基于荧光纳米粒子的一些生物功能成像研究
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摘要
以荧光纳米粒子作为探针的生物荧光成像是当前纳米生物光子学领域的一个研究热点,新型荧光纳米材料的开发及生物荧光成像技术的应用引起了研究者的广泛关注。本论文围绕离体细胞荧光成像、宏观活体荧光成像和显微活体荧光成像技术及生物学应用展开研究工作,研究了多种新颖的荧光成像纳米探针的生物医学应用。
在细胞成像层面：
对氧化石墨烯纳米材料的单光子激发和多光子激发荧光特性进行了系统的表征,利用双光子荧光显微镜作为工具,以氧化石墨烯纳米材料作为荧光造影剂,研究了氧化石墨烯纳米材料在离体HeLa细胞的荧光成像,对氧化石墨烯纳米材料通过细胞膜进入细胞的机理进行了实验分析验证,利用多光谱荧光成像技术和细胞器荧光标记物研究了氧化石墨烯材料在亚细胞层面的分布情况。
利用多孔二氧化硅纳米小球包覆光动力治疗药物(PpIX)制备了具有荧光成像和光动力治疗功能的纳米探针(PpIX@SiO2),提出并验证了利用近红外飞秒脉冲激光激发光动力药物来实现光动力治疗的可行性,利用PpIX@SiO2对离体HeLa细胞进行标记,完成了利用近红外飞秒光激发的细胞荧光成像和细胞光动力治疗。
在宏观活体成像层面：
利用有机修饰的多孔二氧化硅纳米小球(ORMOSIL)包覆近红外荧光染料(IR-820),制备了具有近红外荧光特性的荧光纳米探针(IR-820@ORMOSIL),在人造模拟组织结构中验证了这种近红外荧光探针用于深层组织成像的潜力,利用IR-820@ORMOSIL荧光纳米探针实现了对活体肿瘤的非特异性的标记和宏观活体荧光成像诊断,通过长期的观察验证了这种纳米探针用于肿瘤的长期标记和荧光成像的能力。
利用聚合物分子(DSPE-mPEG5000)包覆了一种具有聚集增强荧光特性的荧光染料(StCN),制备了具有良好荧光特性和生物兼容性的聚合物荧光纳米粒子(StCN@PEG),利用这种纳米颗粒实现了活体SLN荧光成像定位和非特异的活体肿瘤荧光成像诊断。通过化学方法在StCN@PEG纳米粒子表面连接了能够跟肿瘤细胞特异性结合的多肽,利用多肽修饰的StCN@PEG荧光纳米粒子实现了靶向的肿瘤荧光成像。
提出了在油酸-液体石蜡体系中合成近红外荧光发射特性的硫化铅量子点的“绿色”合成方法,通过二氧化硅-聚乙二醇双层包覆的方法对油溶性的PbS量子点进行表面包覆,制备了具有超强化学稳定性和良好生物兼容性的近红外荧光纳米颗粒(PbS@SiO2@PEG),利用这种纳米颗粒实现了对小鼠活体前哨淋巴结(SLN)荧光成像定位。
在显微活体成像层面：
研究了一种新颖的具有聚集诱导荧光特性的荧光染料(TPE-TPA-FN)的单光子激发荧光和双光子激发荧光特性,利用DSPE-mPEG5000聚合物分子包覆TPE-TPA-FN染料分子,制备了具有优良荧光特性和生物兼容性的荧光纳米粒子(TPE-TPA-FN@PEG),利用这种荧光纳米粒子作为双光子荧光成像探针,以双光子荧光共聚焦显微镜作为工具,实现了对小鼠活体耳部血管和脑部血管的荧光成像。
In recent years, fluorescent nanoparticles based bioimaging forms a major thrust of bio-photonics. Much focus has been given to the development of efficient optical agents and fluorescence imaging systems. In this thesis, we focuse on the applications of some novel fluorescent nanoparticles, including in vitro cell bioimaging, in vivo fluorescence bioimaging, and in vivo two-photon excited microscopic functional bioimaging. The detail content of our research work is as follows.
For in vitro cell imaging:
We systemically study the multi-photon excited fluorescence of graphene oxide nanoparticles. Grafted with PEG molecules, GO nanoparticles exhibited high chemical stability under various pH values. GO-PEG nanoparticles were also shown to have negligible cytotoxicity by a cell proliferation assay and histological analysis, which could facilitate their in vitro applications. In in vitro cell imaging, fluorescence bioimaging clearly illustrated the distribution of GO-PEG nanoparticles in cellular/subcellular components.
Mesoporous silica nanoparticles are used to encapsulate PpIX (a kind of photodynamic therapy drugs), and the as-synthesized nanoparticles (PpIX@SiO2) are water soluble, with good chemical stability and biocompatibility. The one-photon and two-photon optical properties of PpIX@SiO2nanoparticles have been systematically investigated, and their applications in in vitro two-photon fluorescence imaging and photodynamic therapy of tumor cells have been demonstrated.
For macroscopical in vivo bioimaging:
Organically modified silica (ORMOSIL) nanoparticles are used to encapsulate a kind near infra-red (NIR) organic fluorescent agents (IR-820). Our study indicates that IR-820doped ORMOSIL nanoparticles, which located beneath1.5cm-depth in phantom, could be easily discriminated by utilizing NIR fluorescence imaging. We also demonstrate that intravenously injected NIR nanoparticles can target the subcutaneously xenografted tumor of a mouse through blood circulation and the "enhanced permeability and retention"(EPR) effect. ORMOSIL nanoparticles have bright prospects in future biomedical applications, such as disease diagnosis and clinical therapies.
We report polymeric nanomicelles doped with organic fluorophores (StCN.(Z)-2.3-bis [4-(N-4-(diphenylamino)styryl)phenyl]-acrylonitrile), which have the property of aggregation-enhanced fluorescence. These fluorescent nanomicelles are utilized as efficient optical probes for in vivo SLN mapping of mice. The StCN@PEG nanomicelles, as well as their bioconjugates with arginine-glycine-aspartic acid (RGD) peptides, are used to target subcutaneously xenografted tumors in mice, and in vivo fluorescence images demonstrate the potential to use PEGylated phospholipid nanomicelles with aggregation-enhanced fluorescence as bright nanoprobes for in vivo diagnosis of tumors.
PbS semiconductor quantum dots (QDs) with NIR photoluminescence were synthesized in oleic acid and paraffin liquid mixture by using aneasily handled and 'green' approach. Surface functionalization of the QDs was accomplishedwith a silica and polyethylene glycol (PEG) phospholipid dual-layer coating and the excellentchemical stability of the nanoparticles is demonstrated. We then successfully applied the ultrastable PbS QDs to in vivo sentinel lymph node (SLN) mapping of mice. Histological analyses were also carried out to ensure that the intravenously injected nanoparticles did not produce any toxicity to the organism of mice. These experimental results suggested that our ultrastable NIR PbS QDs can serve as biocompatible and efficient probes for in vivo optical bioimaging and has great potentials for disease diagnosis and clinical therapies in the future.
For microcosmic in vivo bioimaging:
A new kind of organic fluorescent compounds (TPE-TPA-FN) with aggregation induced emission (AIE) property is studied. TPE-TPA-FN encapsulated DSPE-mPEG nanomicelles are prepared. We intravenously inject TPE-TPA-FN@PEG nanomicelles into mice body from the tail vein, and observed their flow, distributions in blood vessels, by utilizing a deep-penetrating in vivo two-photon imaging technique.
在细胞成像层面：
对氧化石墨烯纳米材料的单光子激发和多光子激发荧光特性进行了系统的表征,利用双光子荧光显微镜作为工具,以氧化石墨烯纳米材料作为荧光造影剂,研究了氧化石墨烯纳米材料在离体HeLa细胞的荧光成像,对氧化石墨烯纳米材料通过细胞膜进入细胞的机理进行了实验分析验证,利用多光谱荧光成像技术和细胞器荧光标记物研究了氧化石墨烯材料在亚细胞层面的分布情况。
利用多孔二氧化硅纳米小球包覆光动力治疗药物(PpIX)制备了具有荧光成像和光动力治疗功能的纳米探针(PpIX@SiO2),提出并验证了利用近红外飞秒脉冲激光激发光动力药物来实现光动力治疗的可行性,利用PpIX@SiO2对离体HeLa细胞进行标记,完成了利用近红外飞秒光激发的细胞荧光成像和细胞光动力治疗。
在宏观活体成像层面：
利用有机修饰的多孔二氧化硅纳米小球(ORMOSIL)包覆近红外荧光染料(IR-820),制备了具有近红外荧光特性的荧光纳米探针(IR-820@ORMOSIL),在人造模拟组织结构中验证了这种近红外荧光探针用于深层组织成像的潜力,利用IR-820@ORMOSIL荧光纳米探针实现了对活体肿瘤的非特异性的标记和宏观活体荧光成像诊断,通过长期的观察验证了这种纳米探针用于肿瘤的长期标记和荧光成像的能力。
利用聚合物分子(DSPE-mPEG5000)包覆了一种具有聚集增强荧光特性的荧光染料(StCN),制备了具有良好荧光特性和生物兼容性的聚合物荧光纳米粒子(StCN@PEG),利用这种纳米颗粒实现了活体SLN荧光成像定位和非特异的活体肿瘤荧光成像诊断。通过化学方法在StCN@PEG纳米粒子表面连接了能够跟肿瘤细胞特异性结合的多肽,利用多肽修饰的StCN@PEG荧光纳米粒子实现了靶向的肿瘤荧光成像。
提出了在油酸-液体石蜡体系中合成近红外荧光发射特性的硫化铅量子点的“绿色”合成方法,通过二氧化硅-聚乙二醇双层包覆的方法对油溶性的PbS量子点进行表面包覆,制备了具有超强化学稳定性和良好生物兼容性的近红外荧光纳米颗粒(PbS@SiO2@PEG),利用这种纳米颗粒实现了对小鼠活体前哨淋巴结(SLN)荧光成像定位。
在显微活体成像层面：
研究了一种新颖的具有聚集诱导荧光特性的荧光染料(TPE-TPA-FN)的单光子激发荧光和双光子激发荧光特性,利用DSPE-mPEG5000聚合物分子包覆TPE-TPA-FN染料分子,制备了具有优良荧光特性和生物兼容性的荧光纳米粒子(TPE-TPA-FN@PEG),利用这种荧光纳米粒子作为双光子荧光成像探针,以双光子荧光共聚焦显微镜作为工具,实现了对小鼠活体耳部血管和脑部血管的荧光成像。
In recent years, fluorescent nanoparticles based bioimaging forms a major thrust of bio-photonics. Much focus has been given to the development of efficient optical agents and fluorescence imaging systems. In this thesis, we focuse on the applications of some novel fluorescent nanoparticles, including in vitro cell bioimaging, in vivo fluorescence bioimaging, and in vivo two-photon excited microscopic functional bioimaging. The detail content of our research work is as follows.
For in vitro cell imaging:
We systemically study the multi-photon excited fluorescence of graphene oxide nanoparticles. Grafted with PEG molecules, GO nanoparticles exhibited high chemical stability under various pH values. GO-PEG nanoparticles were also shown to have negligible cytotoxicity by a cell proliferation assay and histological analysis, which could facilitate their in vitro applications. In in vitro cell imaging, fluorescence bioimaging clearly illustrated the distribution of GO-PEG nanoparticles in cellular/subcellular components.
Mesoporous silica nanoparticles are used to encapsulate PpIX (a kind of photodynamic therapy drugs), and the as-synthesized nanoparticles (PpIX@SiO2) are water soluble, with good chemical stability and biocompatibility. The one-photon and two-photon optical properties of PpIX@SiO2nanoparticles have been systematically investigated, and their applications in in vitro two-photon fluorescence imaging and photodynamic therapy of tumor cells have been demonstrated.
For macroscopical in vivo bioimaging:
Organically modified silica (ORMOSIL) nanoparticles are used to encapsulate a kind near infra-red (NIR) organic fluorescent agents (IR-820). Our study indicates that IR-820doped ORMOSIL nanoparticles, which located beneath1.5cm-depth in phantom, could be easily discriminated by utilizing NIR fluorescence imaging. We also demonstrate that intravenously injected NIR nanoparticles can target the subcutaneously xenografted tumor of a mouse through blood circulation and the "enhanced permeability and retention"(EPR) effect. ORMOSIL nanoparticles have bright prospects in future biomedical applications, such as disease diagnosis and clinical therapies.
We report polymeric nanomicelles doped with organic fluorophores (StCN.(Z)-2.3-bis [4-(N-4-(diphenylamino)styryl)phenyl]-acrylonitrile), which have the property of aggregation-enhanced fluorescence. These fluorescent nanomicelles are utilized as efficient optical probes for in vivo SLN mapping of mice. The StCN@PEG nanomicelles, as well as their bioconjugates with arginine-glycine-aspartic acid (RGD) peptides, are used to target subcutaneously xenografted tumors in mice, and in vivo fluorescence images demonstrate the potential to use PEGylated phospholipid nanomicelles with aggregation-enhanced fluorescence as bright nanoprobes for in vivo diagnosis of tumors.
PbS semiconductor quantum dots (QDs) with NIR photoluminescence were synthesized in oleic acid and paraffin liquid mixture by using aneasily handled and 'green' approach. Surface functionalization of the QDs was accomplishedwith a silica and polyethylene glycol (PEG) phospholipid dual-layer coating and the excellentchemical stability of the nanoparticles is demonstrated. We then successfully applied the ultrastable PbS QDs to in vivo sentinel lymph node (SLN) mapping of mice. Histological analyses were also carried out to ensure that the intravenously injected nanoparticles did not produce any toxicity to the organism of mice. These experimental results suggested that our ultrastable NIR PbS QDs can serve as biocompatible and efficient probes for in vivo optical bioimaging and has great potentials for disease diagnosis and clinical therapies in the future.
For microcosmic in vivo bioimaging:
A new kind of organic fluorescent compounds (TPE-TPA-FN) with aggregation induced emission (AIE) property is studied. TPE-TPA-FN encapsulated DSPE-mPEG nanomicelles are prepared. We intravenously inject TPE-TPA-FN@PEG nanomicelles into mice body from the tail vein, and observed their flow, distributions in blood vessels, by utilizing a deep-penetrating in vivo two-photon imaging technique.
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