CN115678007B - Fluorine-based polyamino acid cobalt nanoparticle and preparation method and application thereof - Google Patents
Fluorine-based polyamino acid cobalt nanoparticle and preparation method and application thereof Download PDFInfo
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Abstract
Description
技术领域Technical field
本发明属于纳米医学技术领域,具体涉及一种用于磁性粒子成像的氟基聚氨基酸钴纳米粒子示踪剂及其制备方法与用途。The invention belongs to the field of nanomedicine technology, and specifically relates to a fluorine-based polyamino acid cobalt nanoparticle tracer for magnetic particle imaging and its preparation method and use.
背景技术Background technique
磁粒子成像技术(Magnetic Particle Imaging,MPI)是基于功能和断层影像技术检测磁性纳米颗粒空间分布的示踪方法。MPI具有三维成像、高时间分辨率、高空间分辨率和高灵敏度,且无电离辐射危害的优点。与传统的磁共振成像(MRI)不同是,MPI是通过直接探测磁性粒子在磁场中的响应性变化,实现对磁性粒子空间分布的直接成像。MPI不显示解剖结构,无背景信号干扰,信号强度与示踪剂浓度成比例,是一种可以获得定量数据的检查方法。MPI在生命科学各个领域的应用研究都有着不错的进展,其可以直接检测到机体内任何时间和空间的纳米颗粒示踪剂,满足临床对安全、快速的三维血管造影技术的需求,帮助研究人员从器官、细胞和分子层面深入认识病程,其应用领域包括细胞追踪、炎症追踪、药物递送与检测、血池造影、肿瘤检测等各个领域。Magnetic Particle Imaging (MPI) is a tracing method based on functional and tomographic imaging technology to detect the spatial distribution of magnetic nanoparticles. MPI has the advantages of three-dimensional imaging, high temporal resolution, high spatial resolution and high sensitivity, without the hazard of ionizing radiation. Different from traditional magnetic resonance imaging (MRI), MPI achieves direct imaging of the spatial distribution of magnetic particles by directly detecting the responsiveness changes of magnetic particles in a magnetic field. MPI does not display anatomical structures, has no background signal interference, and the signal intensity is proportional to the tracer concentration. It is an inspection method that can obtain quantitative data. MPI has made good progress in applied research in various fields of life sciences. It can directly detect nanoparticle tracers at any time and space in the body, meeting clinical needs for safe and fast three-dimensional angiography technology, and helping researchers Understand the disease process deeply from the organ, cellular and molecular levels, and its application fields include cell tracking, inflammation tracking, drug delivery and detection, blood pool imaging, tumor detection and other fields.
MPI成像需要使用示踪剂,只有示踪剂存在于成像区域才能产生信号。示踪剂的性质很大程度上决定了MPI的图像质量。由于机体内正常情况下不会存在示踪剂,因此MPI图像具有极佳的对比度和高灵敏度,使我们能够看到活的有机体中细胞(细胞跟踪)、血液(灌注)和其他功能系统(靶向、药物传递系统)中的示踪剂。磁粒子成像利用磁力学独特的几何结构创建一个磁场自由区(FieldFree Region,FFR),类似于将两块磁铁放在一起时的情况。由敏感点控制纳米颗粒的方向。这与MRI的物理原理截然不同,MRI的图像是由均匀的磁场产生的。快速移动FFR会使得示踪剂纳米颗粒的磁性方位发生翻转,从而在接收线圈中产生信号。因为我们始终知道敏感点在哪里,所以我们可以将信号分配到已知位置,产生定量的MPI图像。MPI的性能、分辨率和灵敏度主要受纳米颗粒的影响。使用更好的或特定的示踪剂可以提高设备的分辨率和/或灵敏度。MPI imaging requires the use of tracers, and signals can only be generated when tracers are present in the imaging area. The nature of the tracer largely determines the image quality of MPI. Since tracers are not normally present in the body, MPI images have excellent contrast and high sensitivity, allowing us to see cells (cell tracking), blood (perfusion) and other functional systems (targets) in living organisms. tracers in drug delivery systems). Magnetic particle imaging uses the unique geometry of magnetism to create a magnetic field free region (FFR), similar to what happens when two magnets are put together. The direction of nanoparticles is controlled by sensitive points. This is completely different from the physics of MRI, where images are produced by a uniform magnetic field. Rapidly moving the FFR flips the magnetic orientation of the tracer nanoparticles, producing a signal in the receiving coil. Because we always know where the sensitive points are, we can assign signals to known locations, producing quantitative MPI images. The performance, resolution and sensitivity of MPI are mainly affected by nanoparticles. Using better or specific tracers can improve the resolution and/or sensitivity of the device.
常用的示踪剂是氧化铁磁性纳米粒子(Fe3O4),也称为超顺磁性氧化铁纳米粒子。但对眼部疾病治疗的药物递送与检测,单一特性的氧化铁磁性纳米粒子无法满足目前对于生物毒性、代谢等生物相容性以及适用性等方面的需求。目前的常见的眼部疾病包括新生血管性青光眼、湿性老年性黄斑变性、糖尿病视网膜病变合并黄斑水肿等,目前的主要治疗方式为玻璃体腔药物注射其药物递送与药代检测对药物的临床应用至关重要,而对于在眼部应用的可以被有效检测到的适宜的磁性材料即磁性纳米粒子示踪剂迄今为止没有报道。A commonly used tracer is iron oxide magnetic nanoparticles (Fe 3 O 4 ), also known as superparamagnetic iron oxide nanoparticles. However, for drug delivery and detection for the treatment of eye diseases, iron oxide magnetic nanoparticles with a single characteristic cannot meet the current needs for biological toxicity, metabolism and other biocompatibility and applicability. Current common eye diseases include neovascular glaucoma, wet age-related macular degeneration, diabetic retinopathy combined with macular edema, etc. The current main treatment method is intravitreal drug injection. The clinical application of drug delivery and pharmacokinetic testing has reached It is very important, but there is no report so far about suitable magnetic materials that can be effectively detected for eye applications, that is, magnetic nanoparticle tracers.
目前需要具有优于目前商用的氧化铁磁性纳米粒子性能,且适用于眼部的药物递送与检测的纳米粒子示踪剂的有效制备方法。There is a need for effective preparation methods for nanoparticle tracers that have properties superior to currently available commercial iron oxide magnetic nanoparticles and are suitable for drug delivery and detection in the eye.
发明内容Contents of the invention
本发明为了解决上述技术问题,进而提出一种制备氟基聚氨基酸钴纳米粒子的方法,包括以下步骤:In order to solve the above technical problems, the present invention further proposes a method for preparing fluorine-based polyamino acid cobalt nanoparticles, which includes the following steps:
步骤一、将氨基酸与三光气溶解于有机溶剂中反应,加入非溶剂沉淀纯化产物,真空干燥得到α-氨基酸-N-羧基酸酐;Step 1: Dissolve the amino acid and triphosgene in an organic solvent to react, add a non-solvent to precipitate the purified product, and dry it under vacuum to obtain α-amino acid-N-carboxylic acid anhydride;
步骤二、将α-氨基酸-N-羧基酸酐与氟基引发剂溶解于有机溶剂中反应,加入非溶剂沉淀纯化产物,真空干燥得到氟基聚氨基酸肽段;Step 2: Dissolve α-amino acid-N-carboxylic acid anhydride and fluorine-based initiator in an organic solvent to react, add a non-solvent to precipitate the purified product, and vacuum dry to obtain a fluorine-based polyamino acid peptide segment;
步骤三、将氟基聚氨基酸肽段溶于有机溶剂形成溶液A,将无机钴金属配合物溶于有机溶剂形成溶液B,然后将溶液B缓慢加入溶液A,在温度梯度下反应,加入非溶剂沉淀纳米粒子,真空干燥得到氟基聚氨基酸钴纳米粒子粉末。Step 3: Dissolve the fluorine-based polyamino acid peptide segment in an organic solvent to form solution A, dissolve the inorganic cobalt metal complex in an organic solvent to form solution B, then slowly add solution B to solution A, react under a temperature gradient, and add a non-solvent. The nanoparticles are precipitated and vacuum dried to obtain fluorine-based polyamino acid cobalt nanoparticle powder.
进一步地,步骤一中,所述氨基酸为甘氨酸、羟基甘氨酸、丙甘氨酸、烯丙基甘氨酸和炔丙基甘氨酸中的一种或多种。Further, in step one, the amino acid is one or more of glycine, hydroxyglycine, prolanglycine, allylglycine and propargylglycine.
进一步地,步骤二中,所述氟基引发剂为2,2,2-三氟乙胺、1H,1H-七氟丁胺、1H,1H-全氟庚基胺和1H,1H,2H,2H-全氟癸基胺中的一种或多种。Further, in step 2, the fluorine-based initiator is 2,2,2-trifluoroethylamine, 1H,1H-heptafluorobutylamine, 1H,1H-perfluoroheptylamine and 1H,1H,2H, One or more of 2H-perfluorodecylamines.
进一步地,步骤三中,所述无机钴金属配合物为二羰基环戊二烯钴、三羰基亚硝酰基钴、八羰基二钴、十二羰基四钴中的一种或多种。Further, in step three, the inorganic cobalt metal complex is one or more of cobalt dicarbonylcyclopentadienyl, cobalt tricarbonylnitrosyl, dicobalt octacarbonyl, and tetracobalt dodecacarbonyl.
进一步地,步骤一中,氨基酸与三光气的摩尔数用量比为1:0.4~1;所述有机溶剂为二甲基亚砜、四氢呋喃、N’N-二甲基甲酰胺中的至少一种;所述反应的条件为在30~60℃下搅拌5~12小时,真空干燥温度为30~60℃。Further, in step one, the molar ratio of amino acid to triphosgene is 1:0.4-1; the organic solvent is at least one of dimethyl sulfoxide, tetrahydrofuran, and N'N-dimethylformamide. ; The reaction conditions are stirring at 30-60°C for 5-12 hours, and the vacuum drying temperature is 30-60°C.
进一步地,步骤二中,α-氨基酸-N-羧基酸酐与氟基引发剂的摩尔数用量比为1:0.1~0.02;所述有机溶剂选自二甲基亚砜、四氢呋喃、N’N-二甲基甲酰胺中的至少一种;所述反应的条件为在0~30℃下搅拌反应24~72小时,真空干燥温度为25~55℃。Further, in step two, the molar ratio of α-amino acid-N-carboxylic acid anhydride to fluorine-based initiator is 1:0.1~0.02; the organic solvent is selected from dimethyl sulfoxide, tetrahydrofuran, N'N- At least one kind of dimethylformamide; the conditions of the reaction are stirring and reaction at 0 to 30°C for 24 to 72 hours, and the vacuum drying temperature is 25 to 55°C.
进一步地,步骤三中,氟基聚氨基酸肽段的浓度为0.5~2mol/L;无机钴配合物的浓度为1~3mol/L;有机溶剂为邻二氯苯、甲苯、四氢呋喃、N’N-二甲基甲酰胺中的一种或多种;所述温度梯度为:在室温下搅拌反应12~48小时,然后在160℃下搅拌反应6~18小时,真空干燥温度为25~55℃。Further, in step three, the concentration of the fluorine-based polyamino acid peptide segment is 0.5~2mol/L; the concentration of the inorganic cobalt complex is 1~3mol/L; the organic solvent is o-dichlorobenzene, toluene, tetrahydrofuran, N'N - One or more dimethylformamides; the temperature gradient is: stir and react at room temperature for 12 to 48 hours, then stir and react at 160°C for 6 to 18 hours, and the vacuum drying temperature is 25 to 55°C .
进一步地,所述非溶剂为正己烷、石油醚、乙醚中的一种或者多种。Further, the non-solvent is one or more of n-hexane, petroleum ether, and diethyl ether.
本发明还包括根据上述方法得到的氟基聚氨基酸钴纳米粒子,以及氟基聚氨基酸钴纳米粒子作为磁性粒子成像示踪剂的应用。The present invention also includes fluorine-based polyamino acid cobalt nanoparticles obtained according to the above method, and the application of fluorine-based polyamino acid cobalt nanoparticles as magnetic particle imaging tracers.
有益效果beneficial effects
本发明的氟基聚氨基酸钴纳米粒子,成像效果好、方法简单、适用性较为广泛,可以制备氟基聚氨基酸铁纳米粒子、氟基聚氨基酸镍纳米粒子等,用于磁性粒子成像MPI的示踪剂,也适用于眼部MPI示踪剂。The fluorine-based polyamino acid cobalt nanoparticles of the present invention have good imaging effects, simple methods, and wide applicability. They can prepare fluorine-based polyamino acid iron nanoparticles, fluorine-based polyamino acid nickel nanoparticles, etc., and are used for the display of magnetic particle imaging MPI. Tracer, also suitable for ocular MPI tracer.
基于目前功能性磁性纳米粒子的尺寸难控,本发明通过调控聚合物的聚合度和结构,制备出了尺度可控(5nm-200nm)的磁性纳米粒子。本发明所制备的氟基聚氨基酸钴纳米粒子,引入氟基后,可更好的在眼部玻腔中定向移动,并且具有良好的MPI成像性能,代谢周期短,生物相容性好。Since the size of functional magnetic nanoparticles is currently difficult to control, the present invention prepares magnetic nanoparticles with controllable size (5nm-200nm) by regulating the degree of polymerization and structure of the polymer. The fluorine-based polyamino acid cobalt nanoparticles prepared by the present invention can better move directionally in the eye glass cavity after introducing fluorine groups, and have good MPI imaging performance, short metabolic cycle, and good biocompatibility.
附图说明Description of drawings
图1为本发明实例1中炔丙基甘氨酸以及产物α-氨基酸-N-羧基酸酐的红外谱图。Figure 1 is the infrared spectrum of propargylglycine and the product α-amino acid-N-carboxylic acid anhydride in Example 1 of the present invention.
图2为本发明实例1中α-氨基酸-N-羧基酸酐的核磁共振氢谱图。Figure 2 is a hydrogen nuclear magnetic resonance spectrum of α-amino acid-N-carboxylic acid anhydride in Example 1 of the present invention.
图3为本发明实例1中氟基聚氨基酸肽的红外谱图。Figure 3 is an infrared spectrum of the fluorine-based polyamino acid peptide in Example 1 of the present invention.
图4为本发明实例1中氟基聚氨基酸钴纳米粒子的红外谱图。Figure 4 is an infrared spectrum of the fluorine-based polyamino acid cobalt nanoparticles in Example 1 of the present invention.
图5为本发明实例1中氟基聚氨基酸钴纳米粒子的XRD衍射图谱。Figure 5 is the XRD diffraction pattern of the fluorine-based polyamino acid cobalt nanoparticles in Example 1 of the present invention.
图6为本发明实例2中氟基聚氨基酸钴纳米粒子的红外谱图。Figure 6 is an infrared spectrum of fluorine-based polyamino acid cobalt nanoparticles in Example 2 of the present invention.
图7为本发明实例2中氟基聚氨基酸钴纳米粒子的XRD衍射图谱。Figure 7 is the XRD diffraction pattern of the fluorine-based polyamino acid cobalt nanoparticles in Example 2 of the present invention.
图8为本发明实例3中氟基聚氨基酸钴纳米粒子的红外谱图。Figure 8 is an infrared spectrum of fluorine-based polyamino acid cobalt nanoparticles in Example 3 of the present invention.
图9为本发明实例3中氟基聚氨基酸钴纳米粒子的XRD衍射图谱。Figure 9 is the XRD diffraction pattern of the fluorine-based polyamino acid cobalt nanoparticles in Example 3 of the present invention.
图10为本发明实例3中氟基聚氨基酸钴纳米粒子的透射电镜TEM图。Figure 10 is a transmission electron microscope TEM image of the fluorine-based polyamino acid cobalt nanoparticles in Example 3 of the present invention.
图11为本发明实例3中氟基聚氨基酸钴纳米粒子的对人视网膜上皮细胞(ARPE-19细胞)增值毒性。Figure 11 shows the incremental toxicity of fluorine-based polyamino acid cobalt nanoparticles to human retinal epithelial cells (ARPE-19 cells) in Example 3 of the present invention.
图12为本发明实例3中氟基聚氨基酸钴纳米粒子对C57BL/6J小鼠组织切片染色图。Figure 12 is a picture of the staining of C57BL/6J mouse tissue sections by fluorine-based polyamino acid cobalt nanoparticles in Example 3 of the present invention.
图13为本发明实例3中氟基聚氨基酸钴纳米粒子作为MPI示踪剂对C57BL/6J小鼠眼部的MPI成像图。Figure 13 is an MPI imaging diagram of C57BL/6J mouse eyes using fluorine-based polyamino acid cobalt nanoparticles as MPI tracers in Example 3 of the present invention.
具体实施方式Detailed ways
以下结合图1至13对本实施方式进行具体说明,实施例中所用原料均为市售。This embodiment will be described in detail below with reference to Figures 1 to 13. The raw materials used in the examples are all commercially available.
本发明的制备氟基聚氨基酸钴纳米粒子的方法,包括以下步骤:The method for preparing fluorine-based polyamino acid cobalt nanoparticles of the present invention includes the following steps:
步骤一、将氨基酸与三光气溶解于有机溶剂中反应,加入非溶剂沉淀纯化产物,真空干燥得到α-氨基酸-N-羧基酸酐;氨基酸与三光气的摩尔数用量比为1:0.4~1;所述有机溶剂为二甲基亚砜、四氢呋喃、N’N-二甲基甲酰胺中的至少一种;所述反应的条件为在30~60℃下搅拌5~12小时,真空干燥温度为30~60℃。氨基酸为甘氨酸、羟基甘氨酸、丙甘氨酸、烯丙基甘氨酸和炔丙基甘氨酸中的一种或多种。非溶剂为正己烷、石油醚、乙醚中的一种或者多种。Step 1: Dissolve the amino acid and triphosgene in an organic solvent for reaction, add a non-solvent to precipitate the purified product, and dry it under vacuum to obtain α-amino acid-N-carboxylic acid anhydride; the molar ratio of the amino acid to triphosgene is 1:0.4~1; The organic solvent is at least one of dimethyl sulfoxide, tetrahydrofuran, and N'N-dimethylformamide; the reaction conditions are stirring at 30 to 60°C for 5 to 12 hours, and the vacuum drying temperature is 30~60℃. The amino acid is one or more of glycine, hydroxyglycine, prolanglycine, allylglycine and propargylglycine. The non-solvent is one or more of n-hexane, petroleum ether, and diethyl ether.
步骤二、将α-氨基酸-N-羧基酸酐与氟基引发剂溶解于有机溶剂中反应,加入非溶剂沉淀纯化产物,真空干燥得到氟基聚氨基酸肽段;α-氨基酸-N-羧基酸酐与氟基引发剂的摩尔数用量比为1:0.1~0.02;所述有机溶剂选自二甲基亚砜、四氢呋喃、N’N-二甲基甲酰胺中的至少一种;所述反应的条件为在0~30℃下搅拌反应24~72小时,真空干燥温度为25~55℃。氟基引发剂为2,2,2-三氟乙胺、1H,1H-七氟丁胺、1H,1H-全氟庚基胺和1H,1H,2H,2H-全氟癸基胺中的一种或多种。非溶剂为正己烷、石油醚、乙醚中的一种或者多种。Step 2: Dissolve α-amino acid-N-carboxylic acid anhydride and fluorine-based initiator in an organic solvent to react, add a non-solvent to precipitate the purified product, and dry it under vacuum to obtain a fluorine-based polyamino acid peptide segment; α-amino acid-N-carboxylic acid anhydride and The molar ratio of the fluorine-based initiator is 1:0.1~0.02; the organic solvent is selected from at least one of dimethyl sulfoxide, tetrahydrofuran, and N'N-dimethylformamide; the conditions of the reaction The reaction is stirred at 0 to 30°C for 24 to 72 hours, and the vacuum drying temperature is 25 to 55°C. The fluorine-based initiator is 2,2,2-trifluoroethylamine, 1H,1H-heptafluorobutylamine, 1H,1H-perfluoroheptylamine and 1H,1H,2H,2H-perfluorodecylamine. one or more. The non-solvent is one or more of n-hexane, petroleum ether, and diethyl ether.
步骤三、将氟基聚氨基酸肽段溶于有机溶剂形成溶液A,将无机钴金属配合物溶于有机溶剂形成溶液B,然后将溶液B缓慢加入溶液A,在温度梯度下反应,加入非溶剂沉淀纳米粒子,真空干燥得到氟基聚氨基酸钴纳米粒子粉末。步骤三中,氟基聚氨基酸肽段的浓度为0.5~2mol/L;无机钴配合物的浓度为1~3mol/L;有机溶剂为邻二氯苯、甲苯、四氢呋喃、N’N-二甲基甲酰胺中的一种或多种;所述温度梯度为:在室温下搅拌反应12~48小时,然后在160℃下搅拌反应6~18小时,真空干燥温度为25~55℃。所述无机钴金属配合物为二羰基环戊二烯钴、三羰基亚硝酰基钴、八羰基二钴、十二羰基四钴中的一种或多种。非溶剂为正己烷、石油醚、乙醚中的一种或者多种。Step 3: Dissolve the fluorine-based polyamino acid peptide segment in an organic solvent to form solution A, dissolve the inorganic cobalt metal complex in an organic solvent to form solution B, then slowly add solution B to solution A, react under a temperature gradient, and add a non-solvent. The nanoparticles are precipitated and vacuum dried to obtain fluorine-based polyamino acid cobalt nanoparticle powder. In step three, the concentration of the fluorine-based polyamino acid peptide is 0.5-2 mol/L; the concentration of the inorganic cobalt complex is 1-3 mol/L; the organic solvent is o-dichlorobenzene, toluene, tetrahydrofuran, and N'N-dimethyl. One or more methyl formamides; the temperature gradient is: stirring and reacting at room temperature for 12 to 48 hours, then stirring and reacting at 160°C for 6 to 18 hours, and the vacuum drying temperature is 25 to 55°C. The inorganic cobalt metal complex is one or more of cobalt dicarbonylcyclopentadienyl, cobalt tricarbonylnitrosyl, dicobalt octacarbonyl, and tetracobalt dodecacarbonyl. The non-solvent is one or more of n-hexane, petroleum ether, and diethyl ether.
本发明还包括根据上述方法得到的氟基聚氨基酸钴纳米粒子,以及氟基聚氨基酸钴纳米粒子作为磁性粒子成像示踪剂的应用。The present invention also includes fluorine-based polyamino acid cobalt nanoparticles obtained according to the above method, and the application of fluorine-based polyamino acid cobalt nanoparticles as magnetic particle imaging tracers.
下面以实施例具体说明:The following is a detailed description with examples:
实施例1Example 1
将三光气(20mmol,5.93g)和炔丙基甘氨酸(40mmol,4.61g)加入圆底烧瓶中,然后加入四氢呋喃(100mL),在30℃下加热搅拌反应6小时。反应完成后,在真空下浓缩至剩余少量四氢呋喃,初产物用石油醚洗涤沉淀纯化产物得到α-氨基酸-N-羧基酸酐白色固体,置于50℃真空干燥后获得最终产物。向剧烈搅拌的5mL含有引发剂2,2,2-三氟乙胺(0.144mmol,14.24mg)的DMF溶液中加入5mL的α-氨基酸-N-羧基酸酐(7.2mmol,1000mg)的DMF溶液,在25℃下进行聚合48h后,将聚合溶液沉降到乙醚中纯化,置于25℃真空干燥后获得氟基聚氨基酸肽段。将含有0.01mol的氟基聚氨基酸溶解在5ml的邻二氯苯(DCB)中形成溶液A;将0.01mol的八羰基二钴(3.42g)溶解在4ml的DCB中,形成溶液B;然后将溶液B缓慢加入溶液,搅拌室温反应12h,然后加热到160℃搅拌6h反应停止,将产物在正己烷中沉淀纯化,得到固定黑色粉末,置于25℃真空干燥后获得氟基聚氨基酸钴纳米粒子固体黑色粉末。Triphosgene (20mmol, 5.93g) and propargylglycine (40mmol, 4.61g) were added to the round-bottomed flask, then tetrahydrofuran (100mL) was added, and the reaction was heated and stirred at 30°C for 6 hours. After the reaction is completed, concentrate under vacuum until a small amount of tetrahydrofuran remains. The initial product is washed with petroleum ether to precipitate and purify the product to obtain α-amino acid-N-carboxylic acid anhydride white solid. The final product is obtained after vacuum drying at 50°C. To the vigorously stirred 5 mL DMF solution containing the initiator 2,2,2-trifluoroethylamine (0.144 mmol, 14.24 mg), 5 mL of α-amino acid-N-carboxylic acid anhydride (7.2 mmol, 1000 mg) in DMF was added. After polymerization at 25°C for 48 hours, the polymerization solution was settled into diethyl ether for purification, and dried under vacuum at 25°C to obtain fluorine-based polyamino acid peptides. Dissolve 0.01 mol of fluorine-based polyamino acid in 5 ml of o-dichlorobenzene (DCB) to form solution A; dissolve 0.01 mol of dicobalt octacarbonyl (3.42 g) in 4 ml of DCB to form solution B; then Solution B was slowly added to the solution, stirred at room temperature for 12 hours, and then heated to 160°C and stirred for 6 hours to stop the reaction. The product was precipitated and purified in n-hexane to obtain a fixed black powder, which was dried under vacuum at 25°C to obtain fluorine-based polyamino acid cobalt nanoparticles. Solid black powder.
实施例2Example 2
将三光气(40mmol,11.86g)和炔丙基甘氨酸(40mmol,4.61g)加入圆底烧瓶中,然后加入四氢呋喃(150mL),在50℃下加热搅拌反应6小时。反应完成后,在真空下浓缩至剩余少量四氢呋喃,初产物用正己烷洗涤沉淀纯化产物得到α-氨基酸-N-羧基酸酐白色固体,置于50℃真空干燥后获得最终产物。向剧烈搅拌的5mL含有引发剂1H,1H-七氟丁胺(0.36mmol,71.65mg)的DMF溶液中加入5mL的α-氨基酸-N-羧基酸酐(7.2mmol,1000mg)的DMF溶液,在25℃下进行聚合72h后,将聚合溶液沉降到乙醚中纯化,置于25℃真空干燥后获得氟基聚氨基酸肽段。将含有0.005mol的氟基聚氨基酸溶解在5ml的邻二氯苯(DCB)中形成溶液A;将0.012mol的八羰基二钴(4.10g)溶解在4ml的DCB中,形成溶液B;然后将溶液B缓慢加入溶液,搅拌室温反应48h,然后加热到160℃搅拌18h反应停止,将产物在正己烷中沉淀纯化,得到固定黑色粉末,置于25℃真空干燥后获得氟基聚氨基酸钴纳米粒子固体黑色粉末。Triphosgene (40mmol, 11.86g) and propargylglycine (40mmol, 4.61g) were added to the round-bottomed flask, then tetrahydrofuran (150mL) was added, and the reaction was heated and stirred at 50°C for 6 hours. After the reaction is completed, concentrate under vacuum until a small amount of tetrahydrofuran remains. The initial product is washed with n-hexane to precipitate and purify the product to obtain α-amino acid-N-carboxylic acid anhydride white solid. The final product is obtained after vacuum drying at 50°C. To a vigorously stirring 5 mL DMF solution containing the initiator 1H, 1H-heptafluorobutylamine (0.36 mmol, 71.65 mg), 5 mL of α-amino acid-N-carboxylic anhydride (7.2 mmol, 1000 mg) in DMF was added. After polymerization for 72 hours at ℃, the polymerization solution was settled into diethyl ether for purification, and dried under vacuum at 25℃ to obtain fluorine-based polyamino acid peptides. Dissolve 0.005 mol of fluorine-based polyamino acid in 5 ml of o-dichlorobenzene (DCB) to form solution A; dissolve 0.012 mol of dicobalt octacarbonyl (4.10 g) in 4 ml of DCB to form solution B; then Solution B was slowly added to the solution, stirred at room temperature for 48 hours, and then heated to 160°C and stirred for 18 hours to stop the reaction. The product was precipitated and purified in n-hexane to obtain a fixed black powder, which was dried under vacuum at 25°C to obtain fluorine-based polyamino acid cobalt nanoparticles. Solid black powder.
实施例3Example 3
将三光气(16mmol,4.74g)和炔丙基甘氨酸(40mmol,4.61g)加入圆底烧瓶中,然后加入四氢呋喃(100mL),在55℃下加热搅拌反应6小时。反应完成后,在真空下浓缩至剩余少量四氢呋喃,初产物用正己烷洗涤沉淀纯化产物得到α-氨基酸-N-羧基酸酐白色固体,置于50℃真空干燥后获得最终产物。向剧烈搅拌的5mL含有引发剂1H,1H,2H,2H-全氟癸基胺(0.72mmol,333.5mg)的DMF溶液中加入5mL的α-氨基酸-N-羧基酸酐(7.2mmol,1000mg)的DMF溶液,在25℃下进行聚合48h后,将聚合溶液沉降到乙醚中纯化,置于25℃真空干燥后获得氟基聚氨基酸肽段。将含有0.01mol的氟基聚氨基酸溶解在5ml的邻二氯苯(DCB)中形成溶液(A);将0.01mol的八羰基二钴(3.42g)溶解在4ml的DCB和1ml四氢呋喃(THF)中,形成溶液(B);然后将(B)溶液缓慢加入溶液,搅拌室温反应24h,然后加热到160℃搅拌16h反应停止,将产物在正己烷中沉淀纯化,得到固定黑色粉末,置于25℃真空干燥后获得氟基聚氨基酸钴纳米粒子固体黑色粉末。Triphosgene (16mmol, 4.74g) and propargylglycine (40mmol, 4.61g) were added to the round-bottomed flask, then tetrahydrofuran (100mL) was added, and the reaction was heated and stirred at 55°C for 6 hours. After the reaction is completed, concentrate under vacuum until a small amount of tetrahydrofuran remains. The initial product is washed with n-hexane to precipitate and purify the product to obtain α-amino acid-N-carboxylic acid anhydride white solid. The final product is obtained after vacuum drying at 50°C. To a vigorously stirred 5 mL DMF solution containing the initiator 1H, 1H, 2H, 2H-perfluorodecylamine (0.72 mmol, 333.5 mg), 5 mL of α-amino acid-N-carboxylic acid anhydride (7.2 mmol, 1000 mg) was added. DMF solution was polymerized at 25°C for 48 hours. The polymerization solution was settled into diethyl ether for purification, and dried under vacuum at 25°C to obtain fluorine-based polyamino acid peptides. Dissolve 0.01 mol of fluorine-based polyamino acid in 5 ml of o-dichlorobenzene (DCB) to form solution (A); dissolve 0.01 mol of dicobalt octacarbonyl (3.42 g) in 4 ml of DCB and 1 ml of tetrahydrofuran (THF) , to form solution (B); then slowly add solution (B) to the solution, stir at room temperature for 24 hours, and then heat to 160°C and stir for 16 hours to stop the reaction. The product is precipitated and purified in n-hexane to obtain a fixed black powder, which is placed at 25 After vacuum drying at ℃, a solid black powder of fluorine-based polyamino acid cobalt nanoparticles was obtained.
效果验证Effect verification
分别对实施例1中原料炔丙基甘氨酸以及产物α-氨基酸-N-羧基酸酐进行FTIR谱图测试,结果如图1所示,炔丙基甘氨酸的特征峰1586cm-1和1652cm-1在进行闭环生成环内酸酐NCA后已消失,进而取代的是α-氨基酸-N-羧基酸酐特征峰1765cm-1称酸酐羰基峰、1852cm-1反对称酸酐羰基峰以及3353cm-1胺基(-NH-)峰。利用核磁共振氢谱对所合成的α-氨基酸-N-羧基酸酐进行表征分析,由图2以及表1所示,α-氨基酸-N-羧基酸酐的结构中一一对应相应的化学位移,可确定α-氨基酸-N-羧基酸酐的成功制备。对氟基聚氨基酸肽段进行FTIR谱图测试,结果如图3所示。对氟基聚氨基酸钴纳米粒子分别进行FTIR谱图测试(图4)、XRD测试(图5),表明氟基聚氨基酸钴纳米粒子的成功制备。下表1为核磁共振氢谱峰位置对照表。The raw material propargylglycine and the product α-amino acid-N-carboxylic anhydride in Example 1 were respectively subjected to FTIR spectrum testing. The results are as shown in Figure 1. The characteristic peaks of propargylglycine are 1586cm -1 and 1652cm -1 . After the ring is closed to form the intracyclic acid anhydride NCA, it disappears and is replaced by the characteristic peaks of α-amino acid-N-carboxylic acid anhydride at 1765cm -1 symmetrical anhydride carbonyl peak, 1852cm -1 antisymmetric acid anhydride carbonyl peak and 3353cm -1 amino group (-NH- )peak. The synthesized α-amino acid-N-carboxylic acid anhydride was characterized and analyzed using hydrogen nuclear magnetic resonance spectroscopy. As shown in Figure 2 and Table 1, the corresponding chemical shifts in the structure of α-amino acid-N-carboxylic acid anhydride can be found one by one. The successful preparation of α-amino acid-N-carboxylic anhydride was determined. The FTIR spectrum test was performed on the fluorine-based polyamino acid peptide segment, and the results are shown in Figure 3. The FTIR spectrum test (Figure 4) and XRD test (Figure 5) were performed on the fluorine-based polyamino acid cobalt nanoparticles, indicating the successful preparation of the fluorine-based polyamino acid cobalt nanoparticles. Table 1 below is a comparison table of peak positions of hydrogen nuclear magnetic resonance spectrum.
表1Table 1
实施例2中对所得到的氟基聚氨基酸钴纳米粒子分别进行FTIR谱图测试(图6)、XRD测试(图7),表明氟基聚氨基酸钴纳米粒子的成功制备。In Example 2, the obtained fluorine-based polyamino acid cobalt nanoparticles were subjected to FTIR spectrum test (Fig. 6) and XRD test (Fig. 7), indicating the successful preparation of the fluorine-based polyamino acid cobalt nanoparticles.
实施例3中对所得到的氟基聚氨基酸钴纳米粒子分别进行FTIR谱图测试(图8)、XRD测试(图9),表明氟基聚氨基酸钴纳米粒子的成功制备。利用透射电镜TEM对氟基聚氨基酸钴纳米粒子进行测试(图10),可见粒径为10nm左右。利用Cell Counting Kit-8(CCK-8)法检测所得氟基聚氨基酸钴纳米粒子对人视网膜上皮细胞(ARPE-19)存活率的影响,结果如图11所示,所得氟基聚氨基酸钴纳米粒子的浓度处于0~5000ppm时,细胞存活率大于80%。In Example 3, the obtained fluorine-based polyamino acid cobalt nanoparticles were subjected to FTIR spectrum test (Fig. 8) and XRD test (Fig. 9), indicating the successful preparation of the fluorine-based polyamino acid cobalt nanoparticles. The transmission electron microscope TEM was used to test the fluorine-based polyamino acid cobalt nanoparticles (Figure 10). It can be seen that the particle size is about 10nm. The Cell Counting Kit-8 (CCK-8) method was used to detect the effect of the obtained fluorine-based polyamino acid cobalt nanoparticles on the survival rate of human retinal epithelial cells (ARPE-19). The results are shown in Figure 11. The obtained fluorine-based polyamino acid cobalt nanoparticles When the concentration of particles is between 0 and 5000 ppm, the cell survival rate is greater than 80%.
为了进一步检测氟基聚氨基酸钴纳米粒子对小鼠主要脏器的潜在毒性,通过苏木精-伊红染色法(H&E)染色方法对玻腔注射氟基聚氨基酸钴纳米粒子后小鼠的主要脏器(眼、脑、心、肝、脾、肺和肾)进行组织学分析如图12所示,结果表明氟基聚氨基酸钴纳米粒子对于小鼠主要脏器没有明显损失,可以证明所得氟基聚氨基酸钴纳米粒子具有良好的生物相容性。In order to further detect the potential toxicity of fluorine-based polyamino acid cobalt nanoparticles to the main organs of mice, the main organs of mice after intravitreal injection of fluorine-based polyamino acid cobalt nanoparticles were analyzed by hematoxylin-eosin (H&E) staining. Histological analysis of organs (eyes, brain, heart, liver, spleen, lungs and kidneys) is shown in Figure 12. The results show that the fluorine-based polyamino acid cobalt nanoparticles have no obvious loss to the main organs of mice, which can prove that the obtained fluorine Polyamino acid-based cobalt nanoparticles have good biocompatibility.
动物成像采用Magnetic Insight生产的磁性粒子成像系统(0-5.5T/m)进行测试。将氟基聚氨基酸钴纳米粒子按照5mg/ml的PBS液进行配制。在C57BL/6J小鼠玻腔中注射3μL氟基聚氨基酸钴纳米粒子分散液,利用小动物CT成像仪器定位与MPI成像拟合,得到成像图13,可见良好的眼部MPI成像性能。Animal imaging was tested using a magnetic particle imaging system (0-5.5T/m) produced by Magnetic Insight. The fluorine-based polyamino acid cobalt nanoparticles were prepared in a PBS solution of 5 mg/ml. Injecting 3 μL of fluorine-based polyamino acid cobalt nanoparticle dispersion into the glass cavity of C57BL/6J mice, using small animal CT imaging instrument positioning and MPI imaging fitting, imaging Figure 13 was obtained, showing good eye MPI imaging performance.
上述内容仅为本发明较好的实施案例,并非用于限制本发明的实施方案,本领域普通技术人员根据本发明的主要构思和精神,可以十分方便地进行相应的变通或修改,如室内标准试件的数量、施工现场取芯的数量,可根据精度要求进行增减,故本发明的保护范围应以权利要求书所要求的保护范围为准。The above content is only a preferred implementation example of the present invention and is not intended to limit the implementation of the present invention. Those of ordinary skill in the art can easily make corresponding modifications or modifications according to the main concept and spirit of the present invention, such as indoor standards. The number of test pieces and the number of cores taken at the construction site can be increased or decreased according to the accuracy requirements. Therefore, the protection scope of the present invention should be subject to the protection scope required by the claims.
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