CN116297945A - A kind of oligonucleotide strong anion exchange liquid chromatography analysis method - Google Patents
A kind of oligonucleotide strong anion exchange liquid chromatography analysis methodDownload PDFInfo
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Abstract
Translated fromChinese
Description
Translated fromChinese技术领域technical field
本发明属于分析领域，具体涉及一种寡核苷酸强阴离子交换液相色谱分析方法。The invention belongs to the field of analysis, and in particular relates to an oligonucleotide strong anion exchange liquid chromatography analysis method.
背景技术Background technique
寡核苷酸(Oligonucleotide)，一般是指2～10核苷酸残基以磷酸二酯键连接而成的线性多核苷酸片段，但在使用这一术语时，对核苷酸残基的数目并无严格规定，在不少文献中，把含有30甚至更多核苷酸残基的多核苷酸分子也称作寡核苷酸。寡核苷酸可由仪器自动合成，它可作为DNA合成的引物(Primer)、基因探针(Probe)等，在现代分子生物学研究中具有广泛的用途。Oligonucleotide (Oligonucleotide) generally refers to a linear polynucleotide fragment of 2 to 10 nucleotide residues linked by phosphodiester bonds, but when using this term, the number of nucleotide residues There are no strict regulations, and in many literatures, polynucleotide molecules containing 30 or more nucleotide residues are also called oligonucleotides. Oligonucleotides can be automatically synthesized by instruments, and can be used as primers (Primer) for DNA synthesis, gene probes (Probe), etc., and have a wide range of uses in modern molecular biology research.
在过去几十年中，人们一直对RNA和DNA水平上调节蛋白质表达的新治疗方法十分感兴趣。寡核苷酸是调节蛋白质表达和基因编辑的一种有吸引力的方法，合成寡核苷酸正日益被开发并用于治疗各种疾病，这些治疗剂主要是核碱、核糖或脱氧核糖(分别为RNA或DNA)和磷酸盐的短线性聚合物，改善稳定性、递送、摄取等。这些寡核苷酸的大小可以从几个碱基到几百个碱基不等。由于序列、修饰和长度的多样性，在开发液相色谱方法时便也变得多元化。Over the past few decades, there has been intense interest in new therapeutic approaches to modulate protein expression at the RNA and DNA levels. Oligonucleotides are an attractive approach to modulate protein expression and gene editing, and synthetic oligonucleotides are increasingly being developed and used to treat various diseases. These therapeutic agents are mainly nucleobases, ribose, or deoxyribose (respectively Short linear polymers of RNA or DNA) and phosphate to improve stability, delivery, uptake, etc. These oligonucleotides can vary in size from a few bases to several hundred bases. Due to the diversity in sequence, modification, and length, there is diversity in the development of LC methods.
分析寡核苷酸的纯度直接影响着原料药和制剂是否能称得上为药品，因此，这项工作至关重要。但目前对寡核苷酸纯度分析方法尚不完善，相关文献报告寥寥无几。The purity of analytical oligonucleotides directly affects whether raw materials and preparations can be called drugs, so this work is very important. However, the analysis method of oligonucleotide purity is not perfect at present, and there are few related literature reports.
发明内容Contents of the invention
本发明针对现有寡核苷酸纯度分析方法研究匮乏，目的在于提供一种寡核苷酸强阴离子交换的纯度分析方法，本发明采用强阴离子交换高效液相色谱法来分析，具有组分峰分离效果好、分辨率高、分析精度高、重现性好，操作简易等优点，达到对寡核苷酸质量进行有效控制的目的。The present invention aims at the lack of research on the existing oligonucleotide purity analysis methods, and aims to provide a method for analyzing the purity of oligonucleotides with strong anion exchange. The present invention uses strong anion exchange high performance liquid chromatography for analysis, and has component peak It has the advantages of good separation effect, high resolution, high analysis precision, good reproducibility, easy operation, etc., and achieves the purpose of effectively controlling the quality of oligonucleotides.
为了实现上述目的，本发明采用以下技术方案：In order to achieve the above object, the present invention adopts the following technical solutions:
一种寡核苷酸强阴离子交换液相色谱分析方法，所述寡核苷酸强阴离子交换液相色谱分析方法包括以下步骤：An oligonucleotide strong anion exchange liquid chromatography analysis method, the oligonucleotide strong anion exchange liquid chromatography analysis method comprises the following steps:
1)配制样品溶液：称取样品置于容量瓶中，溶解后定容，得到样品溶液；1) Preparation of sample solution: Weigh the sample and place it in a volumetric flask, dissolve and then constant volume to obtain the sample solution;
2)配制流动相A与流动相B，经微孔膜过滤，超声脱气后，采用高效液相色谱仪对样品溶液进行检测，检测寡核苷酸纯度；2) preparing mobile phase A and mobile phase B, filtering through a microporous membrane, and ultrasonically degassing, using high performance liquid chromatography to detect the sample solution to detect the purity of the oligonucleotide;
3)采用面积归一化法进行纯度结果计算。3) Calculate the purity result by using the area normalization method.
作为本发明的一种优选方案，步骤1)中，所述样品溶液的浓度为0.8-1.0mg/mL，溶解样品所用的容积为纯化水。As a preferred solution of the present invention, in step 1), the concentration of the sample solution is 0.8-1.0 mg/mL, and the volume used for dissolving the sample is purified water.
作为本发明的一种优选方案，步骤2)中，高效液相色谱仪为Agilent1290超高效液相色谱仪，配紫外检测器和全波长检测。As a preferred solution of the present invention, in step 2), the high-performance liquid chromatograph is an Agilent 1290 ultra-high performance liquid chromatograph equipped with an ultraviolet detector and full-wavelength detection.
作为本发明的一种优选方案，步骤2)中，色谱柱为Thermo ScientificTMDionexTMDNAPacTMPA100，色谱柱规格为长度250mm，内径4.0mm，填料粒径为1.3μm。As a preferred solution of the present invention, in step 2), the chromatographic column is Thermo ScientificTM DionexTM DNAPacTM PA100, the chromatographic column specification is 250 mm in length, 4.0 mm in inner diameter, and 1.3 μm in filler particle size.
作为本发明的一种优选方案，步骤2)中，所述的流动相A为100mM Tris/Cl，10％ACN inH2O；流动相B为100mM Tris/Cl，2M NaCl与10％ACN in H2O。As a preferred version of the present invention, in step 2), the mobile phase A is 100mM Tris/Cl, 10% ACN inH2 O; the mobile phase B is 100mM Tris/Cl, 2M NaCl and 10% ACN in H2 O.
作为本发明的一种优选方案，洗脱梯度为：0min，98％流动相A：2％流动相B；30min，0％流动相A：100％流动相B；40min，0％流动相A：100％流动相B；43min，98％流动相A：2％流动相B，50min，98％流动相A：2％流动相B。As a preferred version of the present invention, the elution gradient is: 0min, 98% mobile phase A: 2% mobile phase B; 30min, 0% mobile phase A: 100% mobile phase B; 40min, 0% mobile phase A: 100% mobile phase B; 43min, 98% mobile phase A: 2% mobile phase B, 50min, 98% mobile phase A: 2% mobile phase B.
作为本发明的一种优选方案，步骤2)中，检测条件为：检测波长260nm；流速2mL/min；进样体积10μL；柱温50℃；进样盘温度4℃As a preferred solution of the present invention, in step 2), the detection conditions are: detection wavelength 260nm; flow rate 2mL/min;
作为本发明的一种优选方案，步骤2)中，过滤所用的微孔膜为0.22μm。As a preferred solution of the present invention, in step 2), the microporous membrane used for filtration is 0.22 μm.
作为本发明的一种优选方案，步骤2)中，超声脱气的时间为5min。As a preferred solution of the present invention, in step 2), the time for ultrasonic degassing is 5 minutes.
采用以上技术方案，本发明具有以下有益效果：By adopting the above technical scheme, the present invention has the following beneficial effects:
(1)本发明分析方法色谱条件范围宽，适用于各类序列和不同长度的寡核苷酸纯度检测。(1) The analysis method of the present invention has a wide range of chromatographic conditions, and is applicable to the purity detection of various sequences and oligonucleotides of different lengths.
(2)本发明分析方法组分峰分离效果好，分离度1.2，理论板数达到2000以上，可以将样品中所含的组分完全分离。(2) The analysis method of the present invention has a good separation effect of component peaks, with a resolution of 1.2 and a theoretical plate number of more than 2000, which can completely separate the components contained in the sample.
(3)本发明分析方法基线平稳，分析精密度高。(3) The analytical method of the present invention has a stable baseline and high analytical precision.
(4)本发明分析方法重现性好，误差小，分析结果稳定。(4) The analysis method of the present invention has good reproducibility, small error and stable analysis results.
(5)本发明分析方法梯度范围宽，可以此为基础，微调梯度，达到各类寡核苷酸最佳分离效果。(5) The analytical method of the present invention has a wide gradient range, which can be used as a basis to fine-tune the gradient to achieve the best separation effect of various oligonucleotides.
(6)本发明分析方法操作简易，分析全部自动化，检测由仪器完成，无论有无实验基础，只要经过操作培训，即可进行操作。(6) The analysis method of the present invention is easy to operate, the analysis is fully automated, and the detection is completed by the instrument. No matter whether there is an experimental basis or not, it can be operated as long as it has been trained in operation.
(7)本发明分析方法达到对寡核苷酸质量进行有效控制的目的。(7) The analytical method of the present invention achieves the purpose of effectively controlling the quality of oligonucleotides.
附图说明Description of drawings
图1是本发明方法分析样品检测所得结果。Fig. 1 is the result obtained by analyzing the samples detected by the method of the present invention.
图2是本发明实施例2第二针检测所得结果。Fig. 2 is the result of the second needle detection in Example 2 of the present invention.
图3是本发明实施例2第三针检测所得结果。Fig. 3 is the result of the third needle detection in Example 2 of the present invention.
图4是本发明实施例2第四针检测所得结果。Fig. 4 is the result of the fourth needle detection in Example 2 of the present invention.
图5是本发明实施例2第五针检测所得结果.Fig. 5 is the result obtained by the fifth needle detection in Example 2 of the present invention.
图6是本发明实施例2第六针检测所得结果。Fig. 6 is the result of the sixth needle detection in Example 2 of the present invention.
具体实施方式Detailed ways
为了使本发明实现的技术手段、创作特征、达成目的与功效易于理解，下面结合具体实施例，进一步阐述本发明，但下述实施例仅仅为本发明的优选实施例，并非全部。基于实施方式中的实施例，本领域技术人员在没有做出创造性劳动的前提下所获得其它实施例，都属于本发明的保护范围。下述实施例中的实验方法，如无特殊说明，均为常规方法，下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。In order to make the technical means, creative features, goals and effects achieved by the present invention easy to understand, the present invention will be further elaborated below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the examples in the implementation manners, other examples obtained by those skilled in the art without making creative efforts all belong to the protection scope of the present invention. The experimental methods in the following examples, unless otherwise specified, are conventional methods, and the materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained from commercial sources.
本发明中所用仪器包括Instruments used in the present invention include
1)Agilent1290超高效液相色谱仪，配紫外检测器和全波长检测。1) Agilent1290 ultra-high performance liquid chromatography equipped with UV detector and full-wavelength detection.
2)色谱柱Thermo ScientificTMDionexTMDNAPacTMPA100(4.0×250mm,13μm)。2) Chromatographic column Thermo Scientific™ Dionex™ DNAPac™ PA100 (4.0×250 mm, 13 μm).
3)超声波脱气装置。3) Ultrasonic degassing device.
本发明一种寡核苷酸强阴离子交换液相色谱分析方法，包括仪器选择、检测条件的设定、样品处理、检测。The invention relates to an oligonucleotide strong anion exchange liquid chromatography analysis method, which includes instrument selection, detection condition setting, sample processing and detection.
本发明的分析方法包括：Analytical method of the present invention comprises:
1)配制样品溶液：称取样品置于容量瓶中，溶解后定容，得到样品溶液；1) Preparation of sample solution: Weigh the sample and place it in a volumetric flask, dissolve and then constant volume to obtain the sample solution;
2)配制流动相A与流动相B，经微孔膜过滤，超声脱气后，采用高效液相色谱仪对样品溶液进行检测，检测寡核苷酸纯度；2) preparing mobile phase A and mobile phase B, filtering through a microporous membrane, and ultrasonically degassing, using high performance liquid chromatography to detect the sample solution to detect the purity of the oligonucleotide;
3)采用面积归一化法进行纯度结果计算。3) Calculate the purity result by using the area normalization method.
使用本发明所述的检测方法，检测寡核苷酸纯度。Using the detection method described in the present invention, the purity of the oligonucleotide is detected.
所述的检测条件的设定，流动相A与流动相B的体积比见表1：The setting of described detection condition, the volume ratio of mobile phase A and mobile phase B is shown in Table 1:
表1.洗脱梯度Table 1. Elution gradient
所述的流动相A为100mM Tris/Cl(pH8.0),10％ACN in H2O；流动相B为100mMTris/Cl,2M NaCl(pH8.0),10％ACN in H2O。The mobile phase A is 100mM Tris/Cl (pH 8.0), 10% ACN in H2 O; the mobile phase B is 100 mM Tris/Cl, 2M NaCl (pH 8.0), 10% ACN in H2 O.
所述的检测条件设定，检测波长260nm；流速2mL/min；进样体积10μL；柱温50℃；进样盘温度4℃。The detection conditions are set as follows: the detection wavelength is 260 nm; the flow rate is 2 mL/min; the injection volume is 10 μL; the column temperature is 50° C.; the sample tray temperature is 4° C.
实施例1Example 1
本实施例提供了寡核苷酸强阴离子交换液相色谱分析方法，包括This embodiment provides an oligonucleotide strong anion exchange liquid chromatography analysis method, including
样品处理：Sample handling:
1)准确称取10mg样品置于10ml容量瓶中，加入少量纯化水溶解后定容；1) Accurately weigh 10mg of the sample and place it in a 10ml volumetric flask, add a small amount of purified water to dissolve and then constant volume;
2)将配制好的流动相A与流动相B经0.22μm膜过滤，超声脱气5分钟后，置于高效液相色谱仪上，脱气使用。2) The prepared mobile phase A and mobile phase B were filtered through a 0.22 μm membrane, ultrasonically degassed for 5 minutes, placed on a high-performance liquid chromatograph, and degassed for use.
3)待出峰后，使用面积归一化法进行纯度结果计算。3) After the peak is released, use the area normalization method to calculate the purity result.
结果见图1与表2，本发明分析方法主峰保留时间24.866min，处于图谱中间位置；主峰峰高79.42mAU；组分峰分离效果好，分离度1.2，理论板数达到2000以上，可以将样品中主成分与杂质分离；样品纯度92.66％，分析精密度高；重现性好，误差小，分析结果稳定；梯度范围宽，可以此为基础，微调梯度，达到各类寡核苷酸最佳分离效果。The results are shown in Fig. 1 and Table 2, the retention time of the main peak of the analytical method of the present invention is 24.866min, which is in the middle of the spectrum; the height of the main peak is 79.42mAU; the component peak separation effect is good, the separation degree is 1.2, and the number of theoretical plates reaches more than 2000, and the sample can be The main components and impurities are separated; the sample purity is 92.66%, and the analysis precision is high; the reproducibility is good, the error is small, and the analysis results are stable; the gradient range is wide, and this can be used as a basis to fine-tune the gradient to achieve the best results for various oligonucleotides. seperate effect.
表2.图1数据结果Table 2. Figure 1 Data Results
实施例2Example 2
按照实施例1的方法连续运行5针样品，进行稳定性实验，结果见图2-图6所示(见表3-表7所示)。According to the method of Example 1, 5 samples were continuously run, and the stability test was carried out. The results are shown in Figures 2-6 (see Tables 3-7).
稳定性实验结果：Stability test results:
参见图1-图6，实施例1与实施例2共连续运行6针样品，基线平稳，主峰峰面积RSD为0.50％，主峰保留时间RSD为0.01％，方法重现性好，误差小，分析结果稳定。Referring to Fig. 1-Fig. 6, Example 1 and Example 2 run a total of 6 samples continuously, the baseline is stable, the RSD of the peak area of the main peak is 0.50%, and the RSD of the retention time of the main peak is 0.01%. The result is stable.
表3.图2数据结果Table 3. Figure 2 Data Results
表4.图3数据结果Table 4. Figure 3 Data Results
表5.图4数据结果Table 5. Figure 4 Data Results
表6.图5数据结果Table 6. Figure 5 data results
表7.图6数据结果Table 7. Figure 6 Data Results
由图1-图6以及表2-表7可见，本发明的方法基线平稳，主峰峰面积RSD为0.50％，主峰保留时间RSD为0.01％，方法重现性好，误差小，分析结果稳定。As can be seen from Fig. 1-Fig. 6 and Table 2-Table 7, the method of the present invention has a stable baseline, the main peak area RSD is 0.50%, and the main peak retention time RSD is 0.01%. The method has good reproducibility, small error, and stable analysis results.
以上所述，仅为本发明的较佳实施例，并非对本发明任何形式上和实质上的限制，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还将可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。凡熟悉本专业的技术人员，在不脱离本发明的精神和范围的情况下，当可利用以上所揭示的技术内容而做出的些许更动、修饰与演变的等同变化，均为本发明的等效实施例；同时，凡依据本发明的实质技术对上述实施例所作的任何等同变化的更动、修饰与演变，均仍属于本发明的技术方案的范围内。The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any form and in essence. Several improvements and supplements can be made, and these improvements and supplements should also be regarded as the protection scope of the present invention. Those who are familiar with this profession, without departing from the spirit and scope of the present invention, when they can use the technical content disclosed above to make some changes, modifications and equivalent changes of evolution, are all included in the present invention. Equivalent embodiments; at the same time, all changes, modifications and evolutions of any equivalent changes made to the above-mentioned embodiments according to the substantive technology of the present invention still belong to the scope of the technical solution of the present invention.
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