高稳定性近红外荧光探针及其活体成像研究
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摘要
目前,疾病诊断成像技术主要包括核磁共振(MRI)、正电子发射计算机断层扫描(PET)、X射线断层扫描光影像(CT)、超声造影、荧光分子成像等。其中,荧光分子成像技术因其简单便携、高时空分辨率(可以观察到细胞亚结构)而倍受关注,利用基于传统染料的荧光探针对疾病早期的变异进行靶向性识别和特异性诊断已成为研究热点。而高质量的荧光成像对其所用的荧光团也提出非常高的要求。鉴于长波长近红外光在体内性穿透深、散射少以及背景荧光干扰小等特点,以及成像过程中的长时间、高强度的激发对染料稳定性的要求,使用具有近红外荧光并且光稳定性良好的荧光团对荧光成像尤为重要。然而,至今为止大多数常用的荧光团的应用往往受阻于短波长的发射(如荧光素类荧光团)或较差的光稳定性(如菁染料)。因此,本论文重点关注长波长的近红外荧光团和发展制备高稳定性荧光染料方法,通过新结构的设计和针对影响稳定性因素的物理包裹的方法,开发高稳定性近红外荧光探针,并寻求在生物医学领域中生物标记、肿瘤标记以及监控药物传输与释放等成像可视化研究。
首先,就荧光成像的概念及原理进行了阐述,并且重点介绍了荧光成像对其中所用的荧光团在波长以及稳定性方面的要求。其后,介绍了荧光探针中的常用传感原理。
目前基于肿瘤组织的增强渗透滞留效应(Enhanced permeability and retention effect,EPR),荧光纳米颗粒的成像研究日益受到重视。第二章中针对常用的近红外染料菁染料在荧光生物成像中的应用受到其极差的光稳定性制约的缺陷,创新地提出了用以菁染料为核心的新型荧光纳米颗粒CyN-12@NHs来代替传统菁染料作为荧光成像剂的方案,并对其进行了性能研究。用两性嵌段共聚物所形成的纳米胶束将含有长碳链的菁染料分子以物理包裹的方式包裹在核心中,再由硅烷偶联试剂MPTMS对胶束表面进行交联,最终形成具有核-壳结构,平均直径约为35nm的荧光纳米颗粒。研究发现,菁染料结构中的长碳链的引入可与两亲性嵌段聚合物能形成球形胶束,纳米颗粒的直径可很好地控制在50nm以下；胶束亲水端在外的特性使得该纳米颗粒具有良好的亲水性,并且在大极性溶剂中拥有比包裹前的染料更好的光学性能。该纳米颗粒将包裹在其中的染料分子与外界环境隔离,使其具有比包裹前的染料和商用染料ICG分别高出50倍和95倍的光稳定性,且荧光效率提高数百倍。该纳米颗粒表面由生物相容性极好的硅氧层构成,因此其几乎没有细胞毒性,能够在细胞成像中取得良好的结果。在使用裸鼠进行的生物活体成像中,该纳米颗粒能够在进行瘤内注射后长时间停留在肿瘤内进行成像,显示出纳米颗粒良好的EPR效应。因此,CyN-12@NHs具备代替传统的小分子菁染料成为性能良好的生物活体成像剂的能力,在提升菁染料的亲水性、稳定性、荧光量子效率方面取得了重要突破。
谷胱甘肽(GSH)是体内浓度最高的含巯基化合物,其对维持生物体系中的氧化还原生理平衡有非常重要的作用。针对大多GSH荧光探针仅能在可见光区对其进行检测的缺陷,在第三章中设计并合成了新型的基于苯并吡喃腈荧光团的高稳定性比色、近红外荧光双通道GSH探针DCM-S。将含有二硫键的响应基团与基于苯并吡喃腈衍生物的荧光团通过氨基甲酸酯进行桥连,使得荧光团的荧光蓝移并且淬灭。在GSH的作用下,二硫键被切断,最终生成荧光团DCM-NH2,在光学性能方面表现为吸收光谱的红移(溶液颜色由黄变红)和荧光的红移(由可见光区红移至近红外区665nm)以及强度增强(荧光量子效率增大6倍)。并且DCM-S能够以荧光比率的方式对GSH进行检测,该检测方法能够消除外界环境、染料浓度等方面的干扰,使得检测更为准确。更重要的是,在与GSH作用之后,DCM-S显示出比市售菁染料ICG长约20倍的荧光强度半衰期,显示出远高于ICG的光稳定性。最后,DCM-S在细胞中以比率的方式对GSH的检测能力同样得到了证实,其极大的Stokes shift(斯托克斯位移,215nm)同样能够减少在生物成像中所受到的背景荧光干扰。研究表明,DCM-S实现了对GSH良好的比色和近红外荧光比率双通道响应以及细胞内比率型荧光检测,更对发展GSH诱导的药物释放体系具有重要的意义。
与荧光团相连的具有诊疗效果的前药因其能对药物在生物体内的分布和激活进行可视化跟踪监测,对生物医学具有重要的意义。针对现有的荧光前药在生物成像中的应用受到其短波长或稳定性差的制约,第四章将DCM-S与抗癌药物羟基喜树碱(CPT)相连,形成基于近红外苯并吡喃腈荧光团的具有高度稳定性的抗癌诊疗前药,并且对其进行了PEG-PLA胶束包裹。与GSH作用时,在其将二硫键切断后,DCM-S-CPT能够释放出具有抗癌活性的药物CPT,并且其665nm处的荧光表现出明显的增强。因此,该近红外荧光的增强可以作为活性药物释放的表征。在与GSH作用后DCM-S-CPT表现出比ICG高出19倍的荧光半衰期即更好的光稳定性。细胞成像方面,由于癌细胞中的GSH浓度远高于正常细胞,DCM-S-CPT及其纳米颗粒对癌细胞表现出与CPT类似的药理效果,而对正常细胞则表现出极低的细胞毒性。在活体成像中,DCM-S-CPT表现出意料之外的极好的肿瘤靶向性能,显示出非常低的边缘效应。DCM-S-CPT的纳米胶束表现出与CPT类似的肿瘤生长抑制效果,但对小鼠本身表现出远低于CPT的毒性。研究显示,该前药可利用肿瘤微环境的调控,集诊断、治疗为一体,充分利用吡喃腈(DCM)染料单元的近红外长波长荧光在生物活体成像中的独特优势,成功实现了在体、原位活体成像监测以及肿瘤前药的可视化控释。特别值得指出的是,该系列近红外染料具有远胜于商用菁染料的光稳定性、优异的肿瘤靶向激活特性,具有良好靶向性和低边缘效应的抗癌诊疗前药的潜力。
铜离子是一种对人体十分重要的过渡金属元素,其生理平衡的失调与多种严重疾病相关。针对铜离子的检测,创新地以新颖的铜离子引发的有机自由基正离子生成反应作为检测机理,在表现优异的太阳能电池敏化染料构建单元吲哚啉-苯并噻二唑的基础上设计了的高选择性铜离子探针IBT和IBTM。由于分子内的强D-A(给体-受体)体系,IBT和IBTM均显示出近红外荧光以及较宽的吸收。当其与铜离子发生作用时,生成相应的带有一单位正电荷的自由基正离子。该过程以及自由基正离子的生成能够由循环伏安以及电子顺磁共振加以证实。另一方面,在自由基正离子生成后其溶液颜色的改变(由红变蓝)、吸收光谱的大幅红移以及荧光的完全淬灭能够对铜离子起到比色和荧光双通道响应的检测作用。该铜离子引发的特征性反应也使得化合物具有良好的铜离子选择性。另外,由于IBT分子中的醛基扩展了电子自旋密度分布并改变了电荷分布,从而使得IBT+"具有比IBTM+高出约40倍的吸光度半衰期。研究表明,IBT在设计以新型的自由基正离子机理发展近红外比色荧光双通道铜离子探针方面取得了重要的进展。
针对铜离子检测中所生成的自由基正离子稳定性相对较差,从而对检测造成的不利影响,在第六章中进一步进行分子修饰改变分子结构,引入双吲哚啉的对称结构,合成了四个能够以相同的机理检测铜离子的化合物。其对铜离子的响应与IBT类似,在铜离子的作用下,显示出吸收峰的大幅红移和近红外荧光的完全淬灭,显示出类似的对铜离子的高度选择性。更重要的是,由于本章中化合物具有双吲哚啉的对称结构,使得与之相应的自由基正离子稳定性远好于IBT+。因此,该工作在发展基于高稳定性的自由基正离子的近红外比色荧光双通道铜离子选择性探针方面取得了重要的进展。
最后,在第七章中设计并合成了两个基于苯并噻二唑和希夫碱基团的荧光增强型铜离子探针BTS和BTDS。不同于大多数以荧光淬灭的形式进行检测的铜离子探针,其能够以荧光增强的方式并以极高的选择性和灵敏度对铜离子进行检测,对发展荧光增强型铜离子荧光探针具有重要的意义。另一方面,研究了市售的4-C1NBD即4-氯-7-硝基苯丙嗯二唑作为比色法硫化氢探针和荧光增强型叠氮离子探针的能力,并与活性低仅能对硫化氢产生响应的4-BrNBTD即4-溴-7-硝基苯并噻二唑进行了对比。
Imaging, especially fluorescent imaging has attracted considerable attention because of the high sensitivity, resolution as well as the simple operation which has been widely utilized in the field of biomedical and life science. Considering the advantages of NIR light such as deep tissue penetration and low auto-fluorescence background and the high density excitation of the contrast agent during the bioimaging, fluorophores with NIR emission and high photostability are especially preferable in bioimaging. However, up to date, the various available fluorophores suffer from either short wavelength emission or poor photostability. Therefore, this dissertation focuses on the development of constructing highly stable fluorescent contrast agents via encapsulation or utilization of novel fluorophores, especially in exploring its parcticle application in biological labelling, tumor imaging and monitoring of controlled drug release.
Firstly, the concept and principle of imaging especially fluorescence imaging, the challenge for the fluorophores used in the imaging and the major response mechanism of fluorescent sensors were introduced.
Considering the advantage of the enhanced permeability and retention (EPR) effect in bioimaging, fluorescent nanoparticles have attracted considerable attention. Cyanine is one of the most commonly used near-infrared (NIR) dyes, whose practical application is critically hindered by the poor stability. In chapter2, a system of cyanine-encapsulated nanoparticles CyN-12@NHs was designed and synthesized, in which cyanine dye molecules were encapsulated by the nanomicelles via the self-assembly of the amphiphilic block copolymer PS-b-PAA, then subsequently cross-linked by MPTMS to present core-shell type nanoparticles with diameter of35nm. The isolation of the dye molecules from environmental factors endows the encapsulated cyanine dye several advantages, such as high hydrophilicity, extremely strong fluorescence in water with large Stokes shift (110nm),50-fold and95-fold higher photostability than the free dye and ICG， respectively. Moreover, the NIR cyanine-based nanoparticles exhibit nearly no cytotoxicity to cells and outstanding performance in living cell imaging. Finally, in the in vivo imaging with tumor-bearing mouse model, the nanoparticles has a long retention in tumor via intratumor injection because of the EPR effect. Therefore, the NIR silica-cyanine hybrid nanocomposites have been successfully developed as highly qualified contrast agent for bioimaging, along with a breakthrough in photostability and bright fluorescence with large Stokes shift.
Glutathione (GSH) plays a critical role in maintaining oxidation-reduction homeostasis in biological systems. Considering the detection of GSH by fluorescence sensors is limited to either the short wavelength emission or the poor photostability, a highly stable colorimetric and ratiometric NIR fluorescent sensor (DCM-S) for GSH detection was constructed on basis of dicyanomethylene-4H-pyran (DCM) chromophore. The specific disulfide bond is incorporated via a carbamate linker as the GSH responsive group, which simultaneously blue-shifts and quenches the fluorescence. Upon addition of GSH, DCM-S exhibits the outstanding colorimetric (from yellow to red) and ratiometric fluorescent response with the6-fold enhancement of NIR fluorescence at665nm in quantum yield. More importantly, the GSH-treated DCM-S (DCM-NH2actually) possesses20-fold longer fluorescence half-life period as well as much better photostability than the FDA-approved ICG. Finally, the ratiometric detection of GSH was also successfully operated in the living cell imaging, exhibiting NIR fluorescence and large Stokes shift (215nm) with nearly no background fluorescence interference. As a consequence, DCM-S can be utilized as colorimetric and ratiometric NIR fluorescent sensor for GSH, with a great potential in the development of GSH-induced drug delivery system.
Theranostic prodrugs equipped with fluorophores has become attractive to monitor the biodistribution and activation of prodrugs. To overcome the disadvantages of exsiting prodrugs such as the short wavelength fluorescence and poor photostability of fluorophores, in Chapter4, an anticancer drug CPT is further conjugated with DCM-S to construct novel NIR DCM-based theranostic prodrug platform DCM-S-CPT (including the PEG-PLA nanoparticles) for cancer treatment in vivo with high photostability. Upon the interaction of GSH, NIR fluorescence centered at665nm is distinctly enhanced along with the GSH-induced release of active CPT. Importantly, in vitro evaluation illustrates that the GSH-treated DCM-S-CPT have significantly better photostability (19-fold enhancement in the fluorescence half-life period) than the commercial ICQ which is highly desirable for in situ fluorescence-tracking of cancer chemotherapy. For the first time, DCM-S-CPT has been successfully utilized for in vivo and in situ tracking of drug release and cancer therapeutic efficacy in living animals by NIR fluorescence. We systematically studied the cytotoxicity, flow cytometry, inhibition rates of tumor growth (IRT) and pharmacokinetic features of the prodrug DCM-S-CPT. In bioimaging in vivo, DCM-S-CPT exhibits fantastic tumor-activatable performance when intravenously injected into tumor-bearing nude mice, as well as specific cancer therapy with little side effects. DCM-S-CPT loaded in PEG-PLA nanoparticles shows even higher antitumor activity than free CPT, and is also retained longer in the plasma. The tumor-targeting ability and the specific drug release in tumors make DCM-S-CPT a promising prodrug to achieve high efficacy and low side-effects, providing significant advances towards deeper understanding and exploration of theranostic drug-delivery systems.
Copper is a crucial nutrient for life and its homeostasis connected to severe diseases such as Menkes and Alzheimer's disease. In Chapter5, the donor-acceptor system of indoline-benzothiadiazole is established as the novel and reactive platform for generating amine radical caitons with the interaction of Cu2+, which has been successfully exploited as the building block to be highly sensitive and selective NIR colorimetric and fluorescent Cu2+sensors. Upon addition of copper ion, an instantaneous red shift of absorption spectra as well as the quenched NIR fluorescence of the substrates is observed, which establishs the two-channel response of IBT and IBTM for Cu2+. The feasibility and validity of the radical cation generation are confirmed by cyclic voltammetry and electron paramagnetic resonance spectra. Moreover, the structure modification (methyl in IBTM to aldehyde unit in IBT) endows IBT+'around40-fold longer half-life period than IBTM+'via the extention of the electron spin density and change of the charge distribution. Therefore, IBT has been proved to be a highly qualified NIR colorimetric and fluorescent sensor for Cu2+with high sensitivity and selectivity, which benefits for the further design of novel radical cation based fluorescent sensors for copper ion.
Considering the relatively poor stability of radical cations generated during the detection of Cu2+, in Chapter6, four diindoline-acceptor based molecules have been synthesized for copper ion detection via the same detection mechanism with much higher stability of radical cations. The four newly developed sensors exhibit similar two-channel response in absorption spectra (red shift) and fluorescence spectra (quench of fluorescence). The selectivity is also guaranteed by the specific detection mechanism. Outstandingly, because of the introduction of two indoline units, the stability of the radical cations is significantly improved even compared with IBT+.Therefore, the diindoline-acceptor type structure has the potential for constructing NIR colorimetric and fluorescent sensor for copper ion with high sensitivity, selectivity and stability.
In Chapter7, two fluorescence sensors for Cu2+were designed and synthesized based on benzothiadiazole and Schiff base unit. The fluorescence of BTS and BTDS in the visible region is significantly enhanced upon the addition of Cu2+with outstanding sensitivity and selectivity, demonstrating the potential application as OFF-ON fluorescent sensors for Cu2+. Moreover, the ability of commercially available4-ClNBD as colorimetric sensor for H2S and OFF-ON fluorescent sensor for N3-simultaneously was investigated.
首先,就荧光成像的概念及原理进行了阐述,并且重点介绍了荧光成像对其中所用的荧光团在波长以及稳定性方面的要求。其后,介绍了荧光探针中的常用传感原理。
目前基于肿瘤组织的增强渗透滞留效应(Enhanced permeability and retention effect,EPR),荧光纳米颗粒的成像研究日益受到重视。第二章中针对常用的近红外染料菁染料在荧光生物成像中的应用受到其极差的光稳定性制约的缺陷,创新地提出了用以菁染料为核心的新型荧光纳米颗粒CyN-12@NHs来代替传统菁染料作为荧光成像剂的方案,并对其进行了性能研究。用两性嵌段共聚物所形成的纳米胶束将含有长碳链的菁染料分子以物理包裹的方式包裹在核心中,再由硅烷偶联试剂MPTMS对胶束表面进行交联,最终形成具有核-壳结构,平均直径约为35nm的荧光纳米颗粒。研究发现,菁染料结构中的长碳链的引入可与两亲性嵌段聚合物能形成球形胶束,纳米颗粒的直径可很好地控制在50nm以下；胶束亲水端在外的特性使得该纳米颗粒具有良好的亲水性,并且在大极性溶剂中拥有比包裹前的染料更好的光学性能。该纳米颗粒将包裹在其中的染料分子与外界环境隔离,使其具有比包裹前的染料和商用染料ICG分别高出50倍和95倍的光稳定性,且荧光效率提高数百倍。该纳米颗粒表面由生物相容性极好的硅氧层构成,因此其几乎没有细胞毒性,能够在细胞成像中取得良好的结果。在使用裸鼠进行的生物活体成像中,该纳米颗粒能够在进行瘤内注射后长时间停留在肿瘤内进行成像,显示出纳米颗粒良好的EPR效应。因此,CyN-12@NHs具备代替传统的小分子菁染料成为性能良好的生物活体成像剂的能力,在提升菁染料的亲水性、稳定性、荧光量子效率方面取得了重要突破。
谷胱甘肽(GSH)是体内浓度最高的含巯基化合物,其对维持生物体系中的氧化还原生理平衡有非常重要的作用。针对大多GSH荧光探针仅能在可见光区对其进行检测的缺陷,在第三章中设计并合成了新型的基于苯并吡喃腈荧光团的高稳定性比色、近红外荧光双通道GSH探针DCM-S。将含有二硫键的响应基团与基于苯并吡喃腈衍生物的荧光团通过氨基甲酸酯进行桥连,使得荧光团的荧光蓝移并且淬灭。在GSH的作用下,二硫键被切断,最终生成荧光团DCM-NH2,在光学性能方面表现为吸收光谱的红移(溶液颜色由黄变红)和荧光的红移(由可见光区红移至近红外区665nm)以及强度增强(荧光量子效率增大6倍)。并且DCM-S能够以荧光比率的方式对GSH进行检测,该检测方法能够消除外界环境、染料浓度等方面的干扰,使得检测更为准确。更重要的是,在与GSH作用之后,DCM-S显示出比市售菁染料ICG长约20倍的荧光强度半衰期,显示出远高于ICG的光稳定性。最后,DCM-S在细胞中以比率的方式对GSH的检测能力同样得到了证实,其极大的Stokes shift(斯托克斯位移,215nm)同样能够减少在生物成像中所受到的背景荧光干扰。研究表明,DCM-S实现了对GSH良好的比色和近红外荧光比率双通道响应以及细胞内比率型荧光检测,更对发展GSH诱导的药物释放体系具有重要的意义。
与荧光团相连的具有诊疗效果的前药因其能对药物在生物体内的分布和激活进行可视化跟踪监测,对生物医学具有重要的意义。针对现有的荧光前药在生物成像中的应用受到其短波长或稳定性差的制约,第四章将DCM-S与抗癌药物羟基喜树碱(CPT)相连,形成基于近红外苯并吡喃腈荧光团的具有高度稳定性的抗癌诊疗前药,并且对其进行了PEG-PLA胶束包裹。与GSH作用时,在其将二硫键切断后,DCM-S-CPT能够释放出具有抗癌活性的药物CPT,并且其665nm处的荧光表现出明显的增强。因此,该近红外荧光的增强可以作为活性药物释放的表征。在与GSH作用后DCM-S-CPT表现出比ICG高出19倍的荧光半衰期即更好的光稳定性。细胞成像方面,由于癌细胞中的GSH浓度远高于正常细胞,DCM-S-CPT及其纳米颗粒对癌细胞表现出与CPT类似的药理效果,而对正常细胞则表现出极低的细胞毒性。在活体成像中,DCM-S-CPT表现出意料之外的极好的肿瘤靶向性能,显示出非常低的边缘效应。DCM-S-CPT的纳米胶束表现出与CPT类似的肿瘤生长抑制效果,但对小鼠本身表现出远低于CPT的毒性。研究显示,该前药可利用肿瘤微环境的调控,集诊断、治疗为一体,充分利用吡喃腈(DCM)染料单元的近红外长波长荧光在生物活体成像中的独特优势,成功实现了在体、原位活体成像监测以及肿瘤前药的可视化控释。特别值得指出的是,该系列近红外染料具有远胜于商用菁染料的光稳定性、优异的肿瘤靶向激活特性,具有良好靶向性和低边缘效应的抗癌诊疗前药的潜力。
铜离子是一种对人体十分重要的过渡金属元素,其生理平衡的失调与多种严重疾病相关。针对铜离子的检测,创新地以新颖的铜离子引发的有机自由基正离子生成反应作为检测机理,在表现优异的太阳能电池敏化染料构建单元吲哚啉-苯并噻二唑的基础上设计了的高选择性铜离子探针IBT和IBTM。由于分子内的强D-A(给体-受体)体系,IBT和IBTM均显示出近红外荧光以及较宽的吸收。当其与铜离子发生作用时,生成相应的带有一单位正电荷的自由基正离子。该过程以及自由基正离子的生成能够由循环伏安以及电子顺磁共振加以证实。另一方面,在自由基正离子生成后其溶液颜色的改变(由红变蓝)、吸收光谱的大幅红移以及荧光的完全淬灭能够对铜离子起到比色和荧光双通道响应的检测作用。该铜离子引发的特征性反应也使得化合物具有良好的铜离子选择性。另外,由于IBT分子中的醛基扩展了电子自旋密度分布并改变了电荷分布,从而使得IBT+"具有比IBTM+高出约40倍的吸光度半衰期。研究表明,IBT在设计以新型的自由基正离子机理发展近红外比色荧光双通道铜离子探针方面取得了重要的进展。
针对铜离子检测中所生成的自由基正离子稳定性相对较差,从而对检测造成的不利影响,在第六章中进一步进行分子修饰改变分子结构,引入双吲哚啉的对称结构,合成了四个能够以相同的机理检测铜离子的化合物。其对铜离子的响应与IBT类似,在铜离子的作用下,显示出吸收峰的大幅红移和近红外荧光的完全淬灭,显示出类似的对铜离子的高度选择性。更重要的是,由于本章中化合物具有双吲哚啉的对称结构,使得与之相应的自由基正离子稳定性远好于IBT+。因此,该工作在发展基于高稳定性的自由基正离子的近红外比色荧光双通道铜离子选择性探针方面取得了重要的进展。
最后,在第七章中设计并合成了两个基于苯并噻二唑和希夫碱基团的荧光增强型铜离子探针BTS和BTDS。不同于大多数以荧光淬灭的形式进行检测的铜离子探针,其能够以荧光增强的方式并以极高的选择性和灵敏度对铜离子进行检测,对发展荧光增强型铜离子荧光探针具有重要的意义。另一方面,研究了市售的4-C1NBD即4-氯-7-硝基苯丙嗯二唑作为比色法硫化氢探针和荧光增强型叠氮离子探针的能力,并与活性低仅能对硫化氢产生响应的4-BrNBTD即4-溴-7-硝基苯并噻二唑进行了对比。
Imaging, especially fluorescent imaging has attracted considerable attention because of the high sensitivity, resolution as well as the simple operation which has been widely utilized in the field of biomedical and life science. Considering the advantages of NIR light such as deep tissue penetration and low auto-fluorescence background and the high density excitation of the contrast agent during the bioimaging, fluorophores with NIR emission and high photostability are especially preferable in bioimaging. However, up to date, the various available fluorophores suffer from either short wavelength emission or poor photostability. Therefore, this dissertation focuses on the development of constructing highly stable fluorescent contrast agents via encapsulation or utilization of novel fluorophores, especially in exploring its parcticle application in biological labelling, tumor imaging and monitoring of controlled drug release.
Firstly, the concept and principle of imaging especially fluorescence imaging, the challenge for the fluorophores used in the imaging and the major response mechanism of fluorescent sensors were introduced.
Considering the advantage of the enhanced permeability and retention (EPR) effect in bioimaging, fluorescent nanoparticles have attracted considerable attention. Cyanine is one of the most commonly used near-infrared (NIR) dyes, whose practical application is critically hindered by the poor stability. In chapter2, a system of cyanine-encapsulated nanoparticles CyN-12@NHs was designed and synthesized, in which cyanine dye molecules were encapsulated by the nanomicelles via the self-assembly of the amphiphilic block copolymer PS-b-PAA, then subsequently cross-linked by MPTMS to present core-shell type nanoparticles with diameter of35nm. The isolation of the dye molecules from environmental factors endows the encapsulated cyanine dye several advantages, such as high hydrophilicity, extremely strong fluorescence in water with large Stokes shift (110nm),50-fold and95-fold higher photostability than the free dye and ICG， respectively. Moreover, the NIR cyanine-based nanoparticles exhibit nearly no cytotoxicity to cells and outstanding performance in living cell imaging. Finally, in the in vivo imaging with tumor-bearing mouse model, the nanoparticles has a long retention in tumor via intratumor injection because of the EPR effect. Therefore, the NIR silica-cyanine hybrid nanocomposites have been successfully developed as highly qualified contrast agent for bioimaging, along with a breakthrough in photostability and bright fluorescence with large Stokes shift.
Glutathione (GSH) plays a critical role in maintaining oxidation-reduction homeostasis in biological systems. Considering the detection of GSH by fluorescence sensors is limited to either the short wavelength emission or the poor photostability, a highly stable colorimetric and ratiometric NIR fluorescent sensor (DCM-S) for GSH detection was constructed on basis of dicyanomethylene-4H-pyran (DCM) chromophore. The specific disulfide bond is incorporated via a carbamate linker as the GSH responsive group, which simultaneously blue-shifts and quenches the fluorescence. Upon addition of GSH, DCM-S exhibits the outstanding colorimetric (from yellow to red) and ratiometric fluorescent response with the6-fold enhancement of NIR fluorescence at665nm in quantum yield. More importantly, the GSH-treated DCM-S (DCM-NH2actually) possesses20-fold longer fluorescence half-life period as well as much better photostability than the FDA-approved ICG. Finally, the ratiometric detection of GSH was also successfully operated in the living cell imaging, exhibiting NIR fluorescence and large Stokes shift (215nm) with nearly no background fluorescence interference. As a consequence, DCM-S can be utilized as colorimetric and ratiometric NIR fluorescent sensor for GSH, with a great potential in the development of GSH-induced drug delivery system.
Theranostic prodrugs equipped with fluorophores has become attractive to monitor the biodistribution and activation of prodrugs. To overcome the disadvantages of exsiting prodrugs such as the short wavelength fluorescence and poor photostability of fluorophores, in Chapter4, an anticancer drug CPT is further conjugated with DCM-S to construct novel NIR DCM-based theranostic prodrug platform DCM-S-CPT (including the PEG-PLA nanoparticles) for cancer treatment in vivo with high photostability. Upon the interaction of GSH, NIR fluorescence centered at665nm is distinctly enhanced along with the GSH-induced release of active CPT. Importantly, in vitro evaluation illustrates that the GSH-treated DCM-S-CPT have significantly better photostability (19-fold enhancement in the fluorescence half-life period) than the commercial ICQ which is highly desirable for in situ fluorescence-tracking of cancer chemotherapy. For the first time, DCM-S-CPT has been successfully utilized for in vivo and in situ tracking of drug release and cancer therapeutic efficacy in living animals by NIR fluorescence. We systematically studied the cytotoxicity, flow cytometry, inhibition rates of tumor growth (IRT) and pharmacokinetic features of the prodrug DCM-S-CPT. In bioimaging in vivo, DCM-S-CPT exhibits fantastic tumor-activatable performance when intravenously injected into tumor-bearing nude mice, as well as specific cancer therapy with little side effects. DCM-S-CPT loaded in PEG-PLA nanoparticles shows even higher antitumor activity than free CPT, and is also retained longer in the plasma. The tumor-targeting ability and the specific drug release in tumors make DCM-S-CPT a promising prodrug to achieve high efficacy and low side-effects, providing significant advances towards deeper understanding and exploration of theranostic drug-delivery systems.
Copper is a crucial nutrient for life and its homeostasis connected to severe diseases such as Menkes and Alzheimer's disease. In Chapter5, the donor-acceptor system of indoline-benzothiadiazole is established as the novel and reactive platform for generating amine radical caitons with the interaction of Cu2+, which has been successfully exploited as the building block to be highly sensitive and selective NIR colorimetric and fluorescent Cu2+sensors. Upon addition of copper ion, an instantaneous red shift of absorption spectra as well as the quenched NIR fluorescence of the substrates is observed, which establishs the two-channel response of IBT and IBTM for Cu2+. The feasibility and validity of the radical cation generation are confirmed by cyclic voltammetry and electron paramagnetic resonance spectra. Moreover, the structure modification (methyl in IBTM to aldehyde unit in IBT) endows IBT+'around40-fold longer half-life period than IBTM+'via the extention of the electron spin density and change of the charge distribution. Therefore, IBT has been proved to be a highly qualified NIR colorimetric and fluorescent sensor for Cu2+with high sensitivity and selectivity, which benefits for the further design of novel radical cation based fluorescent sensors for copper ion.
Considering the relatively poor stability of radical cations generated during the detection of Cu2+, in Chapter6, four diindoline-acceptor based molecules have been synthesized for copper ion detection via the same detection mechanism with much higher stability of radical cations. The four newly developed sensors exhibit similar two-channel response in absorption spectra (red shift) and fluorescence spectra (quench of fluorescence). The selectivity is also guaranteed by the specific detection mechanism. Outstandingly, because of the introduction of two indoline units, the stability of the radical cations is significantly improved even compared with IBT+.Therefore, the diindoline-acceptor type structure has the potential for constructing NIR colorimetric and fluorescent sensor for copper ion with high sensitivity, selectivity and stability.
In Chapter7, two fluorescence sensors for Cu2+were designed and synthesized based on benzothiadiazole and Schiff base unit. The fluorescence of BTS and BTDS in the visible region is significantly enhanced upon the addition of Cu2+with outstanding sensitivity and selectivity, demonstrating the potential application as OFF-ON fluorescent sensors for Cu2+. Moreover, the ability of commercially available4-ClNBD as colorimetric sensor for H2S and OFF-ON fluorescent sensor for N3-simultaneously was investigated.
引文
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