CN1742094A - 基于二氧化硅的荧光纳米颗粒 - Google Patents

基于二氧化硅的荧光纳米颗粒 Download PDF

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CN1742094A
CN1742094A CNA200380109241XA CN200380109241A CN1742094A CN 1742094 A CN1742094 A CN 1742094A CN A200380109241X A CNA200380109241X A CN A200380109241XA CN 200380109241 A CN200380109241 A CN 200380109241A CN 1742094 A CN1742094 A CN 1742094A
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U·B·威斯纳
H·奥
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Abstract

本发明提供了纳米颗粒组合物，所述组合物包括，例如包括一种荧光硅烷化合物的核；和于核上的二氧化硅壳体。还提供了制备纳米颗粒组合物的方法，所述纳米颗粒组合物包括荧光纳米颗粒、复合荧光纳米颗粒、具有治疗剂的复合荧光纳米颗粒以及与分析物偶合或结合的复合荧光纳米颗粒。还提供了以下方法：用于检测复合荧光纳米颗粒；用于将键合的荧光纳米颗粒与所研究的细胞组分结合，并记录或监测细胞组件的移动；用于通过将治疗剂与连接荧光纳米颗粒结合，并将结合物接触或给药至细胞或有机体，以提高治疗剂的治疗性能；用于制备并在例如诊断剂中使用荧光纳米颗粒，以检测多种分析物等应用。

Description

基于二氧化硅的荧光纳米颗粒
本申请要求于2002年11月26日提交的序列号为10/306614的非临时性美国专利申请的优先权。
技术领域
本发明总体上涉及纳米颗粒，更具体地说，涉及复合荧光纳米颗粒(ligated-fluorescent nanoparticle)、制备复合荧光纳米颗粒的方法以及将复合荧光纳米颗粒用作生物标志物(biomarker)的方法，例如，监测细胞系统上或其中的细胞组件的运动或移动，以及在例如完整细胞或活细胞中检测、诊断或治疗疾病或症状。
背景技术
已知荧光和磁性聚合物颗粒可在多种生物医学检测中用作标志物和指示物。其中细胞分类最常用的标志物是免疫轭合物或免疫标记，所述免疫标记包括，例如免疫-荧光标记和免疫-磁性标记。免疫-荧光标记通常包括，例如结合到抗体上的荧光分子。免疫-磁性标记通常包括，例如与初级抗体或者次级抗体结合的超顺磁性颗粒。细胞标记的进行可以通过，例如将抗体附着到细胞表面所关心的标志物(例如受点)上，即细胞表面标志物上。然而，细胞表面标志物的化学和物理结构，以及附着在细胞表面的免疫标记的密度通常难以精确测定。
已经通过，例如将荧光染料包埋于或共价偶合到聚合物颗粒上来制备荧光标记。得到的荧光微粒可通过人工或通过本技术领域已知的其它方法进行分析，优选采用自动化技术，例如流式细胞术(flowcytometry)，如Mansour等人的美国专利U.S.Patent No.4,665,024所公开的。荧光颗粒的多功能性可以通过在单个颗粒中引入多种荧光材料而进一步增强。然而，尽管将单一染料简单吸附至一个颗粒上对于大多数场合是够用的，但是当有多于一种染料吸附至一个颗粒时就会出现如下问题，包括：由例如分子间荧光能量传递引起的发射不一致；由聚合物基体内染料溶解性不同引起的的荧光团吸收率差异；以及由底物引起的嵌入荧光团(intercalated fluorophore)吸收和/或发射光谱的改变。
磁性颗粒，例如已知的磁性活性材料，可以键合或连接到例如抗体上，例如针对特定细胞类型、抗原或其它靶的特异性单克隆抗体。然后可将得到的磁性-抗体与多种细胞类型的大群细胞，例如天然组织样品、在反应器中培养的细胞等混合。因此，磁性-抗体仅连接到其预选类型的靶细胞上，形成磁性-抗体-细胞轭合物。然后可以用磁场将轭合物与其余的细胞群分离。磁性颗粒的一个缺点是磁性标记缺乏专一性，即，多种不同途径都会使细胞或其它生物靶分析物具有顺磁性，这会混淆由该方法提供的分析和诊断信息，例如由于特异性顺磁化合物结合到细胞上的特异性半抗原上，或者由于顺磁性金属或金属复合物特异性或非特异性地直接结合到细胞上，例如金属结合微生物，或者通过噬菌作用。在检测和诊断中使用磁性颗粒遇到的其它问题包括，例如难以对细胞群磁化率高精度量化。除了其磁性能(即磁性、顺磁性和超顺磁性)之外，磁性-抗体还可以根据其相对递减的颗粒尺寸分为，例如三个大类：磁性微粒标记、胶体磁性标记和分子磁性标记，参见例如美国专利US 6,412,359。
已知存在如下乳胶纳米颗粒，所述乳胶纳米颗粒具有一个聚合物核和一个表面，该表面用，例如一个能够与细胞表面特异性结合的配体分子修饰，并可任选地用基因材料，如变异基因修饰；所述颗粒可用于，例如将基因递送至细胞并使其在细胞中表达以破坏肿瘤，以及进行相关治疗。参考例如Science，296，2404(2002)。
具有导电壳体和二氧化硅核的光学活性纳米颗粒，例如荧光纳米颗粒是已知的，并且可用于例如化学物质的受控释放和治疗应用，参见例如美国专利US6,344,272和6,428,811。
现有荧光探针纳米颗粒的一个缺点是，在分散体系中作为荧光探针时亮度有限并且可探测性下降，对于单荧光颗粒尤其如此。
目前需要改进用于检测和分析的荧光纳米颗粒和方法，包括其在分散的生物介质中用作荧光标记物或探针。
发明内容
本发明提供一种荧光纳米颗粒，该颗粒包括：含有一种荧光硅烷化合物的核；以及一层于核上的二氧化硅壳体。
本发明还提供一种荧光纳米颗粒，该颗粒包括：含有一种荧光硅烷化合物的核；以及一层于核上的多孔二氧化硅壳体。
本发明还提供一种荧光纳米颗粒，所述纳米颗粒可进一步包括一个配体，例如抗体，所述配体轭合或包覆在荧光纳米颗粒的表面以形成复合荧光纳米颗粒。当与细胞或细胞组件结合时，本发明的复合荧光纳米颗粒或含有配体的荧光纳米颗粒可以用作，例如，高度靶特异性的诊断剂以及运动监测剂。
本发明还提供一种药用载体或药物释放载体，所述载体包括本发明的荧光纳米颗粒或复合荧光纳米颗粒。
本发明还提供一种荧光显像剂，所述显像剂含有本发明的复合荧光纳米颗粒。
本发明还提供作为药用载体颗粒的复合荧光纳米颗粒。故此，复合荧光纳米颗粒可以进一步包括一种治疗剂，所述治疗剂位于荧光纳米颗粒表面上或与所述表面轭合以形成药用组合物。
本发明还提供一种制备荧光纳米颗粒的方法，包括：
将一种荧光化合物，例如反应性荧光染料，与一种有机硅烷化合物，例如一种共反应性有机硅烷化合物混合，以形成荧光核；以及
将得到的核与一种形成二氧化硅的化合物，例如四烷氧基硅烷混合，以形成核上的二氧化硅壳体。
本发明还提供一种监测细胞的细胞组件移动的方法，包括：
将细胞与复合荧光纳米颗粒接触，以形成复合荧光纳米颗粒选择性修饰的细胞；以及
记录一段时间内荧光位点的运动。
本发明还提供一种治疗疾病的方法，包括：
向需要治疗的患者给药有效量的复合荧光纳米颗粒，所述纳米颗粒可任选地包括一种治疗剂，所述纳米颗粒适于选择性地与引起疾病的细胞组分结合，以形成复合荧光纳米颗粒选择性修饰的细胞；以及
照射该经修饰的细胞。
本发明还提供一种治疗方法，包括：
将细胞与复合荧光纳米颗粒接触，所述纳米颗粒可任选地包括一种治疗剂，以形成复合荧光纳米颗粒选择性修饰的细胞；以及
照射由此得到的经修饰的细胞一段时间。
本发明还提供一种用于检测分析物的试剂盒，所述试剂盒包括本发明所述的复合荧光纳米颗粒。
本发明还提供一种用于检测和监测细胞表面组分的试剂盒，所述试剂盒包括用于检测细胞表面组分的复合荧光纳米颗粒，并可任选地包括用于监测细胞表面组分的记录仪。
本发明还提供一种用于检测用治疗剂处理细胞时，细胞内或细胞表面上细胞组分的运动或位置的改变的方法，该方法包括：
将细胞与复合荧光纳米颗粒接触，以将复合荧光纳米颗粒结合到细胞组分上，其中纳米颗粒包括一种治疗剂；
记录荧光信号。
附图说明
图1示出了本发明的荧光纳米颗粒覆盖整个紫外-可见吸收光谱。
图2示出了通过FCS测量确定的各样品的流体动力学半径和亮度。
图3A-C示出了荧光纳米颗粒的溶剂可及性(accessibility)。
图4A-D示出了通过标记大鼠嗜碱细胞性白血病(RBL)肥大细胞的FcεRI受体，将所述二氧化硅纳米颗粒用作生物成像标志物的可能性。
图5比较了游离染料、二氧化硅纳米颗粒和在577nm处有荧光峰的量子点的亮度。
图6示出了本发明荧光纳米颗粒与乳胶颗粒的荧光亮度的比较实例。
图7A示出了本发明的荧光纳米颗粒的生物分子结合特异性的实例。
图7B示出了对照用乳胶颗粒的生物分子结合特异性的实例。
图8A-C示出了治疗剂在介孔颗粒内的固定。
具体实施方式
申请人发现，本发明的荧光纳米颗粒以及复合荧光纳米颗粒可用于对多种生物或非生物分析物进行标记、检测、鉴定、运动监测等用途。当用作药用载体，例如与合适的治疗剂结合时，本发明的连接或复合荧光纳米颗粒也可用于治疗。
本发明提供的纳米颗粒可以具有有益的多功能结构，例如纳米尺度的荧光核和二氧化硅壳体，所述荧光核可任选地包含其它官能团，例如磁性组分，二氧化硅壳体，该壳体可被制成具有不同的有用厚度范围和表面性能，例如光滑的整体表面或者高度多孔的表面，所述二氧化硅表面还可以用例如配体或治疗剂进一步进行物理或化学修饰。
本发明提供了适用于单颗粒跟踪(SPT)用途的多种尺寸的荧光纳米颗粒的制备和表征。可以制备各种直径且尺寸分布窄的纳米颗粒。制备路线的普适性使得可以依据预期的纳米颗粒用途，引入不同的荧光材料，例如染料。本发明还提供了表面官能化的方法，所述方法可以将特异性配体，例如抗体或蛋白，轭合到荧光纳米颗粒上以形成可用于特定SPT实验的探针。本发明的纳米颗粒制备工艺步骤能够通过纳米颗粒的就地生长，制备尺寸在例如约10到约500nm、约25到约100nm以及如本说明书中举例说明的更窄范围内的荧光纳米颗粒。
荧光纳米颗粒可以与一个分子或实体例如抗体配体或连接物轭合，以提供连接或复合荧光纳米颗粒，所述连接或复合荧光纳米颗粒可以用于鉴定、检测、靶向(即高度确定地定位或指定)、监测或改善疾病状态或症状，例如特定受体的存在或缺失、特定受体的代谢水平以及类似的组件。连接或复合荧光纳米颗粒还可以进一步与，例如治疗剂轭合或缔合；并用于，例如治疗疾病状态或症状，通过例如以高度特异性或定位方式将较高浓度的治疗剂释放至病灶，并以相对受控的方式释放治疗剂。复合荧光纳米颗粒可在多种系统中将治疗剂定向释放到所需位置，例如位于细胞或细胞组分之上或其中，或者位于有机体内，例如人体内，例如穿过血脑屏障。
在实施方案中，治疗剂可以吸附至例如二氧化硅壳的间隙或孔中，和/或包覆在荧光纳米颗粒的二氧化硅壳体上。在其它实施方案中，当二氧化硅壳体不完整时，治疗剂可以通过例如物理吸附或键合相互作用与荧光核结合。如果需要，治疗剂还可以与复合荧光纳米颗粒的配体结合。
本发明的复合荧光纳米颗粒可以用于多种诊断和治疗用途，例如用作治疗剂的药用载体，以及在，例如单核苷多态性(SNPs)实验中用作荧光标志物，例如，在所述实验中，将DNA样品用荧光标志物染色，激光照射下基因活性可通过标记物的彩色辉光(colored glow)被检测到。
本发明的纳米颗粒可以以单独的，或与配体结合的方式用于生物材料，即分析物，例如半抗原、抗原、抗体、酶或核酸的无源(passive)偶合或共价偶合；以及用于多种类型的分析物检测，例如免疫检测、核酸(DNA或RNA)检测、亲和纯化、细胞分离，以及其它医学、诊断、环境和工业用途。纳米颗粒引入已知的荧光响应材料，例如染料、色素或其组合。已知有多种合适的化学反应性荧光染料，参见例如MOLECULAR PROBES HANDBOOK OF FLUORESCENT PROBES AND RESEARCHCHEMICALS，第六版，R.P.Haugland编辑(1996)。典型的荧光团有，例如荧光芳族或芳族杂环化合物，例如芘、蒽、萘、吖啶、芪、吲哚或苯并吲哚、唑或苯并唑、噻唑或苯并噻唑、4-氨基-7-硝基苯-2-氧杂-1，3-二唑(NBD)、花青、羰花青、羰苯乙烯、卟啉、水杨酸酯、氨基苯甲酸酯、甘菊环、二萘嵌苯、吡啶、喹啉、香豆素(包括羟基香豆素和氨基香豆素及其氟化衍生物)，及类似的化合物，参见例如美国专利US 5,830,912、4,774,339、5,187,288、5,248,782、5,274,113、5,433,896、4,810,636及4,812,409。
用于形成荧光核的共反应性有机硅烷具有通式R(4-n)SiXn，其中X可以是可水解基团，例如乙氧基、甲氧基或2-甲氧基-乙氧基；R可以是1到12个碳原子的单价有机基团，该基团可任选地包含一个有机官能团，例如巯基、环氧基、丙烯酰基、甲基丙烯酰基或氨基；n是从0到4的整数。用于形成荧光核的共反应性有机硅烷优选n等于3。用于形成二氧化硅壳体的有机硅烷n等于4。已知可以采用单-、双-和三-烷氧基硅烷偶合和修饰共反应性官能团或羟基官能化表面，包括玻璃表面，参见Kirk-Othmer，Encyclopedia of Chemical Technology，20卷，第三版，J.Wiley，纽约。虽然不希望局囿于理论，但是烷氧基硅烷基团水解成硅烷醇基团以及与表面的羟基基团缩合会引起偶合，参见E.Pluedemann，Silane Coupling Agents，Plenum Press，纽约，1982。因此，以上提到的有机硅烷化合物等偶合剂可以用于：制备核；制备二氧化硅壳体，修饰以得到的二氧化硅壳体包覆的荧光核纳米颗粒的的表面；将配体连接或偶合到荧光纳米颗粒上；或者在将配体与荧光纳米颗粒连接之前或之后对其进行改性。有机硅烷会引起凝胶，因此可能需要采用醇或其它已知的稳定剂。当有机硅烷将与另一种单体，例如反应活性荧光化合物共聚时，可以选择不干扰聚合的稳定剂。醇类，例如甲醇，对此特别适用，并且可以以例如有机硅烷约两倍到约十倍的量使用。
纳米颗粒可任选地引入已知的磁体或磁响应材料，例如超顺磁性、顺磁性、铁磁性金属氧化物及其组合。
本发明的荧光纳米颗粒包括一个含有一种荧光硅烷化合物的核；以及于核上的二氧化硅壳体。所述纳米颗粒的核可以包括例如一种反应性荧光化合物和一种共反应性有机硅烷化合物的反应产物，而壳体可以包括例如一种形成二氧化硅化合物的反应产物。形成二氧化硅化合物可以产生例如一个或多个二氧化硅层，例如从1到约20层，这取决于所需的壳的特性，例如壳体层厚度、壳体厚度与核的厚度或直径的比值、核的二氧化硅壳体表面覆盖率、二氧化硅壳体的孔隙率和承载力等因素。
包覆在核上的二氧化硅壳体可以覆盖例如核表面积的约10％到约100％。当配体连接到荧光纳米颗粒表面时，所述配体可以覆盖例如核表面积的约0.1％到约100％。核的厚度或直径与二氧化硅壳体厚度的比值可以是例如约1∶1到约1∶100。荧光纳米颗粒的直径可以是例如约1纳米到约1,000纳米。复合荧光纳米颗粒的直径可以与荧光纳米颗粒的直径相当或更大，这取决于例如所选择的配体的尺寸和数量。在实施方案中，核的直径可以是例如约10纳米到约300纳米，优选约25纳米到约200纳米，二氧化硅壳体的厚度可以是例如约25纳米到约800纳米，优选约25纳米到约500纳米。在优选实施方案中，例如当选择纳米颗粒作为载体时，将二氧化硅壳体制成多孔状以容纳例如治疗剂，以及本说明书中所具体举例说明的物质。
本发明中荧光纳米颗粒的制备方法可以生产例如尺寸比vanBlaaderen和Vri， Langmuir，8，2921-2925(1992)所报道的纳米颗粒(用染料包覆单分散二氧化硅球核颗粒，再用二氧化硅封装)小约一个数量级的纳米颗粒。二氧化硅壳体既可以是致密的，即相对非多孔的，也可以是介孔的，例如半多孔的。荧光纳米颗粒的二氧化硅壳体优选是电介质。荧光纳米颗粒的二氧化硅壳体可以适用于作为药用载体纳米颗粒，即，使其包含例如治疗剂，例如用于体内或体外运输或释放的药物或蛋白质。因此，本发明的荧光纳米颗粒可以提供一种药用载体系统，所述系统可以适用于治疗剂的受控释放。
在实施方案中，将配体置于荧光纳米颗粒表面上形成复合荧光纳米颗粒。配体的加入可以通过例如共价键连接或物理吸附来完成。荧光纳米颗粒表面的配体可以是，例如生物聚合物、合成聚合物、抗原、抗体、病毒或病毒组分、受体、半抗原、酶、激素、化合物、病原体、微生物或其组分、毒素，表面改性剂，例如用以改变纳米颗粒或纳米颗粒所结合的分析物的表面性能或组织相容性的表面活性剂，及其组合。优选的配体是例如抗体，例如单克隆或多克隆抗体。
本发明还提供了制备分析物的方法，所述分析物通过例如偶合(例如通过共价键)或任何其它已知的将复合荧光纳米颗粒直接结合到分析物上的方法(例如通过离子键、氢键或简单吸附)，选择性地用复合荧光纳米颗粒进行标记。得到的选择性标记的分析物具有偶合的或结合的复合荧光纳米颗粒(即，复合荧光纳米颗粒-分析物复合物)，并可以在例如治疗方法或诊断试剂盒中用作真实样品或参比样品。
本发明的“分析物”是复合荧光纳米颗粒连接或结合的目标或靶。所述分析物可以是例如微生物或其组分、病毒或病毒组分、细胞或其组分、生物聚合物、合成聚合物、合成材料例如碳纳米管、抗原、抗体、受体、半抗原、酶、激素、化合物、病原体、毒素、及其组合，以及类似物质。特别重要的分析物是微生物和细胞，包括病毒、原核和真核细胞、单细胞和多细胞有机体，例如真菌、细菌、哺乳动物等，及其片段或组分。其它特别重要的分析物是病原体。作为复合荧光纳米颗粒一部分的单克隆或多克隆抗体或其它选择性配体可以连接到例如病原体的表面上。
在本发明的实施方案中，提供了制备荧光纳米颗粒的方法，例如包括：
将一种荧光化合物如反应性荧光染料，与一种有机硅烷化合物如共反应性有机硅烷化合物混合，以形成荧光核；
将得到的核与一种可形成二氧化硅的化合物，例如四烷氧基硅烷混合，以形成于核上的二氧化硅壳体，得到荧光纳米颗粒。
本发明制备纳米颗粒的方法可以进一步包括，使得到的荧光纳米颗粒结合配体，例如生物聚合物、合成聚合物、抗原、抗体、微生物、病毒、受体、半抗原、酶、激素、化合物、病原体、毒素、用以例如改变纳米颗粒表面或相容性的表面改性剂、及其组合，以及类似物质。得到的荧光纳米颗粒和配体的组合提供了复合荧光纳米颗粒。制备纳米颗粒的方法还可以进一步包括，将得到的连接或未连接配体的纳米颗粒与治疗剂相结合。将纳米颗粒与配体或治疗剂结合可以通过例如将配体或治疗剂包覆在纳米颗粒表面上来完成。另外，纳米颗粒与配体或治疗剂的结合可以通过例如将配体或治疗剂透入至纳米颗粒的表面中来完成。所述透入指的是吸收或吸入，例如多孔纳米颗粒表面吸收配体、治疗剂或同时吸收这二者。另外，纳米颗粒与配体或治疗剂的结合可以通过例如将配体或治疗剂键合到得到的纳米颗粒的表面来完成。所述键合包括，例如已知的共价键合、离子键合、氢键键合、疏水键键合、配位键键合、粘合及其组合，以及类似的键合结合方法。
由于本发明的纳米颗粒的小尺寸和均匀性，及其表观可溶性或高分散性，所述纳米颗粒可以提供如下“分子标记”，即所述“分子标记”易于与另一个实体例如配体或治疗剂结合或键合，而且其后可以易于传输到并选择性地连接到靶分析物上。选择性的连接能够实现实用的分析检测、诊断或鉴别。用于本发明实施方案中的复合荧光纳米颗粒的尺寸可以根据待连接到分析物上的纳米颗粒的数量和所选择的光学或光谱法的灵敏度来选择。
本发明的实施方案中提供了监测细胞的细胞组件移动的方法，包括：
将细胞与复合荧光纳米颗粒接触，以形成复合荧光纳米颗粒选择性修饰的细胞；
记录一段时间内荧光位点的移动。
荧光位点可以对应于结合到一个细胞组件上的单个复合荧光纳米颗粒。荧光位点也可以对应于结合到一个细胞组件上的两个或多个复合荧光纳米颗粒。监测方法使得操作者可以例如实时或定时技术追踪一个或多个荧光位点的扩散，例如追踪单个复合荧光纳米颗粒所结合的受体的扩散。复合荧光纳米颗粒优选适用于选择性结合细胞的靶向细胞组分，例如通过选择合适的配体。
细胞组分可以是例如受体、抗体、半抗原、酶、激素、生物聚合物、抗原、微生物、病毒、病原体、毒素，及其组合，以及类似的组分。在实施方案中，复合荧光纳米颗粒可以是与抗体轭合的荧光纳米颗粒。在实施方案中，轭合的抗体可以是免疫球蛋白，例如IgE。
在本发明的实施方案中用于检测、记录、测量或显像的适宜工具在本技术领域是已知的，包括，例如流式细胞仪、激光扫描细胞仪、荧光读板仪、荧光显微镜、共焦显微镜、亮视野显微镜、高容量扫描系统等设备。
记录可以通过例如显微用照相机(例如视频显微照相机、数字照相机、卤化银单曝光照相机)等设备来完成。记录时间可以是任何便于观察显著事件或现象的时间间隔，例如约1微秒到约30天的间隔。在典型的细胞外、细胞表面或细胞内事件中，记录的时间间隔可以是例如约1秒到约60分钟，较优选约1秒到约40分钟，更优选约1分钟到约30分钟。记录时间间隔通常可以根据需要，通过改变样品或系统的环境温度方便地缩短或延长。接触和记录可以通过使用常规的显微照相技术在体外完成。接触和记录也可以通过使用，例如装有显微照相机或纤维光学照相机的导管在体内完成。对于本领域的普通技术人员，在本发明的实施方案中，“记录”显然可以与“检测”同义，因为，例如照相记录一个受照样品，也可以同时检测其荧光位点，例如复合荧光纳米颗粒选择性修饰的细胞或细胞组件样品。
本发明实施方案中提供了一种药用载体，所述载体包括本发明的荧光纳米颗粒，并可任选地包括与荧光纳米颗粒缔合的配体。
本发明实施方案中还提供了一种药用组合物，所述组合物包括复合荧光纳米颗粒，以及与荧光纳米颗粒结合的治疗剂。
本发明实施方案中提供了一种显像剂，所述显像剂包括复合荧光纳米颗粒，例如所述复合荧光纳米颗粒的配体位于纳米颗粒表面上。显像剂可以用于常规显像方法，优选用于例如需要高荧光产率或荧光亮度的场合。在实施方案中，本发明的复合荧光纳米颗粒可以提供增强的荧光亮度，所述亮度与常规的表面修饰荧光颗粒例如荧光乳胶颗粒相比高例如约2到约10倍。
本发明实施方案中还提供了一种治疗疾病或病症的方法，包括：
向需要治疗的患者给药有效量的复合荧光纳米颗粒，所述纳米颗粒可任选地包括一种治疗剂，其中纳米颗粒适用于选择性地结合引起疾病的细胞组分，以形成复合荧光纳米颗粒选择性修饰的细胞；
照射经修饰的细胞。
单独或作为修饰细胞部分的复合荧光纳米颗粒，在被照射时可以发出荧光和/或发热。因此，在制备荧光纳米颗粒时，对反应性荧光化合物的选择和配体的选择，可以按经验，依据所需荧光和非荧光(散热)特性的平衡进行。当检测极为重要或困难时，例如在稀释系统中，可能需要较高的荧光特性。当需要高热时，例如为促进治疗剂的释放或实现选择性显微烧灼或显微热疗时，可能需要较高的非荧光特性。在本发明实施方案中，在例如恶性肿瘤的检测和治疗中，可能需要例如同时地或依次地使用两种或两种以上具有不同荧光和非荧光特性的复合荧光纳米颗粒的混合物，以利用不同特性的益处。
因此，本发明的复合荧光纳米颗粒可以用于治疗对光或热敏感的疾病或病症。已知光疗法可用于在活体内的一个或多个治疗部位药物的活化。光疗法的具体实施方案是例如光力学疗法(PDT)，这是一个两步治疗方法，并已发现它能有效地破坏多种类型的肿瘤。PDT通过以下步骤实施：首先全身或局部给药光敏剂等化合物，随后在对应于光敏剂吸收波段的波段内用光照射治疗部位。所述光能使得光敏剂化合物活化，使其破坏疾病组织，参见例如美国专利US 6,454,789。对于本领域普通技术人员显而易见的是，荧光材料，例如本发明的复合荧光纳米颗粒，可以用于代替光敏剂化合物。
同样已知热疗法可以例如使目标组织变小，参见美国专利US6,480,746；局部治疗皮肤疣，参见Arch.Dermatol，(1992年7月)，第128卷，945-948页；以及诱导巨噬细胞凋亡，参见美国专利US6,451,044。在上述及相关应用中，热疗法可以通过例如辐射或照射，例如紫外辐射、红外辐射、微波辐射等，在体内或穿过皮肤完成。本领域普通技术人员一旦掌握本发明，将容易认识到如何使本发明的材料和方法适用于完成光疗法或热疗法。
本发明还提供一种治疗方法，包括：
将细胞与复合荧光纳米颗粒接触，所述纳米颗粒可任选地包括一种与其结合的治疗剂，以形成复合荧光纳米颗粒选择性修饰的细胞；
照射得到的经修饰的细胞一段时间。
接触量和持续时间以及照射量和持续时间可以取决于例如治疗方法的诊断或治疗目的，例如发病状态或症状的荧光检测和/或有效治疗剂的释放。接触和照射的量和持续时间也可以取决于例如复合荧光纳米颗粒对靶分析物的相对浓度，及待治疗细胞的状态，例如体内或体外全细胞、透化细胞、匀浆细胞、敏化细胞等细胞制品。
本发明的复合荧光纳米颗粒也可应用于诊断试剂盒或检测，例如免疫检测，以及应用于改进的显像剂、纯化工艺、药物，例如治疗方案和疗法，例如向特定的靶递送药物以及使肿瘤变小，或应用于鉴定和分离病原体等方面。
本发明提供用于检测分析物的试剂盒，所述试剂盒包括本发明所述复合荧光纳米颗粒。
本发明还提供用于检测和监测细胞表面组分的试剂盒，所述试剂盒包括用于检测细胞表面组分的复合荧光纳米颗粒，并可任选地包括用于监测细胞表面组分的记录仪。
前述试剂盒包括试剂盒组成部分的包装以及试剂盒的使用说明书。
本发明还提供一种检测方法，用以在对细胞用治疗剂处理时，探测在细胞内或细胞表面上细胞组分的运动或位置的改变，包括：
将细胞与复合荧光纳米颗粒接触，其中纳米颗粒包括一种治疗剂，以将复合荧光纳米颗粒结合到细胞组分上；
记录例如从一个或多个荧光位点发出的荧光信号，并确定靶细胞组分的相对运动或位点改变。
荧光位点的运动或移动，即，与复合荧光纳米颗粒结合的分析物的运动或移动，代表所结合分析物如细胞组分的运动或移动并可与此相关联。
用于检测细胞组分的运动或位置改变的检测方法可以包括，例如可任选地对所记录的复合荧光纳米颗粒的位置进行绘图或作图。检测方法可以进一步包括确定复合荧光纳米颗粒所结合的分析物的运动或移动在有无治疗剂时的差别，例如在串联或对照实验设计中。
本发明的纳米颗粒材料，例如复合荧光纳米颗粒，及其使用方法，可以用作例如标记检测剂或由其制得的试剂产品，用于检测诸如酶、受体等细胞组分的存在。细胞组分的位置可以在例如代谢活跃的全细胞内、全细胞裂解液中、透化细胞中、固定细胞中、或用无细胞环境中的部分纯化的细胞组分进行检测和确定。复合荧光纳米颗粒包含一个结合的配体或连接剂，例如抗体，所述纳米颗粒靶向或结合待测的特定细胞组件。复合荧光纳米颗粒在纳米颗粒核中还包含一个荧光标记或荧光组件，当纳米颗粒和靶细胞组件结合并适当照射或辐射时，所述荧光组件标记或报告靶细胞组分的存在。
本发明还提供了给药有效量的连接荧光纳米颗粒治疗疾病的方法。该方法可以涉及单独给予、于药用组合物中给予、或者与其它治疗剂或药用组合物结合给予本发明所述的连接荧光纳米颗粒。
本发明还提供了将治疗剂连接至荧光纳米颗粒以提高治疗剂效力的方法。荧光纳米颗粒及其药用组合物也可以用于缔合治疗剂以提高治疗剂的治疗功效。优选在体外完成用配体轭合荧光纳米颗粒以形成连接或复合荧光纳米颗粒，其中例如可以仔细控制配体的量和条件以生成高纯度和高质量的产物。相似地，用治疗剂修饰连接荧光纳米颗粒也优选在体外实现。
本发明提供荧光纳米颗粒及其复合荧光纳米颗粒，以及将其用于例如免疫标记、亚细胞识别方法、诊断或细胞分类的方法。本发明方法的优点克服了已知方法的缺陷，并在本说明书中举例说明。
本发明提供了可高度分散的复合荧光纳米颗粒，且这些颗粒可用于例如改进的化学和生化分析方法，例如检测生物分析物，包括微生物和亚细胞组分。由于复合荧光纳米颗粒的高度靶选择性或亲和力，及其与已知的荧光颗粒相比亮度增强，因此所述复合荧光纳米颗粒可以提供局部浓度高的荧光材料。荧光材料遍布于纳米颗粒核，而不像多数常规材料那样简单地作为表面包覆材料。
“治疗剂”是一种可以用于诊断、治愈、缓解、治疗或预防人类或其它动物的疾病的物质。这样的治疗剂包括正式的美国药典、正式的美国顺势疗法药典、正式的美国国家药品集、或其任何附录所认可的物质。
可以引入本发明的荧光纳米颗粒或复合荧光纳米颗粒中的治疗剂包括核苷、核苷类似物、寡肽、多肽、COX-2抑制剂、凋亡启动子、尿道剂、阴道剂、血管舒张剂、神经变性剂(例如帕金森氏症)、肥胖剂、眼剂、骨质疏松剂、副交感神经抑制剂、拟副交感神经作用剂、抗麻醉剂、前列腺素、心理治疗剂、呼吸剂、镇静剂、催眠剂、皮肤和粘膜剂、抗菌剂、抗真菌剂、抗致癌剂、心脏保护剂、心血管剂、抗血栓剂、中枢神经系统兴奋剂、胆碱脂酶抑制剂、避孕药、多巴胺受体兴奋剂、勃起机能障碍剂、生育剂、胃肠剂、痛风剂、激素、免疫调制剂、合适地官能化的止痛剂或全身或局部麻醉剂、抗惊厥剂、抗糖尿病剂、抗纤维化剂、抗感染剂、运动病剂、肌肉松弛剂、免疫抑制剂、偏头痛剂、非甾体类抗炎药(NSAID)、戒烟剂或交感神经抑制剂(参见Physician’Desk Reference，第55版，2001，MedicalEconomics Company，Inc.，Montvale，New Jersey，201-202页)。
可以与本发明的荧光纳米颗粒连接、复合或结合的治疗剂的具体实例有氟氧头孢；阿司米星；庆大霉素；葡萄糖氨苯砜；短杆菌肽S；短杆菌肽；葛帕沙星；胍甲环素；缩酮氨苄青霉素；异帕米星；交沙霉素；卡那霉素；氟氧头孢；阿司米星；庆大霉素；葡萄糖氨苯砜；短杆菌肽S；短杆菌肽；葛帕沙星；胍甲环素；缩酮氨苄青霉素；异帕米星；交沙霉素；卡那霉素；杆菌肽；默诺霉素；比阿培南；溴莫普林；丁胺菌素；卷曲霉素；羧苄西林；卡波霉素；卡芦莫南；头孢羟氨苄；头孢孟多；头孢曲秦；头孢拉宗；头孢克定；头孢地尼；头孢托仑；头孢平；头孢他美；头孢克肟；头孢甲肟；头孢米诺；克拉屈滨；阿帕西林；羟哌二甲胺四环素；阿布拉霉素；阿贝卡星；阿扑西林；叠氮氯霉素；氨曲南；氨噻唑头孢菌素；头孢尼西；头孢哌酮；头孢雷特；头孢氨噻；头孢双硫唑甲氧；头孢替安；头孢唑兰；头孢咪唑；头孢匹胺；头孢匹罗；头孢罗齐；头孢沙定；头孢特仑；头孢布坦；头孢唑南；头孢氨苄；头孢甘酸；头孢菌素C；头孢拉定；氯霉素；金霉素；克林沙星；克林霉素；氯莫环素；粘菌素；环青霉素；氨苯砜；去甲金霉素；百里砜；地贝卡星；双氢链霉素；6-巯基嘌呤；硫鸟嘌呤；卡培他滨；多西他赛；依托泊苷；吉西他滨；拓扑替康；长春烯碱；长春新碱；长春碱；替尼泊甙；苯丙氨酸氮芥；甲氨蝶呤；2-对-对氨基苯磺酰氨基苯乙醇；4，4’-对氨基苯磺酰二苯胺；4-磺胺基水杨酸；环丁羟吗喃；纳布啡；链脲霉素；阿霉素；柔红霉素；普卡霉素；去甲柔毛霉素；丝裂霉素C；脱氧助间型霉素；米托蒽醌；阿糖胞苷；磷酸氟达拉滨；环丁羟吗喃；纳布啡；链脲霉素；阿霉素；柔红霉素；普卡霉素；去甲柔毛霉素；丝裂霉素C；脱氧助间型霉素；米托蒽醌；阿糖胞苷；磷酸氟达拉滨；氨苯砜乙酸；醋胺磺胺苯砜；阿米卡星；两性霉素B；氨苄西林；托伐他汀；依那普利；雷尼替丁；环丙沙星；普伐他汀；克拉霉素；环孢素；法莫替丁；醋酸亮丙瑞林；阿昔洛韦；紫杉醇；阿奇霉素；拉米夫定；布地缩松；沙丁胺醇；吲哚那韦；二甲双胍；阿仑特罗；尼扎替丁；齐多夫定；卡铂；美托洛尔；阿莫西林；双氯酚酸钠；赖诺普利；头孢曲松；卡托普利；沙美特罗羟萘甲酸盐；亚胺培南；西司他丁；贝那普利；头孢克洛；头孢他啶；吗啡；多巴胺；比拉米可；氟伐他丁；氧二苯脒；足叶草肼2-乙基肼；吖啶黄；双氮氯胺；胂凡纳明；双脒苯脲；氯喹努德；喹那普利；氢羟吗啡酮；丁丙诺啡；氟尿苷；地红霉素；多西环素；依诺沙星；恩威霉素；依匹西林；红霉素；吉他霉素；林可霉素；洛美沙星；光明霉素；赖甲环素；氯甲烯土霉素；美罗培南；美他环素；小诺米星；麦迪霉素；米诺环素；拉氧头孢；莫匹罗星；那地沙星；那他霉素；新霉素；奈替米星；诺氟沙星；竹桃霉素；土霉素；对氨基苯磺酰苄胺；帕尼培南；巴龙霉素；哌佐沙星；青霉素N；匹哌环素；吡哌酸；多粘菌素；伯霉素；喹那西林；核糖霉素；利福酰胺；甲哌利福霉素；利福霉素SV；利福喷丁；利福西亚胺；利托菌素；利替培南；丙酰白霉素；氢吡四环素；蔷薇霉素；罗红霉素；柳氮磺胺二甲嘧啶；去甲去氧四环素；西索米星；司帕沙星；大观霉素；螺旋霉素；链霉素；琥珀氨苯砜；偶氮磺胺；羟甲酞磺脲；偶氮磺胺；对氨基苯磺酸；亚磺氨苯砜；太古霉素；替马氟沙星；替莫西林；四氧普林；甲砜霉素；噻唑砜；硫链丝霉素；替卡西林；泰格莫南；妥布霉素；托氟沙星；甲氧苄定；出斯托霉素；曲伐沙星；结核放线菌素；万古霉素；氮丝氨酸；克念菌素；氯丙炔碘；制皮菌素；菲律宾菌素；戊霉素；美帕曲星；制霉素；寡霉素；真菌霉素A；杀结核菌素；6-氮尿苷；6-重氮-5-氧-L-正亮氨酸；阿克拉霉素；环胞苷；氨茴霉素；阿扎胞苷；氮丝氨酸；博来霉素；双香豆素乙酯；乙叉双香豆素；伊落前列素；拉米非班；他前列烯；噻氯香豆素；替罗非班；阿普劳斯；布西拉明；胍立莫司；羟基水杨酸；葡美辛；水杨酸羟乙酯；甲氯芬那酸；甲芬那酸；美沙拉秦；氟尼酸；奥沙拉嗪；奥沙西罗；S-enosyl蛋氨酸；双水杨酯；柳氮磺吡啶；托芬那酸；洋红霉素；嗜癌霉素A；氯脲霉素；色霉素；二甲叶酸；多西氟尿啶；依达曲沙；依洛尼塞；依利醋铵；依诺他滨；表阿霉素；甘露醇氮芥；美洛格瑞；二溴甘露醇；二溴乳糖；蒙匹胺醇；霉酚酸；诺加拉霉素；橄榄霉素；培来霉素；吡喃阿霉素；吡曲克辛；松龙苯芥；甲基苄肼；蝶酰三谷氨酸；嘌呤霉素；雷诺氮芥；链黑霉素；硫唑鸟嘌呤；霉酚酸；苯咪唑丙酸；胞壁酰基二肽；西罗莫司(瑞帕霉素)；他克莫司；丁胺卡因；苯醇胺；羟基丁卡因；对氨苯酸戊胺乙酯；凹素卡因；哌啶卡因；水杨醇；3-氨基-4-羟丁酸；醋氯芬酸；阿明洛芬；氨芬酸；溴芬那酸；溴水杨醇；二苯胺戊酰胺；卡洛芬；双氯酚酸钠；二氟苯水杨酸；地他唑；因法来酸；依托度酸；氟灭酸酯；吲哚水杨酸；非拉二醇；氟芬那酸；Tomudex(N-[[5-[[(1，4-二氢-2-甲基-4-氧-6-喹唑啉基)甲基]甲基氨基]-2-噻吩基]羰基]-L-谷氨酸)；曲麦克特；杀结核菌素；羟氨苯丁酰亮氨酸；长春地辛；正定苯酰肼；阿戈托班；双香豆素醚或双香豆素。
其它治疗剂列表可以在以下文献中找到，例如Physicians’DeskReference，第55版，2001，Medical Economics Company，Inc.，Montvale，新泽西；USPN Dictionary of USAN and International DrugNames，2000，The United States Pharmacopeial Convention，Inc.，Rockville，Maryland；以及The Merck Index，第12版，1996，Merck& Co.，Inc.，Whitehouse Station，New Jersey.
本领域普通技术人员将很容易理解如何使用标准测试或本领域已知的其它类似测试确定，例如治疗活性。
“药用组合物”包括一种与本发明的荧光纳米颗粒结合的本说明书所列举的治疗剂，例如其中荧光纳米颗粒可以作为可药用的载体。本发明的药用组合物，除了将荧光纳米颗粒与治疗剂结合以外，还可制成如下剂型或与其它可用的载体制成如下剂型：例如固体、胶体或液体稀释剂或可吸收的胶囊。本发明的药用组合物、其盐、或其混合物可以以合适的药用单位剂型口服给药。本发明的药用组合物可以制备成多种剂型，包括片剂、硬胶囊或软胶囊、水溶液、悬浮液、脂质体和其它缓释制剂，例如成形聚合物凝胶。
口服液体药用组合物可以例如水或油悬浮液、溶液、乳液、糖浆或酏剂的形式存在，或者可以干的产品形式存在而在使用前用水或其它合适的载体复原。所述液体药用组合物可以包含常规的添加剂，例如悬浮剂、乳化剂、非水载体(可以包括食用油)或防腐剂。
本发明的纳米颗粒药用组合物也可以制成非肠道给药(例如注射，例如快速浓注或连续输注)制剂，并且可以以单位剂型存在于针药管、预装填注射器、小容量输注容器或添加有防腐剂的多剂量容器中。药用组合物可以采用例如悬浮液、溶液、油性或水性载体乳液等形式，且可以包含配制剂(formulatory agent)，例如悬浮剂、稳定剂和/或分散剂。或者，本发明的药用组合物可以采用粉末形式，通过无菌分离无菌固体或冻干溶液获得，在使用前用合适的载体如无菌无热原水复原。
为局部给药至表皮，药用组合物可制成软膏、乳膏或洗剂，或者作为皮肤膏药(transdermal patch)的活性成分。合适的皮肤释放系统在例如A.Fisher等(美国专利US 4,788,603)或R.Bawa等(美国专利US 4,931,279；4,668,506和4,713,224)中公开。例如，软膏和乳膏可以与水或油性基质配制并添加合适的增稠剂和/或胶凝剂。洗剂可以与水或油性基质配制，且通常还会包含一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。药用组合物也可以通过离子电泳作用释放，例如美国专利US 4,140,122；4,383,529或4,051,842中所公开。
适合于在口腔中局部给药的药用组合物包括单位剂型，例如将本发明的药用组合物包含在调味基质(通常是蔗糖、阿拉伯树胶或黄芪胶)中的糖锭；将药用组合物包含在惰性基质，例如明胶和甘油或蔗糖和阿拉伯树胶中的锭剂；粘膜粘着凝胶(mucoadherent gels)以及将药用组合物包含在适宜的液体载体中的漱口剂。
为局部给药至眼部，药用组合物可以以滴剂、凝胶(S.Chrai等.，美国专利US4,255,415)、树胶(S.L.Lin等，美国专利US4,136,177)等形式给药，或通过缓释眼植入物(A.S.Michaels，美国专利US3,867,519和H.M.Haddad等，US 3,870,791)给药。
当需要时，上述药用组合物可以通过例如与某种亲水聚合物基体结合而使其适用于持续释放所用的治疗剂化合物，所述聚合物基体包括例如天然凝胶、合成聚合物凝胶或其混合物。
适合于直肠给药且其中载体为固体的药用组合物，优选以单位剂量栓剂存在。合适的载体包括可可油和其它本领域常用的材料。栓剂便于通过如下步骤形成：将药用组合物与软化或熔化的载体混合，然后在模具中冷却并成形。
适合于阴道给药的药用组合物可以以阴道栓剂、棉塞、乳膏、凝胶、糊状物、泡沫或喷雾的形式存在，除纳米颗粒和治疗剂之外，还包含本领域已知的载体。
为吸入给药，本发明的药用组合物便于通过吹药器、喷雾器或压缩包或其它便于递送气溶胶喷雾的工具进行释放。压缩包可以包括合适的抛射剂，例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体。在压缩气溶胶的情况下，剂量单位可以通过提供一个计量释放的阀门来确定。
或者，为吸入或吹入给药，本发明的药用组合物可以采用干粉组合物的形式，例如药用组合物与合适的粉末基质如乳糖或淀粉的粉末混合物。粉末组合物可以单位剂型存在于例如胶囊或弹射剂(cartridge)，或例如凝胶或泡壳(blisterpack)中，其中的粉末可以借助于吸入器或吹入器给药。
对于鼻内给药，本发明的药用组合物可以通过液体喷雾器给药，例如通过塑料瓶喷雾器。典型的液体喷雾器有Mistometer(异丙肾上腺素吸入器-Wintrop)和Medihaler(异丙肾上腺素吸入器-Riker)。
本发明的药用组合物还可以包含其它辅药，例如调味剂、着色剂、抗微生物剂或防腐剂。
可以进一步理解的是，治疗所需使用的药用组合物的量不但会随着所选择的具体的盐而变化，而且会随着给药途径、所治疗症状的性质以及患者的年龄和状况而变化，并且最终由主治医师或临床医生决定。
与本发明的复合荧光纳米颗粒结合的治疗剂，其向指定人类患者给药的量和频率，取决于与病人的精神状况和身体状况有关的多个变量。为评价所述因素，参见J.F.Brien等，Europ.J.Clin. Pharmacol.，14，133(1978)；以及Physicians’DeskReference，Charles E.Baker，Jr.，Pub.，Medical Economics Co.，Oradell，N.J.(第41版，1987)。通常，当与本发明的复合荧光纳米颗粒结合使用时，治疗剂的剂量可以低于其单独给药或以常规的药物剂型给药时的剂量。复合荧光纳米颗粒对靶位点例如位于细胞表面上的受体的高度特异性可以提供局部浓度较高的治疗剂，或者，在较长时间段内提供持续释放的治疗剂。
本发明的复合荧光纳米颗粒和治疗剂的“可药用的盐”可以包括但不限于无毒的有机酸和无机酸加成盐，例如柠檬酸盐、重碳酸盐、丙二酸盐、酒石酸盐、葡萄糖酸盐、盐酸盐、硫酸盐、磷酸盐等。另外，在其中的纳米颗粒具有足够的碱性或酸性以形成稳定的酸或碱盐的情况下，将纳米颗粒制备为盐可能是适宜的。可药用的盐的实例有与能够形成可接受的阴离子的酸形成的有机酸加成盐，例如甲苯磺酸盐、甲基磺酸盐、醋酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸盐及α-甘油磷酸盐。也可以形成合适的无机盐，包括盐酸盐、硫酸盐、硝酸盐、重碳酸盐及碳酸盐。可药用的盐可以通过使用本领域已知的标准方法得到，例如将碱性足够强的化合物如胺与合适的酸反应，所述酸提供可诊断用的阴离子。也可以制备碱金属(例如钠、钾或锂)或碱土金属(例如钙)的羧酸盐。
“受体”是任何能够识别(例如具有较高的结合亲和力)分子的特定空间结构和极性结构即表位或决定基位点的大分子化合物或组合物。示例性的受体包括天然存在的受体，例如甲状腺素结合球蛋白、抗体、酶、免疫球蛋白(Fab)片段、凝集素、见于细胞表面上的多种蛋白(分化群或CD分子)等。CD分子特指位于真核细胞表面上的已知和未知蛋白，例如CD4是主要见于辅助性T淋巴细胞的分子。
“半抗原”可以包括天然存在的激素、天然存在的药物、合成药物、污染物、过敏原、效应剂分子、生长因子、趋化因子、细胞因子、淋巴因子、氨基酸、寡肽、化学中间体、核苷酸、寡核苷酸等。所述化合物可用于检测药物滥用、治疗剂量监测、健康状况、移植供体匹配、妊娠(例如hCG或α-胎蛋白)，检测疾病，例如内毒素、肿瘤抗原、病原体等。
“免疫轭合物”是将两个不同的分子或实体附着形成的分子，所述分子或实体的其中一个是例如与荧光纳米颗粒复合的抗体，另一个通常是生物活性分子实体(分析物)，例如有机药物分子、放射性核素、酶、毒素、蛋白等可与抗体轭合形成轭合物的物质。抗体部分将所附着的荧光纳米颗粒指向或导向至靶分析物上，使得荧光纳米颗粒能够有效地产生生物或标记效应。重要的病原体可以是例如病毒，例如孢疹病毒、痘病毒、披膜病毒、正黏病毒、副黏病毒、弹状病毒、冠状病毒、沙粒病毒和反转录病毒。半抗原也包括朊病毒和细菌，包括但不限于大肠杆菌、铜绿假单胞菌、阴沟肠杆菌、金黄色葡萄球菌、粪肠球菌、肺炎克雷伯菌、鼠伤寒沙门菌、表皮葡萄球菌、粘质沙雷菌、牛分枝杆菌、抗甲氧苯青霉素金黄色葡萄球菌和普通变形杆菌。所述有机体和与其相关联的疾病的非穷举的列表见于例如美国专利US5,795,158。
采用本发明纳米颗粒的检测可以在生物流体中进行，包括分离的或未过滤的生物流体，例如尿液、脑脊髓液、胸膜液、滑液、腹膜液、羊水、胃液、血液、血清、血浆、淋巴液、组织液、组织匀浆、细胞提取物、唾液、痰、粪便、生理分泌液、泪液、粘液、汗液、乳汁、精液、阴道分泌液，来自溃疡和其它表面疹、水泡、脓肿的流体及组织提取物，包括正常、恶性和可疑组织的活组织切片，或包含所研究分析物的身体的任何其它组成部分的活组织切片。所研究的还有其它类似的样品，例如细胞或组织培养物或培养基。或者，样品可以取自环境，例如土壤、水或空气；或者取自工业源，例如取自废水流、水源、供应线或生产区。工业源也包括发酵培养基，例如来自生物反应器或食品发酵过程例如酿造；或者食品，例如肉、猎物、农产品或奶制品。测试样品可以在使用之前进行预处理，例如从血液中制备血浆、稀释粘性液体等；预处理方法可以涉及过滤、分馏、蒸馏、浓缩、钝化干扰化合物、添加反应物等，或其组合。
检测多种亚群分析物的方法是已知的(参见例如Lehnen的美国专利US 5,567,627)，并且可以适用于本发明。用一个或多个纳米颗粒检测核酸的方法可以适用于本发明，所述纳米颗粒上附着有寡核苷酸，所述方法包括用附着有氧化还原活性分子的探针寡核苷酸进行电化学检测，例如Mirkin等的美国专利US 6,417,340中所述。在吸附于电极上的寡核苷酸双链内进行电化学检测以及定位基因点突变和其它碱基堆积扰动的方法，例如Barton等的美国专利US 6,221,586，也可以适用于本发明。在一个样品中对多个分析物进行多重荧光分析的方法，例如Chandler等的美国专利US 6,268,222，可以适用于本发明。其它检测方法，包括使用紫外和可见光谱，参见例如X.Gong和E.S.Yeung，Anal.Chem.，71，4989(1999)，“An Absorption Detection Approachfor Multiplexed Capillary Electrophoresis Using a LinearPhotodiode Array”。采用流过分部细胞分选法对细胞进行分离的方法可以适用于本发明，所述方法基于将磁力作用于具有不同磁标记密度的细胞，例如Zborowski等的美国专利US 5,968,820。通过非共价键结合和凝聚将彼此结合的颗粒分离的方法，例如Masson等的美国专利US 4,279,617，可以适用于本发明。
就本发明的目的而言，纳米颗粒的荧光组件应该提供与样品中分析物的存在相关的信号。类似地，当选择一个包括荧光纳米颗粒的配体时，所述配体应该提供与样品中分析物的存在相关的荧光信号，且所述信号可以电磁辐射的形式检测到，特别是以紫外、可见或红外范围内的辐射形式检测到。
“可任选的”或“可任选地”表示随后描述的事件或状态可以但不是必须发生，且该描述包括其中的事件或状态发生的实例和不发生的实例。例如，“可任选地包括”表示所指定的组分可以存在但不是必须存在，且该描述包括其中指定的组分被包括的情况和其中指定的组分不被包括的情况。
术语“包括”、“例如”、“诸如”等是说明性的，并不是要限制本发明。
在本申请包括权利要求书中适用“一个”一词时，表示“至少一个”或“一个或多个”，除非特别另外指出。
以下通用方法用于制备和评价本发明的纳米颗粒、及其轭合物或加合物。
荧光纳米颗粒的制备
制备本发明的荧光纳米颗粒的方法和中间体作为本发明进一步的实施方案予以提供，并由下列步骤说明，其中上位基团的含义如其所述，除非另外指明。
在本发明实施方案中，本发明的荧光纳米颗粒可以通过以下方法制备：例如，将一种反应性荧光化合物，例如一种反应性荧光材料，例如一种染料(D)，与一种共反应性有机硅烷化合物，例如一种已知的有机官能性硅烷化合物(OS)混合，以形成荧光核颗粒(D-OS)；并将得到的核颗粒(D-OS)与一种可形成二氧化硅的化合物例如(Si(OR)4)混合，以形成于核上的二氧化硅壳体，其产物是荧光纳米颗粒(D-OS)(SiO2)。
反应性荧光材料(D)与共反应性有机硅烷化合物(OS)的摩尔当量比可以是例如约1∶1到约1∶100。荧光核颗粒(D-OS)与可形成二氧化硅化合物(Si(OR)4)的摩尔当量比可以是例如约1∶1到约1∶100。
本发明的荧光纳米颗粒可以通过例如任何已知的化学偶合反应，例如碳二酰亚胺偶合，选择性地与配体和/或分析物连接。其它偶合方法包括使用羧酸酯、酯、醇、碳酰二胺、醛、胺、硫氧化物、氮氧化物、或卤素，也可以使用本领域其它的已知方法。将荧光纳米颗粒与配体偶合、或将复合荧光纳米颗粒与分析物偶合，以及类似的结合方法，通常可以通过采用美国专利US 6,268,222所公开的方法和原理，或本领域已知的其它方法在本发明中实现。
在本发明实施方案中，连接的荧光纳米颗粒，例如本发明的表面修饰的荧光纳米颗粒，可以由例如一种预先形成的荧光纳米颗粒荧光纳米颗粒(D-OS)(SiO2)和一种配体(例如生物活性化合物(化学式X1-R1-X2))，以及任选的一种连接剂前体(化学式Z1-L-Z2)来制备，其中X1、X2、Z1和Z2可以选自下表中的值。在没有任选的连接剂前体时，二氧化硅壳体的表面硅烷醇(Si-OH)基团可以用于与配体连接或结合。使用已知的合成技术(例如通过缩合反应)可以将配体与连接剂前体反应或聚合，以提供本发明的复合荧光纳米颗粒或连接产物。根据配体的反应性官能团(X1或X2)，对应的官能团(Z1或Z2)可以选自下表，用以向复合荧光纳米颗粒或连接产物提供酯键、硫酯键或酰胺键。
  配体上的官能团(X1或X2)   连接剂前体上的官能团(Z1或Z2)   复合荧光纳米颗粒中生成得到的连键
  -COOH   -OH   酯
  -COOH   -NHR   酰胺
  -COOH   -SH   硫酯
  -OH   -COOH   酯
  -SH   -COOH   硫酯
  -NHR   -COOH   酰胺
  -SO3H   -OH   硫酸酯
  -OH   -SO3H   硫酸酯
本领域普通技术人员都清楚，连接反应过程中可以使用合适的保护基团。例如，存在于生物活性化合物中、纳米颗粒表面上或连接剂前体中的其它官能团，可以在连接过程中被部分地或完全地予以保护，并且可以随后去除保护基团以提供本发明的复合荧光纳米颗粒。合适的保护基团及其引入和去除方法在本领域是已知的(参见例如Greene，T.W.；Wutz，P.G.M.“Protecting Groups In OrganicSynthesis”，第二版，1991，纽约，John Wiley & sons，Inc.)。
另外，当羧酸与羟基基团、巯基基团或胺基基团反应以提供酯键、硫酯键或酰胺键时，可以在反应之前对羧酸进行活化，例如通过形成相应的酰氯。许多用于活化羧酸的方法以及用于制备酯键、硫酯键和酰胺键的方法在本领域是已知的(参见例如Advanced OrganicChemistry：Reaction Mechanisms and Structure，第四版，JerryMarch，John Wiley & sons，419-437和1281页)。
如果需要，纳米颗粒的二氧化硅壳体表面可以使用已知的交联剂，通过例如表面官能化反应进行进一步的修饰，以提供表面官能团，如本发明的举例说明。所述交联剂有，例如二乙烯苯、乙二醇二甲基丙烯酸酯、三羟甲基丙烷三甲基丙烯酸酯、N，N’-亚甲基-二-丙烯酰胺、烷基醚、糖、肽、DNA片段，或其它已知的功能相同的试剂。对于本领域普通技术人员，显而易见的是，多种交联剂可以在形成本发明的复合荧光纳米颗粒时与配体结合或适合用作配体。对于掌握本发明的本领域普通技术人员，显而易见的是，交联剂可以用在表面修饰反应中，以改变荧光纳米颗粒或复合荧光纳米颗粒的表面特性，如本发明的举例说明。
材料和方法
所有试剂无需经进一步纯化和蒸馏即可使用。氨水的摩尔浓度在每次合成前通过甲基蓝指示剂滴定确定。玻璃器皿按文献所述方法清洗，并在合成前用热风器干燥。在摩尔浓度计算中忽略混合后的体积。荧光核合成中3-氨基丙基三乙氧基硅烷(APTS)的量在表I的单体摩尔浓度计算中未考虑。
纳米颗粒合成材料
无水乙醇(Aldrich)、四氢呋喃(Aldrich)、氨水(Fluka，28％)、四乙氧基硅烷(Aldrich，98％)、3-氨基丙基三乙氧基硅烷(Aldrich，99％)、3-巯基丙基三乙氧基硅烷(Gelest，99％)、四甲基若丹明-5-(和-6-)-异硫氰酸酯*混合异构体*(TRITC)(Molecular Probes，88％)，Alexa Fluor488 C5马来酰亚胺(Meleimide)(Molecular Probes，97％)、Alexa Fluor488羧酸、和琥珀酰亚胺酯(Molecular Probes，≥50％)。
制备核(荧光种子)纳米颗粒的通用方法
用量筒称量水、氨水和溶剂。荧光种子颗粒的合成在1L锥形烧瓶中进行，并用涂有TEFLON的磁性搅拌棒搅拌，转速约600rpm。将去离子水和氨水溶液加入乙醇中并搅拌。将含有约425微摩尔APTS的乙醇或THF中的约2mL的反应性染料前体加入到反应容器中。得到的混合物室温下搅拌约1至约3小时，反应容器用铝箔覆盖以将曝光降到最低，以提供荧光种子颗粒混合物。氮气保护下蒸出四氢呋喃(THF)和无水乙醇(EtOH)。取出储藏于约-20℃的有机染料并置于室温中，然后置于手套箱中。
制备核(荧光种子)颗粒上的二氧化硅壳体的通用方法
二氧化硅壳体的包覆和生长步骤在上述荧光种子颗粒反应混合物中进行，定期加入溶剂，例如乙醇、甲醇或异丙醇，以防止在加入可形成二氧化硅的单体四乙氧基硅烷(TEOS)时，溶液的离子强度急剧变化。这一方法防止了合成过程中会使颗粒尺寸分布变宽的颗粒聚集。
荧光纳米颗粒的表征
得到的荧光纳米颗粒的颗粒尺寸和颗粒尺寸分布通过电子显微镜(SEM)和荧光相干光谱(FCS)进行表征。
图1示出了本发明的荧光纳米颗粒覆盖整个紫外-可见吸收光谱。
图2A-B显示每个部分、单一TRITC染料、富染料核以及核/壳结构的流体动力学半径和亮度的一个实例。图2A说明各部分的FCS曲线具有单一扩散系数，表明样品在测量精度内是单分散的。TRITC的扩散系数为0.21μm2/ms，与其它报道一致，对应的流体动力学Stokes-Einstein半径为约1.0nm(图2A，红圈)。核仅仅略微大于游离染料，半径为2.2nm(图2A，绿圈)。在增加二氧化硅壳体后，颗粒半径增加到15nm。由于TEM分析过程中电子束辐射的衰减作用(degradation)，干的二氧化硅纳米颗粒会显得比流体动力学半径小。
图2B示出了在相同的激发功率下三个合成阶段的亮度。自相关振幅提供了扩散种类的数量，平均计数率(count rate)是收集自光学定义焦点体积(focal volume)的光子的度量。因此可以得到各扩散种类的每分子的计数率，即探针亮度的直接度量。核的荧光实际上小于游离TRITC的荧光，表明致密的富染料核与游离染料相比有严重的淬灭。然而，在核的外部增加无染料的二氧化硅壳体后，荧光增加了30倍。
图3A-D示出了荧光纳米颗粒合成中间体的溶剂可及性和漂白行为(bleaching behavior)。核/壳颗粒的溶剂可及性在图3A-C中表示为更换溶剂后激发光谱和发射光谱的移动。游离染料和核的激发和发射光谱在将乙醇换为水后表现出红移(图3A、B)。然而，二氧化硅纳米颗粒光谱表现出少许的光谱移动，如果存在的话(图3C)，表明纳米颗粒壳很大程度上是不能被溶剂渗透的。
图3D示出了染料、核、核/壳和荧光素的光漂白(bleach)行为。核和核/壳的漂白均小于游离TRITC，并且核/壳与核相比表现出减弱的光漂白。有趣的是，注意到TRITC是具有相当光稳定程度的荧光团，因此游离染料和二氧化硅纳米颗粒之间光稳定性的差别较小。然而，与荧光素异硫氰酸酯，一种快速漂白荧光团相比，所述纳米颗粒的光稳定性明显高得多。结合溶剂更换的结果，所述测量表明CU点中的染料对于溶剂而言是相对不可及的，且该保护增强了光稳定性。
图4A-D示出了通过标记大鼠嗜碱性白血病(RBL)肥大细胞的FcεRI受体，将二氧化硅纳米颗粒用作生物成像标志物的可能性。已知抗体免疫球蛋白E(IgE)和它的细胞表面受体FcεRI形成可逆、但牢固的复合物。IgE以结合检测迭代确立的最优比例1∶1吸附到CU点的表面。图4A、B示出了用抗体吸附的二氧化硅纳米颗粒标记RBL的一般情况。在细胞的中纬剖面(equatorial section)上，仅有细胞的外围被标记，这正如对跨膜FcεRI受体所期望的。作为阴性对照，RBL肥大细胞在与未修饰的二氧化硅纳米颗粒一起培养之前用IgE预敏化过夜。
图4C、D示出，观察到很少的边缘着色，表明所述二氧化硅纳米颗粒和细胞表面之间的非特异性相互作用最小。
图5比较了游离染料、二氧化硅纳米颗粒和在577nm处有荧光峰的量子点的亮度(对于二氧化硅纳米颗粒和量子点，是计数/颗粒，对于TRITC，是计数/分子)。量子点和CU点的亮度均比自由TRITC大一个数量级。
图6给出了本发明的荧光纳米颗粒(10)的荧光亮度特性与聚苯乙烯乳胶珠(20)相比较的实例。使用荧光相干光谱(FCS)得到纳米颗粒和乳胶珠的计数率如下：100或300纳米的荧光纳米颗粒为299.1kHz每颗粒；300纳米的聚苯乙烯乳胶珠为69.84kHz每珠。荧光计数率表明荧光纳米颗粒(10)的亮度比聚苯乙烯乳胶珠的亮度大约4倍。
进行光物理表征以确定：每颗粒容积染料含量的荧光寿命，及作用截面(action cross-sections)。作用截面度量(metric)实质上是量子产率和吸收曲线的乘积。荧光对时间以纳秒(ns)为单位的时间分辨荧光测量表明，引入纳米颗粒的染料的寿命，比溶液中游离染料的寿命短。纳米颗粒的荧光寿命据测量为1.9ns，而TRITC的寿命据测量为2.1ns。单从寿命数据，可能得出以下结论，即染料在致密的核-壳颗粒中淬灭，但是稳态测量却表示出不同结论。结合荧光寿命与量子效率可以唯一确定辐射和非辐射率常数。辐射率的提高比游离TRITC大2.2倍，导致观察到的荧光总体地增强了一个数量级。
通过250到650纳米范围内的吸收测量确定，例如每个纳米颗粒具有约20个染料分子。例如，样品R30中每个纳米颗粒具有约23个TRITC染料分子；样品R29中每个纳米颗粒具有约21个TRITC染料分子。然而，在700到约1000nm范围内，对25nm颗粒的两个独立制品(样品R29和R30)的作用截面测量，σ2p(GM)表明在该范围内，特别是在约700和约840纳米的最大吸收处，R30的亮度几乎是R29的两倍，尽管其染料含量几乎相同。该观察结果表明核与壳体之间相互作用效应存在高度复杂性，且所述相互作用效应可能是观察到量子效率提高的原因。这样，就有可能通过简单直接的方法，例如改变核或壳体的厚度，对本发明的纳米颗粒的荧光特性进行进一步的优化，以用作例如生物标志物，如本发明所公开的。
现将通过以下非限制性的实施例对本发明加以说明：
实施例1
红核纳米颗粒的制备。将10mg四甲基若丹明-5-(和-6-)异硫氰酸酯(TRITC)溶解于乙醇中。3-氨基丙基三乙氧基硅烷(APTS)与TRITC的摩尔比为50∶1，每mg APTS 2mL乙醇。TRITC在乙醇中完全溶解后，将APTS加入反应容器中。反应在避光条件下于手套箱中室温搅拌约12个小时。
实施例2
绿核纳米颗粒的制备。
将5mg Alexa Fluor488 C5马来酰亚胺(Meleimide)溶解于乙醇中。3-巯基丙基三乙氧基硅烷(MPTS)的摩尔比为100∶1，每mg MPTS2mL乙醇。将TRITC在乙醇中完全溶解后，MPTS加入反应容器中，并在避光条件下室温搅拌约12个小时。
将5mg Alexa Fluor488羧酸琥珀酰亚胺酯溶解于THF中。3-氨基丙基三乙氧基硅烷(APTS)与Alexa Fluor488羧酸琥珀酰亚胺酯的摩尔比为100∶1，每mg APTS 2mL THF。Alexa Fluor488羧酸琥珀酰亚胺酯在THF中完全溶解后，将APTS加入反应容器中，并在避光条件下室温搅拌12个小时。由于数量微少，在二氧化硅壳体沉积之前未将荧光染料-核加合物从反应介质中分离。
实施例3
多种尺寸的二氧化硅包覆的荧光纳米颗粒的制备
不同尺寸的二氧化硅包覆荧光纳米颗粒的制备，通过使用不同的相对摩尔量的上述试剂来完成。用于合成20nm到200nm颗粒的试剂的摩尔量列于表I中。所有的二氧化硅包覆荧光纳米颗粒的方法都在环境条件中完成，即室温下以乙醇作为溶剂。一个代表性的方法如下：
将170μM由实施例2和实施例3合成的前体加入至合适量的催化剂、水和表I所列溶剂中，合成得到富染料二氧化硅核。加完后将混合物反应过夜。向包含荧光核颗粒的该混合物中连续逐滴加入(例如经约20分钟)溶于另外的100mL溶剂中的2mL TEOS。剩余的较多量的TEOS以更快的速度加入，例如在约45分钟内加入并同时加入另外的400mL溶剂。任选地，在该阶段加入水以使生长的颗粒大于约100nm，并保持水与TEOS的摩尔比如表I所列。得到的悬浮液在避光条件下室温搅拌过夜。
表I.用于制备的反应物(以摩尔计)及得到的二氧化硅壳体包覆的荧光纳米颗粒的颗粒尺寸
  额定颗粒尺寸 [NH3] [H2O] [TEOS] 溶剂   FCS测得的尺寸   SEM测得的尺寸
  500nm300nm200nm100nm70nm50nm40nm30nm25nm   6.127M6.127M3.892M3.892M0.0085M0.0085M0.318M0.150M0.200M   16.83M16.83M10.80M10.80M17.60M26.68M1.153M1.710M1.494M   0.1923M0.1923M0.2443M0.2443M0.2003M0.1518M0.155M0.155M0.155M   i-PrOHEtOHEtOHi-PrOH∶MeOH(v∶v＝3∶1)EtOHMeOHEtOHEtOHEtOH   -----48.6nm37.6nm28.8nm24.4nm   500nm300nm200nm125nm75nm--30nm-
i-PrOH＝异丙醇；MeOH＝甲醇；EtOH＝乙醇
25nm到40nm和100nm到500nm颗粒的氨的来源是28％的氨水；对于额定纳米颗粒尺寸为50nm和70nm的样品，氨的来源是2.0M氨的甲醇溶液。
或者，为制备在低于约70nm且具有窄的颗粒尺寸范围的纳米颗粒，将TEOS以小等分试样周期性地加至包含富染料荧光核的混合物中，例如在约10到15分钟的间隔内加入300微升，并在避光条件下室温搅拌过夜。去离子水与单体的摩尔比保持在约至少6倍但不能更大。为更好地监测反应混合物中水的含量，依据合成的初始溶剂，将2.0M的氨用作催化剂源，溶解于乙醇、甲醇或异丙醇中，例如2.0M氨的乙醇溶液。在制备了富染料核/种子颗粒后，间歇加入原硅酸四乙酯单体，例如每10分钟加入300微升以生长二氧化硅壳体。与通过滴液漏斗连续加入单体的大颗粒制备方法相反，较小颗粒尺寸的制备方法(用于小于约70nm的颗粒的制备)中TEOS单体是间歇加入的。已经设计了制备二氧化硅壳包覆的荧光纳米颗粒的替代方法，因为通过已知的Stber方法(J.Colloid and Interface Sci.，26 62-69(1968))制得的二氧化硅纳米颗粒的尺寸分布，在颗粒尺寸增长超过70nm并继续向反应混合物中加入更多单体时，具有自锐性(self-sharpening)特征。因而，小于70nm的二氧化硅纳米颗粒通常具有更宽的尺寸分布。因此，将实施例3中最初提到的方法按其后所述进行修改，以在约10到约70nm范围内得到比预期颗粒尺寸分布窄的纳米颗粒。
实施例4
纳米颗粒通过吸附与IgE复合(偶合)
实施例3的二氧化硅包覆的荧光纳米颗粒用pH值为7的磷酸盐缓冲盐水(PBS)或Tyrodes缓冲液稀释(1∶10-1∶20)。通过将免疫球蛋白E(IgE)(原液浓度为0.85mg/mL)与荧光纳米颗粒在室温下培育约3小时，使所述免疫球蛋白E吸附到荧光纳米颗粒上以提供例如约1∶1到约1∶4的纳米颗粒-IgE比率。对于大于约50nm的纳米颗粒，未结合的IgE通过离心除去。对于尺寸为50nm或更小的纳米颗粒，未结合的IgE通过加入100微升(在总体积500微升的纳米颗粒-IgE中)0.25wt％的乳胶颗粒除去，所述乳胶颗粒的尺寸为1∶2微米。未结合的IgE与大乳胶颗粒粘结的后如果若干小时不扰动，例如在4℃培育过夜，就会从悬浮液中沉淀出来。残余的小球团经证实主要是与IgE结合的乳胶颗粒，因此丢弃。将得到的包含IgE偶联的纳米颗粒(IgE复合荧光纳米颗粒)的上清液仔细分离并置于瓶中。将得到的IgE偶联的纳米颗粒样品(即吸附在纳米颗粒上的IgE)于4℃储藏以用于细胞结合实验。IgE偶联的纳米颗粒在与细胞结合前稀释于Tyrodes-BSA中。稀释根据所需要的每细胞IgE偶联的纳米颗粒数量密度来进行。
实施例5
纳米颗粒表面官能化
可以对纳米颗粒的表面进行进一步的化学修饰以提高纳米颗粒的多功能性和稳定性，例如引入羧酸基团等化学官能团。向二氧化硅包覆的纳米颗粒表面引入官能团，例如羧酸基团，可以提供连接点，以使生物分子，例如蛋白质和抗体共价连接在纳米颗粒表面。表面官能团，特别是可离子化基团，为纳米颗粒提供了其他所需的特性，例如在缓冲介质中的电荷稳定作用。带电荷的羧酸盐表面基团可以将纳米颗粒保持为单颗粒胶态分散体，从而避免纳米颗粒凝聚或使其降至最低。纳米颗粒表面官能化方法是已知的，并且包括，例如碳二酰亚胺修饰，如本发明所举例说明。
材料
3-氨基丙基二甲基乙氧基硅烷(APDMES)(Gelest Inc.)；双官能交联剂(Pierce Endogen Inc.)：甲基N-琥珀酰亚胺基己二酸(MSA)。
纳米颗粒表面官能化通过如下步骤完成。使用直径25nm的纳米颗粒的悬浮液20mL，如表I所示。通过荧光相干光谱及干燥、称重体积已知的悬浮液，确定其纳米颗粒的浓度为4.33mg/mL。鉴于颗粒尺寸、表面积、浓度等因素的不同对本方法进行适当的修改后，可以根据本方法对其他尺寸和浓度的颗粒进行表面修饰。
具有二氧化硅壳体的荧光纳米颗粒经过上述初始制备后经透析进行净化。通过在真空干燥箱中干燥纳米颗粒悬浮液的等分试样并称重，或通过荧光相干光谱，确定二氧化硅外壳纳米颗粒悬浮液的浓度。假设密度为2g/mL并已知纳米颗粒的尺寸，每mL悬浮液的颗粒数经计算为约1.78×1016。纳米颗粒，假设为实心颗粒，则其总表面积为例如约3.35×1019nm2。根据文献值(例如R.Iler，The Chemistry ofSilica)，硅醇基团的密度可以估计为每平方纳米约1.4个-OH基团，因此可以有约7.78×10-5摩尔的-OH基团与APDMES反应以获得100％的胺覆盖率。加入的APDMES过量2摩尔，并用约5mg氟化铵作为催化剂，可在环境温度下反应12小时，并与环境光线隔离。过量的未反应的APDMES在pH值为7的磷酸盐缓冲液中透析12小时去除。然后将得到的悬浮在pH值为7的磷酸盐缓冲液中的胺化纳米颗粒与溶解在二甲基亚砜中的过量2摩尔的MSA在环境温度下反应约2到6小时。过量的未反应的MSA在pH值为9.5的磷酸盐缓冲液中透析约6到12小时去除，同时也将MSA中的酯基水解，以提供通过共价键连接到纳米颗粒表面的羧酸基团。
通过FTIR表征纳米颗粒
上述各官能化步骤中的纳米颗粒产物通过傅立叶变换红外光谱(FTIR)进行表征。单取代酰胺基团在1500-1600cm-1的振动谱带及1700cm-1的羧酸特征峰表明，硅烷化合物APDMES的胺基基团与MSA化合物的琥珀酰亚胺酯基团之间有连键存在。观察到的相对于初始纳米颗粒的光谱变化表明表面官能化反应是成功的。
实施例6
纳米颗粒通过共价轭合进行复合(偶合)
其它表面官能化的实例可以通过荧光纳米颗粒与上述多种生物分子的共价轭合完成。
实施例7
与IgE偶联荧光纳米颗粒结合的细胞
采用大鼠嗜碱性白血病(RBL)肥大细胞模型系统的特异性结合实验表明，基于二氧化硅的荧光纳米颗粒具有特异性结合的特征。用胰蛋白酶-EDTA收获细胞(例如大鼠嗜碱性白血病(RBL)肥大细胞)。然后对细胞计数以确定细胞浓度(每mL细胞数)。将合适数量的细胞与IgE偶联纳米颗粒，例如每个细胞约2×105个IgE偶联纳米颗粒，在冰上培育约1小时以避免任何内化(internalization)。得到的纳米颗粒-IgE结合细胞，即结合到细胞上的IgE偶联纳米颗粒，用Tyrodes-BSA清洗，然后在共焦显微镜下观察细胞的特异性结合。
共焦显微镜图像显示，例如，细胞的顶部表面由红色纳米颗粒修饰，而抗体IgE由绿色荧光团标记以显示抗体与纳米颗粒的共定位(co-localization)。从细胞的赤道面观(equitorial view)得到的另一组图像显示一个共焦视图，其中可以通过SPT监测用荧光纳米颗粒标记的抗体受体的扩散运动。合适的对照实验按如下进行以检测非特异性结合。对照细胞用IgE预敏化过夜以阻断所有受点。然后以与上述相同的方式用胰岛素-EDTA收获所述阻断的细胞，以相同的每细胞IgE偶联纳米颗粒浓度对其进行标记。然后在共焦显微镜下观察所述细胞的任何非特异性结合(或粘结)。
参考图7A和7B，其中示出了例如本发明直径为100或300纳米的荧光纳米颗粒(图7A)与聚苯乙烯乳胶珠(图7B)相比具有高度生物分子结合特异性的实例，所述特异性由细胞计数统计测定。结果表明，与IgE偶联纳米颗粒偶合的大鼠嗜碱性白血病(RBL)肥大细胞和与聚苯乙烯乳胶珠偶合的细胞的特异性相互作用(由条形对的左侧表示)具有可比性，而对于不太需要或不需要的非特异性相互作用(由条形对的右侧表示)，例如“粘结”相互作用，则是聚苯乙烯乳胶珠和细胞之间的作用大于IgE偶联纳米颗粒和细胞之间的作用。预计本发明的荧光纳米颗粒具有相似的结果，直径在25纳米到100纳米之间。
在图7A和7B中，图例：
“IgEM”表示将与大鼠嗜碱性白血病(RBL)肥大细胞的IgE受体特异性结合的小鼠IgE。
“对照：IgEH”表示将不与前述大鼠细胞的IgE受体结合的人类IgE；
“对照：单独的颗粒”表示各IgE偶联荧光纳米颗粒和细胞的结合以及聚苯乙烯乳胶珠和细胞的结合。
实施例8
单颗粒跟踪(SPT)
通过共焦跟踪选定的单个亮荧光点(对应于单个受体结合颗粒)的运动进行约20-30分钟单荧光纳米颗粒跟踪实验，以跟踪单个颗粒所结合的受体的扩散。或者，可以跟踪多个选定的单个亮荧光点。
单颗粒跟踪能够评价个别组分在细胞表面上的横向扩散。该方法基于直接观察与所研究的大分子特异性轭合的亮荧光探针。对个别组件的跟踪揭示了多种有趣和有用的行为，包括局限于小区域内或沿某一轨迹运动。该信息使得可以理解组件在细胞内、在细胞膜上等结构或组件中是如何相互作用的。然而，该方法高度依赖于探针的质量。该方法的一个重要缺点是颗粒对细胞的非特异性结合。本发明的荧光纳米颗粒和复合荧光纳米颗粒提供了增强的亮度和对于所研究组件的高轭合特异性。已证明本发明的复合荧光纳米颗粒具有生物相容性并可将非特异性结合相互作用最小化。
实施例9
用于治疗剂靶向释放和受控释放的介孔二氧化硅纳米颗粒
荧光核纳米颗粒根据例如实施例1和2制备，并与以上通用的核制备方法相一致。
介孔壳体
将一种表面活性剂，N-十六烷基三甲基溴化铵(2.4g，6.6mmol，HDTB)溶解于含荧光种子核纳米颗粒的反应混合物中。搅拌混合物(450rpm)直至HDTB完全溶解，然后一次性加入3.4g TEOS(16mmol)。HDTB作为模板剂(templating agent)，围绕该模板剂的二氧化硅壳的形成被有序化和干扰，以使通过随后去除与表面结合的HDTB形成孔成为可能。随后将HDTB从纳米颗粒上清洗或去除，得到介孔二氧化硅壳体的荧光纳米颗粒。
清洗方法
与TEOS反应约5小时后，在6000rpm下离心洗涤三次回收固体。在各离心步骤中，上清液用无水乙醇更新。离心步骤后在去离子水中通过过滤洗涤两次。离心和过滤步骤去除约90％的HDTB表面活性剂。回收的含有纳米颗粒的固体最终悬浮于无水乙醇中。悬浮液用超声搅拌均一化。
进行减压蒸馏以用二甲基亚砜(DMSO)替换乙醇溶剂。通过干燥悬浮液的等分试样并称重固体质量确定最终浓度。在DMSO中得到的介孔纳米颗粒适于填载治疗剂，如下文说明。
用治疗剂填载介孔纳米颗粒
搅拌上述悬浮于DMSO中的介孔纳米颗粒并将其转移至50mLFalcon管中。溶液以3000rpm离心约5分钟，倒去6mL上层液体使DMSO的体积减少至4mL。将16mg治疗剂喜树碱(CPT)样品加至溶液中。5小时后，将溶液离心，用磷酸盐缓冲盐水(PBS)进行两次洗涤。每次洗涤加入20mL PBS，并对颗粒进行超声处理及离心。超声处理在15％的功率下，以1.0秒开1.0秒关的脉冲速率进行，用脉冲处理30秒或者直至溶液看似均匀。离心在25℃以3000rpm进行5分钟。填载有治疗剂的颗粒于室温下储藏。
所有的出版物、专利、专利文献在此通过援引的方式纳入本申请，如同通过援引的方式单独纳入一样。参照多种具体的优选实施方案和技术对本发明进行了描述。然而，应该理解的是，可以对其进行多种变化和修改而仍处于本发明的主旨和范围内。
图8A表明，红核和绿色染料均在488nm固定于纳米颗粒的孔内。图8A进一步表明，用一些绿色染料将红核截留在孔中的介孔颗粒将使颗粒产生两种荧光信号。当颗粒在488nm，即绿色染料的最大吸收处被激发时，绿色染料的信号较红核的信号增强更多，因为红色染料仅有最低限度的吸收。当相同的悬浮液在585nm，即红核最大吸收处被激发时，红色信号增强，进一步证实介孔颗粒内确实存在红核。在红核的最大吸收，即，585nm处激发时，红核仍然固定于纳米颗粒内。
图8B示出了涉及使用表面活性剂分子N-十六烷基三甲基溴化铵合成MCM 48。还描述了固定绿色染料或化学治疗剂的方案。
图8C示出了纳米颗粒的TEM表征：将纳米颗粒(无红核)包埋于环氧树脂中，显微切割为30nm的薄片并置于铜栅格上。用LEO 922能量过滤(energy-filterd)TEM在200keV的弹性(elastic)亮视野中以44,000X的放大率摄得图像。立方-双连续的规则介孔清晰可见。

Claims (58)

1.一种荧光纳米颗粒，该纳米颗粒包括：
含有一种荧光硅烷化合物的核；和
于核上的二氧化硅壳体。
2.权利要求1的纳米颗粒，其中所述核包括一种反应性荧光化合物与一种有机硅烷的反应产物，所述壳体包括一种可形成二氧化硅化合物的反应产物。
3.权利要求1的纳米颗粒，该纳米颗粒进一步包括位于荧光纳米颗粒表面上的一种配体，以形成复合荧光纳米颗粒。
4.权利要求3的纳米颗粒，其中荧光纳米颗粒表面上的配体通过共价键键合或物理吸附附着。
5.权利要求3的纳米颗粒，其中荧光纳米颗粒表面上的配体选自生物聚合物、合成聚合物、抗原、抗体、微生物、病毒、受体、半抗原、酶、激素、化合物、病原体、毒素、表面修饰剂及其组合。
6.权利要求1的纳米颗粒，其中包覆在核上的二氧化硅壳体覆盖核表面积的约10％到约100％。
7.权利要求3的纳米颗粒，其中荧光纳米颗粒表面上的配体覆盖核表面积的约10％到约100％。
8.权利要求1的纳米颗粒，其中核的厚度与二氧化硅壳体的厚度的比值为约1∶1到约1∶100。
9.权利要求1的纳米颗粒，其中纳米颗粒的直径为约1到约1,000纳米。
10.权利要求1的纳米颗粒，该纳米颗粒进一步包括一种治疗剂。
11.权利要求3的纳米颗粒，该纳米颗粒进一步包括一种治疗剂。
12.权利要求10或11的纳米颗粒，其中治疗剂选自药物、生物分子、表面修饰剂及其组合。
13.权利要求10或11的纳米颗粒，其中治疗剂吸附到纳米颗粒的二氧化硅壳体中。
14.权利要求10或11的纳米颗粒，其中治疗剂包覆在纳米颗粒的二氧化硅壳体上。
15.权利要求3的纳米颗粒，其中治疗剂与纳米颗粒的配体结合。
16.一种制备荧光纳米颗粒的方法，该方法包括：
将一种荧光化合物与一种有机硅烷化合物混合以形成荧光核；以及
将得到的核与一种可形成二氧化硅化合物混合以形成于核上的壳体，制得所述荧光纳米颗粒。
17.权利要求16的方法，该方法进一步包括将得到的纳米颗粒与一种配体结合，所述配体选自生物聚合物、合成聚合物、抗原、抗体、微生物、病毒、受体、半抗原、酶、激素、化合物、病原体、毒素、表面修饰剂及其组合。
18.权利要求16的方法，该方法进一步包括将得到的荧光纳米颗粒与一种治疗剂结合，所述治疗剂选自药物、生物分子、表面修饰剂及其组合。
19.权利要求17或18的方法，其中，所述结合包括将配体或治疗剂包覆在纳米颗粒表面上。
20.权利要求17或18的方法，其中，所述结合包括使配体或治疗剂透入纳米颗粒表面中。
21.权利要求17或18的方法，其中所述结合包括将配体或治疗剂键合到得到的纳米颗粒表面上。
22.一种监测细胞的细胞组分移动的方法，包括：
将细胞与复合荧光纳米颗粒接触以形成复合荧光纳米颗粒选择性修饰的细胞，并形成一个荧光位点；以及
记录一段时间内该荧光位点的运动，以监测细胞组分的移动。
23.权利要求22的方法，其中荧光位点对应于结合到细胞组分上的一个或多个复合荧光纳米颗粒。
24.权利要求22的方法，其中荧光位点对应于结合到细胞组分上的单个复合荧光纳米颗粒。
25.权利要求22的方法，其中复合荧光纳米颗粒适用于选择性地与细胞的细胞组分缔合。
26.权利要求22的方法，其中细胞组分是受体、抗体、半抗原、酶、激素、生物聚合物、抗原、微生物、病毒、病原体、毒素和其组合。
27.权利要求22的方法，其中复合荧光纳米颗粒是与抗体轭合的荧光纳米颗粒。
28.权利要求27的方法，其中抗体是免疫球蛋白。
29.权利要求28的方法，其中抗体是IgE。
30.权利要求22的方法，其中记录通过显微适用的照相机完成。
31.权利要求22的方法，其中记录时间是约1微秒到约30天。
32.权利要求22的方法，其中记录时间是约1秒到约60分钟。
33.权利要求22的方法，其中接触和记录在体外完成。
34.权利要求22的方法，其中接触和记录在体内完成。
35.一种药用载体，该药用载体包括权利要求1的荧光纳米颗粒，并任选包括一种配体。
36.一种药用组合物，该药用组合物包括权利要求3的复合荧光纳米颗粒，并任选包括一种治疗剂。
37.一种显像剂，该显像剂包括权利要求3的复合荧光纳米颗粒。
38.一种治疗疾病或病症的方法，该方法包括：
向需要治疗的患者给药有效量的复合荧光纳米颗粒，所述纳米颗粒任选包括一种治疗剂，纳米颗粒适于与引起疾病的细胞组分选择性地结合，以形成复合荧光纳米颗粒选择性修饰的细胞；以及
照射经修饰的细胞以治疗疾病或病症。
39.权利要求38的方法，其中复合荧光纳米颗粒在照射时发出荧光并发热。
40.权利要求38的方法，其中复合荧光纳米颗粒是一个与荧光纳米颗粒复合的抗体。
41.权利要求38的方法，其中疾病是恶性肿瘤。
42.权利要求38的方法，其中疾病对荧光和/或热敏感。
43.一种治疗疾病或病症的方法，该方法包括：
将细胞与复合荧光纳米颗粒接触以形成复合荧光纳米颗粒选择性修饰的细胞；以及
照射得到的经修饰的细胞一段时间以治疗疾病或病症。
44.一种用于检测分析物的试剂盒，所述试剂盒包括含有复合荧光纳米颗粒的包装材料。
45.一种用于检测和监测细胞表面组件的试剂盒，所述试剂盒包括含有复合荧光纳米颗粒的包装材料，用于检测细胞表面组分，并任选包括一个记录仪，用以监测细胞表面组分。
46.一种用于在对细胞用治疗剂处理时，检测细胞的细胞组分的运动或位置改变的检测方法，该方法包括：
将细胞与复合荧光纳米颗粒接触，所述纳米颗粒包括一种治疗剂，以将复合荧光纳米颗粒结合到细胞组分上；以及
记录荧光信号，以检测组分的运动或位置改变。
47.权利要求46的方法，该方法进一步包括确定有、无治疗剂结合的复合荧光纳米颗粒的运动或移动的差别。
48.一种检测分析物存在的方法，该方法包括：
将可能含分析物的样品与复合荧光纳米颗粒接触，所述复合荧光纳米颗粒适用于与可能存在的分析物结合，以形成复合荧光纳米颗粒-分析物复合物；
任选分离未复合的复合荧光纳米颗粒；以及
检测复合荧光纳米颗粒-分析物复合物的荧光信号以确定分析物的存在。
49.权利要求48的方法，其中复合荧光纳米颗粒-分析物包括：
一种复合荧光纳米颗粒，其中配体选自细胞组分、生物聚合物、合成聚合物、抗原、抗体、受体、半抗原、酶、激素、化合物、病原体、毒素及其组合；以及
一种分析物，选自微生物、病毒、细胞、细胞组分、生物聚合物、合成聚合物、抗原、抗体、受体、半抗原、酶、激素、化合物、病原体、毒素及其组合。
50.一种荧光纳米颗粒，包括：
含有一种荧光硅烷化合物的核；和
于所述核上的多孔二氧化硅壳体。
51.权利要求50的纳米颗粒，该纳米颗粒进一步包括荧光纳米颗粒表面上的一种治疗剂、一种配体或其混合物。
52.权利要求51的纳米颗粒，该纳米颗粒进一步包括荧光纳米颗粒表面上的一种配体。
53.权利要求51的纳米颗粒，该纳米颗粒进一步包括荧光纳米颗粒表面上的一种治疗剂。
54.权利要求51的纳米颗粒，该纳米颗粒进一步包括荧光纳米颗粒核中的一种磁性组分。
55.权利要求16的方法，该方法进一步包括在核上形成二氧化硅壳体之前用模板剂处理荧光核。
56.权利要求55的方法，其中模板剂是一种季铵盐。
57.权利要求55的方法，该方法进一步包括在核上形成二氧化硅壳体后去除模板剂，以提供多孔二氧化硅壳。
58.权利要求57的方法，该方法进一步包括用配体、治疗剂或其混合物处理所述多孔二氧化硅壳。
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