高分子纳米复合造影材料研究
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摘要
纳米医疗技术经历了几十年的发展,取得了巨大的研究进展,诸如胶束和复合纳米微球等纳米粒子在临床中获得了应用。目前,高分子-无机复合纳米微球由于兼有高分子微球和无机材料两者的优势而备受关注。其中,尤其是由可塑及生物相容性的高分子与拥有特殊光、磁和电学性质的无机物组成的复合纳米微球,在疾病诊断和治疗中非常有用。然而,迄今为止绝大部分复合纳米微球的合成需要在复杂的过程中用到有机溶剂或者表面活性剂,这些试剂都有一定的毒性。另外,无机纳米粒子的光不稳定性和低的磁化驰豫率也限制了复合纳米微球的生物医学应用。因此,以性能优越的无机材料和良好生物相容性的高分子为主要材料的复合纳米微球成为本领域的研究热点之一,采用环境友好的水相制备法,排除高毒性的有机溶剂和表面活性剂是人们高度期望的。
本课题组过去提出了“不良溶剂辅助静电络合法”,通过静电作用制备稳定的聚电解质纳米微球。在本论文中,我们将这种方法扩展到高分子-无机复合纳米微球的自组装体系。我们以具有良好生物相容性的阳离子壳聚糖和阴离子乙二胺四乙酸(EDTA)为反离子对,包覆了不同功能的无机纳米材料,并制备出多种稳定的复合纳米微球。探索并展示了这些复合纳米微球在生物医药领域的应用潜力。详细工作如下：
(1)利用乙醇辅助的相反电荷络合法在水溶液中成功合成了包覆CdSe/ZnS量子点的壳聚糖复合纳米微球(CS-QD)。CS-QD复合纳米微球不仅拥有壳聚糖基质球提供的能装填多个QDs的空间,还有所负载QDs的特殊荧光性质。而且,这些复合纳米微球在生理环境中具有良好的生物相容性与光学稳定性。CS-QD复合纳米微球的癌细胞摄入研究表明其可以用作光学显微镜下细胞成像标记试剂。另外,复合纳米微球能够用于瘤内注射的荷瘤小鼠肿瘤成像,并通过荧光成像发现尾静脉注射的复合微球经过血液循环在瘤内富集。因此,一方面壳聚糖微球提供了QDs的生物相容性并保证了其胶体和光学稳定性；另一方面量子点“点亮”了高分子微球,显示了高分子微球在细胞和活体内的踪迹。
(2)我们以高温热解法合成了超顺磁性水溶的铁酸锌(ZnFe2O4)纳米粒子。在这一合成中,四甘醇(TEG)作为配位和稳定试剂,赋予了纳米粒子水溶性和稳定性。通过XRD、TEM、EDS、XPS和FTIR表征了所得纳米粒子。随后,在不良溶剂辅助下由TEG稳定的ZnFe2O4纳米粒子、壳聚糖和EDTA自组装制备了壳聚糖-铁酸锌(CS-ZnFe2O4)复合纳米微球。微球中无机粒子的负载量是可控的,ZnFe2O4纳米粒子提供了复合纳米微球的超顺磁性,而且无机纳米粒子在微球核内的团簇效应和高的负载量,导致了复合纳米微球比单分散ZnFe2O4纳米粒子具有高得多的r2驰豫率值。此外,所得复合纳米微球具有良好的生物相容性和稳定性,有利于进一步的生物应用。
(3)对CS-ZnFe2O4复合纳米微球作为磁共振成像(MRI)T2造影剂的潜能进行了评估。同时,为了获得肿瘤靶向效果,将癌症特异性靶向试剂cRGD肽连接到复合纳米微球上获得了主动靶向的复合纳米微球(RGD-CS-ZnFe2O4)。CS-ZnFe2O4和RGD-CS-ZnFe2O4复合纳米微球的体内磁共振成像研究说明了它们卓越的T2增强造影能力,而且靶向复合纳米微球比非靶向复合纳米微球显示出更高的瘤内MRI敏感性。另外,体内分布分析表明CS-ZnFe2O4复合微球可通过高通透和滞留效应(EPR效应)富集在荷瘤小鼠的肿瘤部位,而表面连接了RGD的磁性复合纳米微球则通过主动靶向效应进一步提高了微球在肿瘤内的富集。因此,RGD-CS-ZnFe2O4复合纳米微球是一种高效的MRI T2造影探针。
Medical nanotechnology has been developing for decades, and innovative applications are coming to fruition. Nanoparticle formulations, such as micelle and hybrid nanospheres, have been used in biomedical area. Currently, polymer-inorganic hybrid nanospheres have attracted increasing attention because of the synergic properties arising from both the polymeric nanospheres and inorganic nanomaterials. Especially, those that have plasticity and biocompatibility of polymer as well as unique optical, magnetic and electric properties of inorganic materials are greatly useful in diagnosis and therapy disease. Unfortunately, the most construction of hybrid nanospheres reported so far require complicated synthesis processes and may cause environmental toxicity, which arise from either the use of surfactants or the organic solvents. Moreover, photo instability and low magnetic relaxation rate of inorganic nanomaterials limit their applications in biomedicine yield yet. Therefore, inorganic materials with excellent properties and biocompatible polymer become a research hotspot, taking into account that hybrid nanospheres can be prepared in aqueous phase without any aid of organic solvents or surfactants.
Our group previously reported "non-solvent aided counter-ion complexation strategies" for preparing stable polyelectrolyte nanospheres through electrostatic interactions. In this thesis, the strategy was extended to study the self-assembly behaviors of polymer-inorganic hybrid nanospheres. We chose biocompatible cationic chitosan and anion ethylenediaminetetraacetic (EDTA) as counterion complex, and enwrapped different inorganic functional nanomaterials to prepare stable hybrid nanospheres based on their characteristics. Their huge potential in biomedical field was explored as well. The detailed work is described as blew:
(1) CdSe/ZnS quantum dot-encapsulated chitosan hybrid nanospheres (CS-QD) have been successfully fabricated by utilizing ethanol-aided counterion complexation in aqueous solution. The obtained CS-QD hybrid nanospheres have not only the loading space provided by the chitosan spherical matrix for loading multiply QD but also unique fluorescent properties provided by the encapsulated QDs. Moreover, these hybrid nanospheres possess good biocompatibility and optical stability in physiological environment. It has been demonstrated that CS-QD hybrid nanospheres can be internalized by tumor cells and hence act as labeling agent in cell imaging by optical microscopy. In addition, CS-QD hybrid nanospheres can be used for imaging of tumor in tumor-bearing mice via intratumoral administration and can accumulate at tumor site via the blood circulation based on intravenous injection. Thus, on the one hand, chitosan nanospheres provide the protection in both colloidal and optical stability arising from QDs and offer biocompatibility. On the other hand, the encapsulated QDs light up polymer nanospheres and display the fate of polymer nanospheres in cells and bodies.
(2) We used a thermal decomposition approach to synthesize water-soluble superparamagnetic zinc ferrite (ZnFe2O4) nanoparticles. In this approach, tetraethylene glycol (TEG) was utilized as a coordination and stabilization agent, rendering the nanoparticles water-soluble and stable. The formed nanoparticles were characterized by XRD, TEM, EDS, XPS and FTIR technologies. Subsequently, CS-ZnFe2O4 hybrid nanospheres were synthesized via self-assembly of TEG stabilized ZnFe2O4 nanoparticles, CS and EDTA based on simple nonsolvent-aided method. The loading content of ZnFe2O4 nanoparticles is controllable. The obtained hybrid nanospheres exhibited not only the superparamagnetic property provided by pure ZnFe2O4 nanoparticles but also higher r2 relaxivity value than monodisperse ZnFe2O4 nanoparticles, which can be attributed to the high ZnFeCO4 loading content and ZnFe2O4 nanoparticles clustering effect in the core of the nanospheres. Moreover, these hybrid nanospheres possess good biocompatibility and stability, which is in favor of further biological applications.
(3) The imaging property of CS-ZnFe2O4 hybrid nanospheres was evaluated as a T2 contrast agent for magnetic resonance imaging (MRI). Meanwhile, the hybrid nanospheres were conjugated with cancer-specific targeting agent cyclic RGD peptide to obtain hybrid nanospheres (RGD-CS-ZnFe2O4) with the tumor-targeting effect. The in vivo MR images demonstrated that both CS-ZnFe2O4 and RGD-CS-ZnFe2O4 hybrid nanospheres had an excellent T2 enhanced contrast ability, while RGD-CS-ZnFe2O4 exhibited a higher MRI sensitivity in the tumor compared CS-ZnFe2O4·In addition, the biodistribution analysis revealed the CS-ZnFe2O4 hybrid nanospheres can accumulate at tumor site via enhanced permeability and retention (EPR) effect in tumor-bearing mice, and RGD-CS-ZnFe2O4 nanospheres showed enhanced accumulation in tumor significantly. Hence, RGD-CS-ZnFe2O4 hybrid nanospheres with tumor-targeting ability can serve as highly efficient T2 contrast probes for cancer diagnosis and treatment.
本课题组过去提出了“不良溶剂辅助静电络合法”,通过静电作用制备稳定的聚电解质纳米微球。在本论文中,我们将这种方法扩展到高分子-无机复合纳米微球的自组装体系。我们以具有良好生物相容性的阳离子壳聚糖和阴离子乙二胺四乙酸(EDTA)为反离子对,包覆了不同功能的无机纳米材料,并制备出多种稳定的复合纳米微球。探索并展示了这些复合纳米微球在生物医药领域的应用潜力。详细工作如下：
(1)利用乙醇辅助的相反电荷络合法在水溶液中成功合成了包覆CdSe/ZnS量子点的壳聚糖复合纳米微球(CS-QD)。CS-QD复合纳米微球不仅拥有壳聚糖基质球提供的能装填多个QDs的空间,还有所负载QDs的特殊荧光性质。而且,这些复合纳米微球在生理环境中具有良好的生物相容性与光学稳定性。CS-QD复合纳米微球的癌细胞摄入研究表明其可以用作光学显微镜下细胞成像标记试剂。另外,复合纳米微球能够用于瘤内注射的荷瘤小鼠肿瘤成像,并通过荧光成像发现尾静脉注射的复合微球经过血液循环在瘤内富集。因此,一方面壳聚糖微球提供了QDs的生物相容性并保证了其胶体和光学稳定性；另一方面量子点“点亮”了高分子微球,显示了高分子微球在细胞和活体内的踪迹。
(2)我们以高温热解法合成了超顺磁性水溶的铁酸锌(ZnFe2O4)纳米粒子。在这一合成中,四甘醇(TEG)作为配位和稳定试剂,赋予了纳米粒子水溶性和稳定性。通过XRD、TEM、EDS、XPS和FTIR表征了所得纳米粒子。随后,在不良溶剂辅助下由TEG稳定的ZnFe2O4纳米粒子、壳聚糖和EDTA自组装制备了壳聚糖-铁酸锌(CS-ZnFe2O4)复合纳米微球。微球中无机粒子的负载量是可控的,ZnFe2O4纳米粒子提供了复合纳米微球的超顺磁性,而且无机纳米粒子在微球核内的团簇效应和高的负载量,导致了复合纳米微球比单分散ZnFe2O4纳米粒子具有高得多的r2驰豫率值。此外,所得复合纳米微球具有良好的生物相容性和稳定性,有利于进一步的生物应用。
(3)对CS-ZnFe2O4复合纳米微球作为磁共振成像(MRI)T2造影剂的潜能进行了评估。同时,为了获得肿瘤靶向效果,将癌症特异性靶向试剂cRGD肽连接到复合纳米微球上获得了主动靶向的复合纳米微球(RGD-CS-ZnFe2O4)。CS-ZnFe2O4和RGD-CS-ZnFe2O4复合纳米微球的体内磁共振成像研究说明了它们卓越的T2增强造影能力,而且靶向复合纳米微球比非靶向复合纳米微球显示出更高的瘤内MRI敏感性。另外,体内分布分析表明CS-ZnFe2O4复合微球可通过高通透和滞留效应(EPR效应)富集在荷瘤小鼠的肿瘤部位,而表面连接了RGD的磁性复合纳米微球则通过主动靶向效应进一步提高了微球在肿瘤内的富集。因此,RGD-CS-ZnFe2O4复合纳米微球是一种高效的MRI T2造影探针。
Medical nanotechnology has been developing for decades, and innovative applications are coming to fruition. Nanoparticle formulations, such as micelle and hybrid nanospheres, have been used in biomedical area. Currently, polymer-inorganic hybrid nanospheres have attracted increasing attention because of the synergic properties arising from both the polymeric nanospheres and inorganic nanomaterials. Especially, those that have plasticity and biocompatibility of polymer as well as unique optical, magnetic and electric properties of inorganic materials are greatly useful in diagnosis and therapy disease. Unfortunately, the most construction of hybrid nanospheres reported so far require complicated synthesis processes and may cause environmental toxicity, which arise from either the use of surfactants or the organic solvents. Moreover, photo instability and low magnetic relaxation rate of inorganic nanomaterials limit their applications in biomedicine yield yet. Therefore, inorganic materials with excellent properties and biocompatible polymer become a research hotspot, taking into account that hybrid nanospheres can be prepared in aqueous phase without any aid of organic solvents or surfactants.
Our group previously reported "non-solvent aided counter-ion complexation strategies" for preparing stable polyelectrolyte nanospheres through electrostatic interactions. In this thesis, the strategy was extended to study the self-assembly behaviors of polymer-inorganic hybrid nanospheres. We chose biocompatible cationic chitosan and anion ethylenediaminetetraacetic (EDTA) as counterion complex, and enwrapped different inorganic functional nanomaterials to prepare stable hybrid nanospheres based on their characteristics. Their huge potential in biomedical field was explored as well. The detailed work is described as blew:
(1) CdSe/ZnS quantum dot-encapsulated chitosan hybrid nanospheres (CS-QD) have been successfully fabricated by utilizing ethanol-aided counterion complexation in aqueous solution. The obtained CS-QD hybrid nanospheres have not only the loading space provided by the chitosan spherical matrix for loading multiply QD but also unique fluorescent properties provided by the encapsulated QDs. Moreover, these hybrid nanospheres possess good biocompatibility and optical stability in physiological environment. It has been demonstrated that CS-QD hybrid nanospheres can be internalized by tumor cells and hence act as labeling agent in cell imaging by optical microscopy. In addition, CS-QD hybrid nanospheres can be used for imaging of tumor in tumor-bearing mice via intratumoral administration and can accumulate at tumor site via the blood circulation based on intravenous injection. Thus, on the one hand, chitosan nanospheres provide the protection in both colloidal and optical stability arising from QDs and offer biocompatibility. On the other hand, the encapsulated QDs light up polymer nanospheres and display the fate of polymer nanospheres in cells and bodies.
(2) We used a thermal decomposition approach to synthesize water-soluble superparamagnetic zinc ferrite (ZnFe2O4) nanoparticles. In this approach, tetraethylene glycol (TEG) was utilized as a coordination and stabilization agent, rendering the nanoparticles water-soluble and stable. The formed nanoparticles were characterized by XRD, TEM, EDS, XPS and FTIR technologies. Subsequently, CS-ZnFe2O4 hybrid nanospheres were synthesized via self-assembly of TEG stabilized ZnFe2O4 nanoparticles, CS and EDTA based on simple nonsolvent-aided method. The loading content of ZnFe2O4 nanoparticles is controllable. The obtained hybrid nanospheres exhibited not only the superparamagnetic property provided by pure ZnFe2O4 nanoparticles but also higher r2 relaxivity value than monodisperse ZnFe2O4 nanoparticles, which can be attributed to the high ZnFeCO4 loading content and ZnFe2O4 nanoparticles clustering effect in the core of the nanospheres. Moreover, these hybrid nanospheres possess good biocompatibility and stability, which is in favor of further biological applications.
(3) The imaging property of CS-ZnFe2O4 hybrid nanospheres was evaluated as a T2 contrast agent for magnetic resonance imaging (MRI). Meanwhile, the hybrid nanospheres were conjugated with cancer-specific targeting agent cyclic RGD peptide to obtain hybrid nanospheres (RGD-CS-ZnFe2O4) with the tumor-targeting effect. The in vivo MR images demonstrated that both CS-ZnFe2O4 and RGD-CS-ZnFe2O4 hybrid nanospheres had an excellent T2 enhanced contrast ability, while RGD-CS-ZnFe2O4 exhibited a higher MRI sensitivity in the tumor compared CS-ZnFe2O4·In addition, the biodistribution analysis revealed the CS-ZnFe2O4 hybrid nanospheres can accumulate at tumor site via enhanced permeability and retention (EPR) effect in tumor-bearing mice, and RGD-CS-ZnFe2O4 nanospheres showed enhanced accumulation in tumor significantly. Hence, RGD-CS-ZnFe2O4 hybrid nanospheres with tumor-targeting ability can serve as highly efficient T2 contrast probes for cancer diagnosis and treatment.
引文
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