功能化纳米材料的生物效应与分子机制研究
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摘要
纳米材料已愈来愈多地应用于人类生活的方方面面,例如能源、环境、电子及生物医学。纳米材料的广泛应用使其在人类与自然环境中迅速渗透,而人们对其生物效应却知之甚少。随着越来越多有关纳米毒性的报道,人们对纳米材料安全性的关注也逐渐被提上日程,其中的关键问题是了解纳米材料的基本生物行为及其分子机制。本文立足于对几种重要功能纳米材料生物效应的研究,通过多种物理、化学与生物学手段发现了功能纳米材料的蛋白质结合、细胞摄取和对细胞信号传导通路影响的若干规律。这些规律的发现为纳米材料的生物效应提供了理论解释,阐明了纳米材料生物行为的可能的机制和调控机理。这些发现同时也具有重要的应用价值：它为有效降低纳米材料毒性、提高生物相容性提供方法学参考,并为纳米材料作为治疗试剂提供了可能性。
本文首先研究了纳米颗粒与蛋白质的结合。纳米颗粒趋于结合蛋白质的性质决定了它在人类和动物体内的毒性以及自身被免疫系统调理和清除的命运。在该项工作中,通过改变多壁碳纳米管(MWCNT)的直径、表面化学以及蛋白质种类,借助稳态荧光光谱、时间分辨荧光光谱和圆二色光谱等分析方法,研究了MWCNT与蛋白质结合的机制。在对不同直径(40 nm与10 nm)MWCNT的研究中发现,直径较大的具有更强的结合蛋白质的能力。这个现象说明纳米颗粒的表面曲率在其与蛋白质结合过程中起到了关键作用。此外,碳纳米管(CNT)的表面电荷和空间位阻也参与调节其与蛋白质的结合,说明了CNT与蛋白质双方的电荷和立体化学性质都对它们之间的结合产生了影响。另外,尽管蛋白质的自身荧光由于与CNT的结合而发生了淬灭,而其荧光寿命并没有改变,说明这种荧光淬灭是由于形成复合物而发生的稳态淬灭。通过圆二色谱法研究蛋白质二级结构时发现,蛋白质的高级结构受到了其与CNT结合的影响,因此可能会影响蛋白质的生物功能。
当CNT与细胞表面受体或细胞内蛋白相互作用时,将会影响细胞的信号传导通路。因此评估其细胞摄取和细胞内定位对了解其生物效应的机制是必不可少的。目前已知CNT可以非常容易地穿过各种各样的生物学屏障而进入多种有机体,包括动物、植物及微生物,然而对其细胞摄取的机制和进入细胞后的转运并不完全清楚。目前对CNT的细胞摄取、细胞内定位和转移机制尚存争议。为了阐明细胞摄取的机制,我们利用透射电子显微镜对表面带电荷的MWCNT的细胞摄取进行了超微结构的观察,发现了MWCNT的直接穿膜、内吞、内吞体泄露和细胞核定位等现象。我们结合文献报道和自己的实验观察,推出了一个细胞摄取模型。在该模型中,将MWCNT分为两组,一组是凝聚态的CNT团簇,另一组是单个分散的CNT。团簇通过能量依赖性的内吞过程进入细胞并首先进入内吞体；内吞体内的团簇随后变得疏松,使单根CNT释放出来,释放出来的单根CNT穿过内吞体膜进入细胞质；高度分散的单个CNT通过直接穿膜进入细胞质；短CNT有可能进入细胞核；最后,所有种类的CNT都进入溶酶体并排出细胞。该模型将会对CNT的药物传递和毒性研究产生重要影响。例如,基于此模型,细胞内的CNT都有可能进入细胞质并与其中的功能性分子发生未知的作用,从而造成某些细胞机能的缺失。
CNT进入细胞后,将不可避免地与细胞内组分发生相互作用并产生时间和剂量依赖性的细胞反应。我们利用一个新型实时细胞电子传感技术动态地监控了CNT的细胞反应。这项技术利用整合在96孔细胞培养板底部的电子传感器对贴附在其上的细胞进行电阻测量,并通过换算得出反应细胞多项指标的参数(细胞指数),细胞指数反应了细胞增殖、细胞形态、贴附及延展。这种技术无须生物标记、实时并且可以高通量的进行测试,克服了目前对于CNT细胞效应研究中基于光度测量的诸多缺点,并使CNT细胞反应的动态监控成为可能。利用该手段我们获得了动态细胞反应曲线、时间依赖性ICs0及细胞生长曲线的斜率等参数。这些参数是无法用传统方法获得的,为CNT及多种纳米材料的生物效应研究提供了重要信息。
由于CNT自身可以与蛋白发生相互作用、进入细胞并造成动态的细胞反应,因此,了解其细胞内行为的分子机制是亟待解决的问题。这些问题包括哪些信号通路受到了影响、哪些基因的表达发生了改变及其后续的生理效应是怎样的。我们通过对羧基化单壁碳纳米管(SWCNT-COOH)的动态细胞反应的监控、全基因组表达分析和其他细胞生物学手段,发现它可以通过一种非凋亡的机制抑制细胞增殖。该机制与目前研究报道中未修饰碳管的效应是截然不同的。基于SWCNT-COOH对细胞增殖、基因和蛋白质表达及蛋白质磷酸化的影响,我们得出结论：该CNT抑制了Smad依赖性的骨形态发生蛋白信号传导通路并下调Id蛋白的表达。这些分子行为造成了细胞周期G1／S过渡期的停滞和细胞增殖的抑制。SWCNT-COOH对该信号通路及基因表达的抑制表明了功能化CNT对人类细胞具有非凋亡效应。这个发现同样对人类疾病的治疗具有潜在的价值,例如与骨形态发生蛋白信号通路相关(骨科疾病)或与Id蛋白相关(乳腺癌)的疾病。
尽管目前对纳米颗粒／蛋白质结合以及纳米颗粒的细胞毒性研究都有分别报道,却没有关于纳米颗粒／蛋白质团簇形成与纳米颗粒细胞摄取和动态细胞效应之间关系的研究。本课题研究并发现不同粒径和表面化学修饰的磁性纳米颗粒可以结合不同种类和数量的蛋白质而不影响蛋白质二级结构。羧基化磁性纳米颗粒具有较高的细胞毒性,而PEG的修饰则降低了它们的细胞摄取和毒性。与较大粒径材料相比,小粒径磁性纳米颗粒(羧基尤为严重)能够结合更多的血清蛋白,进入细胞较少,但是却造成更强的动态细胞反应。因而我们得出结论：对于水溶性磁性纳米颗粒,除了其自身粒径和表面电荷的影响外,纳米／蛋白团簇的细胞效应还受吸附蛋白种类和数量的影响,并且与蛋白质构象变化无关。
纳米技术的迅速发展,尤其是新型纳米结构的不断涌现,需要我们首先对其生物学效应进行评估。在论文的最后一部分,我们研究了一种新型功能化纳米材料—核／壳-铁／碳纳米颗粒的细胞效应。该材料是最新开发的具有磁共振成像、磁热治疗和药物传递应用前景的复合纳米材料。但是目前对该材料与生物系统的相互作用并不清楚。为了阐明该材料潜在毒性及表面化学-生物相容性的关系,我们选择几种不同化学修饰的核／壳-铁／碳纳米颗粒,研究了它们的动态细胞反应、细胞摄取、氧化应激和对细胞凋亡及细胞周期的影响。结果表明该新型材料的细胞生物相容性同时具有表面化学和细胞种类的依赖性,并且除羧基修饰外,其他材料基本不造成细胞毒性。我们的研究表明该类新型功能纳米材料可以进行进一步地功能化修饰并在多个领域广泛应用。
Nanotechnology and nanomaterials are increasingly applied in various aspects of human life, such as energy, environment, electronics and biomedicine. However, people know little about their biological effects. With more and more studies on nanotoxicities have been reported, nanomaterials'safety has caused wide public concern. The key problem is to understand basic biological behavior and mechanisms of nanomaterials. Here, we selected several important types of nanomaterials to study their biological activities. Using multiple physical, chemical and biological approaches, we found important rules on nanoparticles'protein binding, cell uptake and effects on cellular signaling transductions. These findings offer theoretical explanations to nanomaterials biological effects and help elucidate novel interaction and regulation mechanisms. These findings also provide methodological reference to effectively reduce nanotoxicity and improve biocompatibility, and make functional nanomaterials to be probably used as therapeutic agents.
We firstly studied nanoparticles'protein binding. The protein binding propensity of nanoparticles determines their in vivo toxicity and their fate to be opsonized and cleared by human defense systems. In this work, protein binding mechanisms of pristine and functionalized multi-walled carbon nanotubes (MWCNT) were investigated by varying MWCNT's diameters, nanotube surface chemistry, and proteins using steady-state and time-resolved fluorescence, and circular dichroism (CD) spectroscopies. The MWCNT with a larger diameter (～40 nm) generally exhibited stronger protein binding compared with those with a smaller diameter (～10 nm), demonstrating that the curvature of nanoparticles plays a key role in determining the protein binding affinity. Negative charges or steric properties on MWCNT enhanced binding for some proteins, but not others, indicating that the electrostatic and stereochemical nature of both nanotubes and proteins govern nanotube/protein binding. Protein fluorescence lifetime was not altered by the binding while the intensity was quenched indicating a static quenching through complex formation. The binding-induced conformational changes were further confirmed by CD studies.
Effects on cellular signaling pathways can occur when nanotubes interact with cell surface receptors or with intracellular proteins. The evaluation of cell uptake and intracellular location of SWCNT-COOH are crucial for understanding its biological impact mechanism. CNT can readily penetrate various biological barriers in mammals, plants, and microorganisms. However, the mechanism of cell uptake and cellular transfer of CNT is not fully understood. The current explanations on cell uptake of CNT, their intracellular translocation, and subcellular localization are still controversial. To fill this gap, we examined cell uptake of surface charged MWCNT using TEM. We observed direct membrance penetration, endocytosis, endosomal leakage and nuclear translocation of MWCNT. Previous reports and our own experimental results are consistent with a working model for the cell uptake of CNT. CNT clusters are taken up by cells through energy-dependent endocytosis process. The CNT bundles become unpacked in the endosomes and generate single nanotubes that escape endosomes by penetrating endosome membrane and entering the cytoplasm. Alternatively, the highly dispersed single CNT cross cell membrane and enter cells directly by penetrating cellular membranes. All CNT are finally recruited into lysosomes for excretion. The model will have major impacts on both drug delivery and toxicity studies of CNT. For example, all cellular CNT may be exposed to cytoplasm so that the unexpected interactions with cellular functional molecules are likely to happen.
After nanoparticles enter cells, they will inevitably interact with cellular components and time-and dose-dependent cellular responses are likely to occur. We use a novel real-time cell-based electronic sensing (RT-CES) technology to dynamically monitor cellular responses to carbon nanotubes. This approach is based on the parallel impedance measurement of attached cells using electronic sensors integrated in wells of 96-well E-plate. It measures the real-time multi-parameter index of cell growth named cell index (CI), which reflects the cell proliferation, morphology, attachment and spreading. The label-free, real-time and high-throughput assay overcomes many drawbacks in current optical based cytotoxicity assays in carbon nanotubes research, and enables dynamic monitoring of cellular responses to carbon nanotubes. Using this assay, we obtained dynamic cellular response curves, time-dependent IC50s and cell growth slopes which can not be obtained by conventional assays.
Since nanoparticles intrinsically interact with proteins and enter cells and cause dynamic cellular responses, it's urgent to elucidate the underlying molecular mechanisms of a nanoparticle's cellular behavior, including what signaling pathway is affected, what genes are changed and what are the consequences. Through our dynamic monitoring of cellular responses and evaluation of genome expression, as well as other cellular biological approaches, we discovered that SWCNT-COOH inhibited cell proliferation via a non-apoptotic mechanism, which is different from effects caused by pristine CNT. On the basis of SWCNT-COOH's perturbations on cells, expression of genes and protein, and protein phosphorylations, we conclude that SWCNT-COOH suppresses Smad-dependent bone morphogenetic protein (BMP) signaling pathway and down-regulates Id proteins. These molecular actions cause cell cycle arrest at G1/S transition and inhibit cell proliferation. The specific suppression of BMP signaling and Id proteins by SWCNT-COOH demonstrates non-apoptotic effects of functionalized CNT on human cells. This finding may have potential therapeutic value to treat human diseases related to Id proteins or BMP signaling such as breast cancer and bone diseases.
Although nanoparticle/protein binding and the cytotoxicity of nanoparticles have been separately reported, there has been no study linking the nature of nanoparticle/protein clusters to cell uptake and the dynamic cellular responses. We report here that water soluble iron oxide based magnetic nanoparticles (MNPs) with different sizes and surface chemistry bind different serum proteins in terms of protein identity and quantity without changing the protein secondary structures. Carboxylated MNPs resulted in higher cytotoxicity and PEG-coating reduced both cell uptake and the cytotoxicity. Smaller MNPs (especially the carboxylated one) bind more serum proteins, are much less taken up by cells compared to larger particles, yet elicit more dynamic cytotoxic responses. Besides the intrinsic effects of size and surface charge of the water soluble MNPs, the cellular effects of MNPs/protein clusters were also attributed to the identity and quantity of the adsorbed proteins rather than the binding-induced new epitopes on the proteins.
The rapid development of nanotechnology, especially the increasingly emerging nanostructures requires prerequisite bio-activity evaluations. Core/shell iron/carbon nanoparticles (Fe@CNPs) are novel nanomaterials which have potential applications in magnetic resonance imaging (MRI), magnetic hyperthermia and drug delivery, etc. However, their interactions with biological systems are totally unknown at present. To elucidate their potential cytotoxicity and explore the relationship of biocompatibility with their surface chemistry, we synthesized different types of polymer grafted Fe@CNPs and studied their dynamic cellular responses, cell uptake, oxidative stress and their effects on cell apoptosis and cell cycle. The results show that cellular biocompatibility of Fe@CNPs is both surface chemistry dependent and cell type specific and generally non-toxic except for the carboxyl modified Fe@CNPs. Our study indicates that these novel materials can be used for further functionalizations and widely applied in many fields.
本文首先研究了纳米颗粒与蛋白质的结合。纳米颗粒趋于结合蛋白质的性质决定了它在人类和动物体内的毒性以及自身被免疫系统调理和清除的命运。在该项工作中,通过改变多壁碳纳米管(MWCNT)的直径、表面化学以及蛋白质种类,借助稳态荧光光谱、时间分辨荧光光谱和圆二色光谱等分析方法,研究了MWCNT与蛋白质结合的机制。在对不同直径(40 nm与10 nm)MWCNT的研究中发现,直径较大的具有更强的结合蛋白质的能力。这个现象说明纳米颗粒的表面曲率在其与蛋白质结合过程中起到了关键作用。此外,碳纳米管(CNT)的表面电荷和空间位阻也参与调节其与蛋白质的结合,说明了CNT与蛋白质双方的电荷和立体化学性质都对它们之间的结合产生了影响。另外,尽管蛋白质的自身荧光由于与CNT的结合而发生了淬灭,而其荧光寿命并没有改变,说明这种荧光淬灭是由于形成复合物而发生的稳态淬灭。通过圆二色谱法研究蛋白质二级结构时发现,蛋白质的高级结构受到了其与CNT结合的影响,因此可能会影响蛋白质的生物功能。
当CNT与细胞表面受体或细胞内蛋白相互作用时,将会影响细胞的信号传导通路。因此评估其细胞摄取和细胞内定位对了解其生物效应的机制是必不可少的。目前已知CNT可以非常容易地穿过各种各样的生物学屏障而进入多种有机体,包括动物、植物及微生物,然而对其细胞摄取的机制和进入细胞后的转运并不完全清楚。目前对CNT的细胞摄取、细胞内定位和转移机制尚存争议。为了阐明细胞摄取的机制,我们利用透射电子显微镜对表面带电荷的MWCNT的细胞摄取进行了超微结构的观察,发现了MWCNT的直接穿膜、内吞、内吞体泄露和细胞核定位等现象。我们结合文献报道和自己的实验观察,推出了一个细胞摄取模型。在该模型中,将MWCNT分为两组,一组是凝聚态的CNT团簇,另一组是单个分散的CNT。团簇通过能量依赖性的内吞过程进入细胞并首先进入内吞体；内吞体内的团簇随后变得疏松,使单根CNT释放出来,释放出来的单根CNT穿过内吞体膜进入细胞质；高度分散的单个CNT通过直接穿膜进入细胞质；短CNT有可能进入细胞核；最后,所有种类的CNT都进入溶酶体并排出细胞。该模型将会对CNT的药物传递和毒性研究产生重要影响。例如,基于此模型,细胞内的CNT都有可能进入细胞质并与其中的功能性分子发生未知的作用,从而造成某些细胞机能的缺失。
CNT进入细胞后,将不可避免地与细胞内组分发生相互作用并产生时间和剂量依赖性的细胞反应。我们利用一个新型实时细胞电子传感技术动态地监控了CNT的细胞反应。这项技术利用整合在96孔细胞培养板底部的电子传感器对贴附在其上的细胞进行电阻测量,并通过换算得出反应细胞多项指标的参数(细胞指数),细胞指数反应了细胞增殖、细胞形态、贴附及延展。这种技术无须生物标记、实时并且可以高通量的进行测试,克服了目前对于CNT细胞效应研究中基于光度测量的诸多缺点,并使CNT细胞反应的动态监控成为可能。利用该手段我们获得了动态细胞反应曲线、时间依赖性ICs0及细胞生长曲线的斜率等参数。这些参数是无法用传统方法获得的,为CNT及多种纳米材料的生物效应研究提供了重要信息。
由于CNT自身可以与蛋白发生相互作用、进入细胞并造成动态的细胞反应,因此,了解其细胞内行为的分子机制是亟待解决的问题。这些问题包括哪些信号通路受到了影响、哪些基因的表达发生了改变及其后续的生理效应是怎样的。我们通过对羧基化单壁碳纳米管(SWCNT-COOH)的动态细胞反应的监控、全基因组表达分析和其他细胞生物学手段,发现它可以通过一种非凋亡的机制抑制细胞增殖。该机制与目前研究报道中未修饰碳管的效应是截然不同的。基于SWCNT-COOH对细胞增殖、基因和蛋白质表达及蛋白质磷酸化的影响,我们得出结论：该CNT抑制了Smad依赖性的骨形态发生蛋白信号传导通路并下调Id蛋白的表达。这些分子行为造成了细胞周期G1／S过渡期的停滞和细胞增殖的抑制。SWCNT-COOH对该信号通路及基因表达的抑制表明了功能化CNT对人类细胞具有非凋亡效应。这个发现同样对人类疾病的治疗具有潜在的价值,例如与骨形态发生蛋白信号通路相关(骨科疾病)或与Id蛋白相关(乳腺癌)的疾病。
尽管目前对纳米颗粒／蛋白质结合以及纳米颗粒的细胞毒性研究都有分别报道,却没有关于纳米颗粒／蛋白质团簇形成与纳米颗粒细胞摄取和动态细胞效应之间关系的研究。本课题研究并发现不同粒径和表面化学修饰的磁性纳米颗粒可以结合不同种类和数量的蛋白质而不影响蛋白质二级结构。羧基化磁性纳米颗粒具有较高的细胞毒性,而PEG的修饰则降低了它们的细胞摄取和毒性。与较大粒径材料相比,小粒径磁性纳米颗粒(羧基尤为严重)能够结合更多的血清蛋白,进入细胞较少,但是却造成更强的动态细胞反应。因而我们得出结论：对于水溶性磁性纳米颗粒,除了其自身粒径和表面电荷的影响外,纳米／蛋白团簇的细胞效应还受吸附蛋白种类和数量的影响,并且与蛋白质构象变化无关。
纳米技术的迅速发展,尤其是新型纳米结构的不断涌现,需要我们首先对其生物学效应进行评估。在论文的最后一部分,我们研究了一种新型功能化纳米材料—核／壳-铁／碳纳米颗粒的细胞效应。该材料是最新开发的具有磁共振成像、磁热治疗和药物传递应用前景的复合纳米材料。但是目前对该材料与生物系统的相互作用并不清楚。为了阐明该材料潜在毒性及表面化学-生物相容性的关系,我们选择几种不同化学修饰的核／壳-铁／碳纳米颗粒,研究了它们的动态细胞反应、细胞摄取、氧化应激和对细胞凋亡及细胞周期的影响。结果表明该新型材料的细胞生物相容性同时具有表面化学和细胞种类的依赖性,并且除羧基修饰外,其他材料基本不造成细胞毒性。我们的研究表明该类新型功能纳米材料可以进行进一步地功能化修饰并在多个领域广泛应用。
Nanotechnology and nanomaterials are increasingly applied in various aspects of human life, such as energy, environment, electronics and biomedicine. However, people know little about their biological effects. With more and more studies on nanotoxicities have been reported, nanomaterials'safety has caused wide public concern. The key problem is to understand basic biological behavior and mechanisms of nanomaterials. Here, we selected several important types of nanomaterials to study their biological activities. Using multiple physical, chemical and biological approaches, we found important rules on nanoparticles'protein binding, cell uptake and effects on cellular signaling transductions. These findings offer theoretical explanations to nanomaterials biological effects and help elucidate novel interaction and regulation mechanisms. These findings also provide methodological reference to effectively reduce nanotoxicity and improve biocompatibility, and make functional nanomaterials to be probably used as therapeutic agents.
We firstly studied nanoparticles'protein binding. The protein binding propensity of nanoparticles determines their in vivo toxicity and their fate to be opsonized and cleared by human defense systems. In this work, protein binding mechanisms of pristine and functionalized multi-walled carbon nanotubes (MWCNT) were investigated by varying MWCNT's diameters, nanotube surface chemistry, and proteins using steady-state and time-resolved fluorescence, and circular dichroism (CD) spectroscopies. The MWCNT with a larger diameter (～40 nm) generally exhibited stronger protein binding compared with those with a smaller diameter (～10 nm), demonstrating that the curvature of nanoparticles plays a key role in determining the protein binding affinity. Negative charges or steric properties on MWCNT enhanced binding for some proteins, but not others, indicating that the electrostatic and stereochemical nature of both nanotubes and proteins govern nanotube/protein binding. Protein fluorescence lifetime was not altered by the binding while the intensity was quenched indicating a static quenching through complex formation. The binding-induced conformational changes were further confirmed by CD studies.
Effects on cellular signaling pathways can occur when nanotubes interact with cell surface receptors or with intracellular proteins. The evaluation of cell uptake and intracellular location of SWCNT-COOH are crucial for understanding its biological impact mechanism. CNT can readily penetrate various biological barriers in mammals, plants, and microorganisms. However, the mechanism of cell uptake and cellular transfer of CNT is not fully understood. The current explanations on cell uptake of CNT, their intracellular translocation, and subcellular localization are still controversial. To fill this gap, we examined cell uptake of surface charged MWCNT using TEM. We observed direct membrance penetration, endocytosis, endosomal leakage and nuclear translocation of MWCNT. Previous reports and our own experimental results are consistent with a working model for the cell uptake of CNT. CNT clusters are taken up by cells through energy-dependent endocytosis process. The CNT bundles become unpacked in the endosomes and generate single nanotubes that escape endosomes by penetrating endosome membrane and entering the cytoplasm. Alternatively, the highly dispersed single CNT cross cell membrane and enter cells directly by penetrating cellular membranes. All CNT are finally recruited into lysosomes for excretion. The model will have major impacts on both drug delivery and toxicity studies of CNT. For example, all cellular CNT may be exposed to cytoplasm so that the unexpected interactions with cellular functional molecules are likely to happen.
After nanoparticles enter cells, they will inevitably interact with cellular components and time-and dose-dependent cellular responses are likely to occur. We use a novel real-time cell-based electronic sensing (RT-CES) technology to dynamically monitor cellular responses to carbon nanotubes. This approach is based on the parallel impedance measurement of attached cells using electronic sensors integrated in wells of 96-well E-plate. It measures the real-time multi-parameter index of cell growth named cell index (CI), which reflects the cell proliferation, morphology, attachment and spreading. The label-free, real-time and high-throughput assay overcomes many drawbacks in current optical based cytotoxicity assays in carbon nanotubes research, and enables dynamic monitoring of cellular responses to carbon nanotubes. Using this assay, we obtained dynamic cellular response curves, time-dependent IC50s and cell growth slopes which can not be obtained by conventional assays.
Since nanoparticles intrinsically interact with proteins and enter cells and cause dynamic cellular responses, it's urgent to elucidate the underlying molecular mechanisms of a nanoparticle's cellular behavior, including what signaling pathway is affected, what genes are changed and what are the consequences. Through our dynamic monitoring of cellular responses and evaluation of genome expression, as well as other cellular biological approaches, we discovered that SWCNT-COOH inhibited cell proliferation via a non-apoptotic mechanism, which is different from effects caused by pristine CNT. On the basis of SWCNT-COOH's perturbations on cells, expression of genes and protein, and protein phosphorylations, we conclude that SWCNT-COOH suppresses Smad-dependent bone morphogenetic protein (BMP) signaling pathway and down-regulates Id proteins. These molecular actions cause cell cycle arrest at G1/S transition and inhibit cell proliferation. The specific suppression of BMP signaling and Id proteins by SWCNT-COOH demonstrates non-apoptotic effects of functionalized CNT on human cells. This finding may have potential therapeutic value to treat human diseases related to Id proteins or BMP signaling such as breast cancer and bone diseases.
Although nanoparticle/protein binding and the cytotoxicity of nanoparticles have been separately reported, there has been no study linking the nature of nanoparticle/protein clusters to cell uptake and the dynamic cellular responses. We report here that water soluble iron oxide based magnetic nanoparticles (MNPs) with different sizes and surface chemistry bind different serum proteins in terms of protein identity and quantity without changing the protein secondary structures. Carboxylated MNPs resulted in higher cytotoxicity and PEG-coating reduced both cell uptake and the cytotoxicity. Smaller MNPs (especially the carboxylated one) bind more serum proteins, are much less taken up by cells compared to larger particles, yet elicit more dynamic cytotoxic responses. Besides the intrinsic effects of size and surface charge of the water soluble MNPs, the cellular effects of MNPs/protein clusters were also attributed to the identity and quantity of the adsorbed proteins rather than the binding-induced new epitopes on the proteins.
The rapid development of nanotechnology, especially the increasingly emerging nanostructures requires prerequisite bio-activity evaluations. Core/shell iron/carbon nanoparticles (Fe@CNPs) are novel nanomaterials which have potential applications in magnetic resonance imaging (MRI), magnetic hyperthermia and drug delivery, etc. However, their interactions with biological systems are totally unknown at present. To elucidate their potential cytotoxicity and explore the relationship of biocompatibility with their surface chemistry, we synthesized different types of polymer grafted Fe@CNPs and studied their dynamic cellular responses, cell uptake, oxidative stress and their effects on cell apoptosis and cell cycle. The results show that cellular biocompatibility of Fe@CNPs is both surface chemistry dependent and cell type specific and generally non-toxic except for the carboxyl modified Fe@CNPs. Our study indicates that these novel materials can be used for further functionalizations and widely applied in many fields.
引文
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[27]Schins RPF, Duffin R, Hohr D, Knaapen AM, Shi T, Weishaupt C, et al. Surface Modification of Quartz Inhibits Toxicity, Particle Uptake, and Oxidative DNA Damage in Human Lung Epithelial Cells. Chemical Research in Toxicology.2002; 15:1166-73.
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[30]Huang DM, Hsiao JK, Chen YC, Chien LY, Yao M, Chen YK, et al. The promotion of human mesenchymal stem cell proliferation by superparamagnetic iron oxide nanoparticles. Biomaterials.2009;30:3645-51.
[31]Yang H, Wu QY, Tang M, Kong L, Xia T, Yin HR, et al. Cytotoxicity and DNA-damage in Mouse Macrophage Exposed to Silica Nanoparticles. In:Ding JY, Wang XY, Hong Q, Guo WW, Xin XP, editors.8th National Postgraduate Symposium on Environmental and Occupational Medicine, Proceedings. Shanghai:Shanghai Ctr Dis Control & Prevention; 2009. p.100-5.
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