式的预先假设。因此,这允许将荧光系统近似用于如生物组织的未知和复杂缓冲动力学法。此方法允许从实验输入-输出数据来直接恢复动力学系统的固有属性。所述技术使用标准正交的拉盖尔函数展开IRF并估算拉盖尔展开系数(LEC)。标准的荧光光谱通过将离散强度值除以最大发射时的强度值来获得。另外,为了表征荧光衰减的时间动力学,使用两组参数:1)平均寿命(τλ),计算为IRF衰减到其最大值的内插时间,以及2)相应LEC的标准值。因此,从每个样本作为发射波长λE的函数的荧光的完整描述通过一组光谱参数在不同波长下的变化来给出(发射强度-Iλ,荧光发射的平均寿命-τfλ,以及拉盖尔系数LECf)。用于表征荧光衰减的此分析性方法最近由我们的研究团队开发出并在别处详细描述。申请人能够恢复寿命和拉盖尔系数值。
上述各种方法和技术提供若干实现本申请的途径。当然,应理解根据本文中描述的任何特定实施方案不一定可以实现所述的所有目标或优势。因此,例如,本领域技术人员将认识到,所述方法可以以实现或最优化如本文中教导的一个优势或一组优势的方式进行,而不一定需要实现本文中教导或指出的其他目标或优势。本文中提到多种替代方案。应理解,一些优选实施方案专门地包括一个、另一个或几个特征,而其他的实施方案专门地排除一个、另一个或几个特征,而又一些其他的实施方案通过包括一个、另一个或几个有利的特征而弱化特定的特征。
此外,本领域技术人员将认识到来自不同实施方案的各种特征的适用性。类似地,本领域的普通技术人员可以以各种组合使用上述各种元素、特征和步骤以及各个这样的元素、特征或步骤的其他已知等效物来执行根据本文中描述的原理的方法。在不同的实施方案中,所述各元素、特征和步骤中的一些将被专门地包括而其他的则被专门地排除。
虽然已经在某些实施方案和实施例的上下文中公开了本申请,但是本领域技术人员将理解,本申请的实施方案将专门公开的实施方案扩展到其他替代实施方案和/或用途以及其修改和等效物。
在一些实施方案中,在描述本申请的特定实施方案的环境(特别是在某些下列权利要求的环境中)中使用的术语“一个”和“一种”和“所述”和类似的引用可以理解为涵盖单数和复数。本文中列举的数值范围仅仅希望作为单独提及落入范围中的每个独立数值的简写方法。除非本文另外指明,否则每个单独数值均并入在本说明书中,如同本文单独列举每个单独数值一样。可按任何合适的顺序来执行本文所述的所有方法,除非本文另外指明或明显地与上下文矛盾。使用相对于本文中的某些实施方案提供的任何和所有实例或示例性语言(例如,“如”)的目的仅仅是希望更好地阐明本申请而不对另外要求的本申请施加限制。不应该将说明书中的语言理解为表示对实践本发明必需的任何未要求的要素。
本文中描述了本申请的优选实施方案,包括发明人已知的实现本申请的最佳方式。通过阅读上述描述,那些优选实施方案的演变形式对普通技术人员而言将变得显而易见。预计本领域技术人员可以适当地使用这些演变形式,并且可以用本文中特定描述的其他方式实践本应用。因此,经适用的法律许可,本申请的许多实施方案包括在此附加的权利要求中叙述的所有标的物的改良形式和等价物。此外,除非另外在文中指出或明显与上下文矛盾,否则本申请涵盖所有可能的演变形式的上述元素的任何组合。
本文中提及的所有专利、专利申请、专利申请公布和其他材料(如论文、书籍、说明书、出版物、记录、事物和/或类似的东西)均在此通过引用的方式全部并入本文以达到所有目的,与上述文件相关的任何起诉文档记录、与本文件不一致或冲突的任何上述文件或对迟早与本文件相关的权利要求书的广泛范畴有限定作用的任何上述文件除外。举例来说,如果任何并入材料相关的与本文件相关的描述、定义和/或术语使用之间有任何不一致或冲突,那么本文件中的描述、定义和/或术语使用应当优先。
最后,应理解本文中公开的本申请的实施方案是本申请的实施方案的原理的说明。可以使用的其他修改可以在本申请的范畴之内。因此,举例来说,但不限制,可以根据本文中的教导使用本申请的实施方案的替代构造。因此,本申请的实施方案不严格限于如图所示和所述的实施方案。
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Claims (16)
1.一种通过分析在激发时来自生物样本的荧光发射来表征所述生物样本的系统,所述系统包括:
(i)激光源,其通过激发光纤(ExF)连接到生物样本,其中所述激光器被配置成用预定波长的激光脉冲来辐射所述生物样本,以促使所述生物样本产生响应荧光信号;
(ii)采集光纤(CF),其中所述CF从所述样本采集所述荧光信号,并将所述信号传递到多路分配器;
(iii)多路分配器,其包括波长分割滤波器以便将来自所述CF的信号按预定波长分割以获得光谱带;以及
(iv)光学延迟装置。
2.如权利要求1所述的系统,其还包括光电倍增管,所述光电倍增管包括前置放大器以便在将所述信号数字化之前、在所述信号穿过所述光电倍增管之后将所述信号放大。
3.如权利要求2所述的系统,其还包括数字化仪,以便将从所述光电倍增管接收到的所述信号数字化;以及计算机系统,以处理并显示所述信号。
4.如权利要求1所述的系统,其中所述光学延迟装置适于将来自所述多路分配器的所述光谱带连接至所述延迟装置中,使得所述光谱带经过所述延迟装置并且在所述光谱带经过延迟装置时引入控制的时间延迟,以便在单次激发中捕获多个波长。
5.如权利要求1所述的系统,其中所述采集光纤形成单个束。
6.如权利要求1所述的系统,其中所述多路分配器以355nm(小于360nm)、365-410nm、410-450nm、450-480nm、500-560nm、560-600nm和大于600nm的波长来分割输入信号。
7.一种通过分析在激发时生物样本发射的荧光信号来表征所述生物样本的方法,所述方法包括:
(i)用预定波长的激光脉冲辐射所述生物样本以促使所述生物样本产生响应荧光信号;
(ii)从所述样本采集所述荧光信号;
(iii)将所述信号以预定波长分割以获得光谱带;
(iv)使所述光谱带通过时间延迟机制;
(v)获得所述时间延迟的光谱带;以及
(vi)处理所述时间延迟的光谱带的信号。
8.如权利要求7所述的方法,其中处理所述信号包括:使所述信号经过数字化仪以便将从光电倍增管接收的所述信号数字化,并送到计算机系统以处理并显示信号。
9.如权利要求7所述的方法,其中分割所述信号包括:用多路分配器以355nm(小于365nm)、365-410nm、410-450nm、450-480nm、500-560nm、560-600nm和大于600nm的波长分割输入信号。
10.如权利要求7所述的方法,其中所述荧光信号由生物分子发射。
11.如权利要求10所述的方法,其中所述生物分子为下述中的任一种或多种:PLP-GAD(吡哆醛-5’-磷酸盐(PLP)谷氨酸脱羧酶(GAD))、结合NADH、游离NADH、黄素单核苷酸(FMN)核黄素、黄素腺嘌呤二核苷酸(FAD)核黄素、脂色素、内生卟啉中或它们的组合。
12.一种用于确定组织活力的方法,所述方法包括用权利要求7所述的方法分析所述组织中的生物分子发射的荧光信号,其中相对于正常受试者,所述受试者中的所述生物分子的荧光增加指示较差的组织活力。
13.一种持续监测细胞新陈代谢的方法,所述方法包括用权利要求7所述的方法分析发射的荧光信号。
14.一种用于确定血浆中药物或代谢物水平的方法,所述方法包括用权利要求7所述的方法分析生物分子发射的荧光信号。
15.如权利要求14所述的方法,其中所述生物分子为NADH。
16.如权利要求15所述的方法,其中NADH为游离形式、结合形式或它们的组合。
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