寡核苷酸药物分析方法研究进展

郭乘凤, 刘莉莎, 杨洪淼, 刘博, 张佟, 刘万卉, 范慧红

中国药学杂志 ›› 2022, Vol. 57 ›› Issue (11) : 869-873.

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中国药学杂志
PDF(944 KB)
中国药学杂志 ›› 2022, Vol. 57 ›› Issue (11) : 869-873. DOI: 10.11669/cpj.2022.11.001
综述

寡核苷酸药物分析方法研究进展

  • 郭乘凤1,2,3, 刘莉莎2,3, 杨洪淼2,3, 刘博2,3, 张佟2,3, 刘万卉1, 范慧红2,3*
作者信息 +

Research Progress in Analysis Methods of Oligonucleotide Drugs

  • GUO Cheng-feng1,2,3, LIU Li-sha2,3, YANG Hong-miao2,3, LIU Bo2,3, ZHANG Tong2,3, LIU Wan-hui1, FAN Hui-hong2,3*
Author information +
文章历史 +

摘要

寡核苷酸是一类由15～50个碱基的短链核苷酸组成的化合物,因其在RNA水平上调控疾病基因的转录及翻译过程的独特作用机制,使该类药物被认为是新一代治疗药物开发的热点。寡核苷酸药物结构较为复杂,合成和纯化难度较大,也为这类药物的分析方法与质量研究工作增加了难度。本研究结合课题组前期研究经验介绍了基于现代仪器分析技术的寡核苷酸药物的杂质分析研究进展,为更为精准的控制寡核苷酸药物的产品质量提供参考。

Abstract

Oligonucleotide is a kind of compound composed of short-chain nucleotides of about 15-50 bases. Because of its unique mechanism of regulating the transcription and translation of disease genes at the RNA level, this class of drugs is considered as an hot spot in the development of a new generation of therapeutic drugs. Oligonucleotide drugs are complex in structure and difficult to synthesize and purify, which also adds difficulty to the analysis methods and quality research of such drugs. Based on the previous research experience of our research group, this article introduced the research progress in the impurity analysis of oligonucleotide drugs based on modern instrumental analysis technology to provide a reference for more precise control of the product quality of oligonucleotide drugs.

关键词

寡核苷酸药物 / 仪器分析 / 液相色谱 / 质谱 / 毛细管电泳 / 二维液相

Key words

oligonucleotide drug / instrumental analysis / liquid chromatography / mass spectrometry / capillary electrophoresis / two-dimensional liquid phase

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导出引用
郭乘凤, 刘莉莎, 杨洪淼, 刘博, 张佟, 刘万卉, 范慧红. 寡核苷酸药物分析方法研究进展[J]. 中国药学杂志, 2022, 57(11): 869-873 https://doi.org/10.11669/cpj.2022.11.001
GUO Cheng-feng, LIU Li-sha, YANG Hong-miao, LIU Bo, ZHANG Tong, LIU Wan-hui, FAN Hui-hong. Research Progress in Analysis Methods of Oligonucleotide Drugs[J]. Chinese Pharmaceutical Journal, 2022, 57(11): 869-873 https://doi.org/10.11669/cpj.2022.11.001
中图分类号： R917   

参考文献

[1] DENG P, ZHONG D F, CHEN X Y. Quantitative analysis and metabolite identification of therapeutic oligonucleotides in biological samples using LC/MS[J].J Chin Mass Spectrtiom Soc(质谱学报), 2011, 32(1):13-23.
[2] WANG X L, XIAN J N, CHEN G,et al. Therapeutic oligonucleotides: a review[J].Chin J Biotechnol(生物工程学报),2018,34(5):664-675.
[3] STEIN C A, CASTANOTTO D. FDA-approved oligonucleotide therapies in 2017[J]. Mol Ther,2017,25(5): 1069-1075.
[4] JULIANO R L. The delivery of therapeutic oligonucleotides[J]. Nucl Acids Res,2016,44(14): 6518-6548.
[5] ROBERTS T C, LANGER R, WOOD M J A. Advances in oligonucleotide drug delivery[J]. Nat Rev Drug Discov, 2020, 19(10): 673-694.
[6] MATSUI M, COREY D R. Non-coding RNAs as drug targets[J]. Nat Rev Drug Discov,2017,16(3): 167-179.
[7] YANG H M,FAN H H.Progress of ion-pairing reverse liquid chromatography for analysis of oligonucleotides[J].Chin J Biochem Pharm(中国生化药物杂志),2015,35(7):161-164.
[8] MUSAIMI O A, SHAER D A, ALBERICIO F,et al. 2020 FDA TIDES(peptides and oligonucleotides) harvest[J]. Pharmaceuticals(Basel), 2021, 14(2):145.doi: 10.3390/ph14020145.
[9] SHAER D A, MUSAIMI O A, ALBERICIO F,et al. 2021 FDA TIDES(peptides and oligonucleotides) Harvest[J].Pharmaceuticals(Basel), 2022,(2):222.doi:10.3390/ph 15020222.
[10] MAO K Y,CHEN D M,FAN Y L,et al.Development status and trend analysis of oligonucleotide therapies[J].China Biotechnol(中国生物工程杂志),2018,38(4):96-106.
[11] SUN Y, NITTA S I, SAITO K,et al. Development of a bioanalytical method for an antisense therapeutic using high-resolution mass spectrometry[J].Bioanalysis,2020, 12(24):1739-1756.
[12] APFFEL A, CHAKEL J A, FISCHER S,et al. Analysis of oligonucleotides by HPLC-electrospray ionization mass spectrometry[J].Anal Chem, 1997, 69(7):1320-1325.
[13] KILANOWSKA A, NUCKOWSKI Ł, STUDZIŃSKA S. Studying in vitro metabolism of the first and second generation of antisense oligonucleotides with the use of ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry[J].Anal Bioanal Chem,2020, 412(27):7453-7467.
[14] FRANZONI S, MORBIOLI L, TURTORO A,et al. Development and validation of bioanalytical methods for LNA-i-miR-221 quantification in human plasma and urine by LC-MS/MS[J].J Pharm Biomed Anal,2020,188: 113451.doi:10.1016/j.jpba.2020.113451.
[15] LI P, GONG Y, KIM J,et al. Hybridization liquid chromatography-tandem mass spectrometry: an alternative bioanalytical method for antisense oligonucleotide quantitation in plasma and tissue samples[J].Anal Chem, 2020, 92(15):10548-10559.
[16] GOYON A, ZHANG K. Characterization of antisense oligonucleotide impurities by Ion-pairing reversed-phase and anion exchange chromatography coupled to hydrophilic interaction liquid chromatography/mass spectrometry using a versatile two-dimensional liquid chromatography setup[J]. Anal Chem, 2020, 92(8): 5944-5951.
[17] STUDZICŃSKA S, CYWONIUK P, SOBCZAK K. The role offluoroalcohols as counter anions for ion-pairing reversed-phase liquid chromatography/high-resolution electrospray ionization mass spectrometry analysis of oligonucleotides[J]. Rapid Commun Mass Spectrom, 2019, 33(7):697-709.
[18] WU Y, ZHENG Y Y, LIN Q, et al. Detection and quantification of RNA phosphorothioate modifications using mass spectrometry[J]. Curr Protoc Nucleic Acid Chem, 2020, 82(1): e113. Doi:10.1002/cpnc.113.
[19] GOTO R, MIYAKAWA S, INOMATA E, et al. De novo sequencing of highly modified therapeutic oligonucleotides by hydrophobic tag sequencing coupled with LC-MS[J]. J Mass Spectrom,2017, 52(2):78-93.
[20] COOK K, THAYER J. Advantages of ion-exchange chromatography for oligonucleotide analysis[J]. Bioanalysis, 2011, 3(10): 1109-1120.
[21] SUN J, JOSHI D, BETANCOURT F,et al. Anion exchange chromatography of oligonucleotides under denaturing conditions[J]. Nucleosides Nucleotides Nucleic Acids,2020,39(6): 818-828.
[22] ZHANG H Y, LU D D, WU L X,et al. Analysis of the related substances in phosphorothioate antisense oligonucleotide FT19[J]. Chin J Chromatogr(色谱),2008, 26(5): 540-543.
[23] ALPERT A J. Hydrophilic-interaction chromatography for the separation of petides, nucleic acids and other polar compounds[J]. J Chromatogr, 1990, 499: 177-196.
[24] HUANG M, XU X, QIU H, et al.Analytical characterization of DNA and RNA oligonucleotides by hydrophilic interaction liquid chromatography-tandem mass spectrometry[J].J Chromatogr A, 2021, 1648: 462184. Doi:10.1016/j.chroma.2021.462184.
[25] LOBUE P A, JORA M, ADDEPALLI B,et al. Oligonucleotide analysis by hydrophilic interaction liquid chromatography-mass spectrometry in the absence of ion-pair reagents[J].J Chromatogr A, 2019, 1595: 39-48. Doi:10.1016/j.chroma.2019.02.016.
[26] DEMELENNE A, GOU M J, NYS G, et al. Evaluation of hydrophilic interaction liquid chromatography, capillary zone electrophoresis and drift tube ion-mobility quadrupole time of flight mass spectrometry for the characterization of phosphodiester and phosphorothioate oligonucleotides[J]. J Chromatogr A,2020,1614: 460716.Doi:10.1016/j.chroma.2019.460716.
[27] BARAKAT F, GAUDIN K, VIALET B,et al. Analysis of lipid-oligonucleotide conjugates by cyclodextrin-modified capillary zone electrophoresis[J]. Talanta, 2020, 219: 121204.Doi:10.1016/j.talanta.2020.121204.
[28] MADSEN M, ROUSSIS S, SCHNIEPP E,et al. Assay determination by mass spectrometry for oligonucleotide therapeutics[J]. Rapid Commun Mass Spectrom, 2019, 33(22): 1774-1780.
[29] HAGELSKAMP F, BORLAND K, RAMOS J,et al. Broadly applicable oligonucleotide mass spectrometry for the analysis of RNA writers and erasers in vitro[J]. Nucleic Acids Res, 2020, 48(7): e41.Doi:10.1093/nar/gkaa091.
[30] BUGOVSKY S, BALIKA W, KORANDA M,et al. Quality control of oligonucleotide synthesis by means of matrix-assisted laser desorption/ionization linear time-of-flight mass spectrometry on a nanocoated disposable target[J]. Rapid Commun Mass Spectrom, 2016, 30(5):665-668.
[31] FRANZONI S, VEZZELLI A, TURTORO A,et al. Development and validation of a bioanalytical method for quantification of LNA-i-miR-221, a 13-mer oligonucleotide,in rat plasma using LC-MS/MS[J].J Pharm Biomed Anal, 2018, 150: 300-307.Doi:10.1016/j.jpba.2017.12.027.
[32] LI J, LIU J, ENDERS J,et al. Discovery of a novel deaminated metabolite of a single-stranded oligonucleotide in vivo by mass spectrometry[J].Bioanalysis, 2019, 11(21): 1955-1965.
[33] WENG G, SUN B, LIU Z,et al. Analysis of oligonucleotides by ion-pair reversed-phase liquid chromatography coupled with positive mode electrospray ionization mass spectrometry[J]. Anal Bioanal Chem, 2019, 411(18): 4167-4173.
[34] WENG G F. The separation and analysis of oligonucleotides by mass spectrometry[D]. Hangzhou:Zhejiang University, 2019.
[35] ZIMMERMANN A, GRECO R, WALKER I,et al. Synthetic oligonucleotide separations by mixed-mode reversed-phase/weak anion-exchange liquid chromatography[J]. J Chromatogr A, 2014, 1354: 43-55.Doi:10.1016/j.chroma.2014.05.048.
[36] BARTLETT M G, OMURO S. Evaluation of alkylamines and stationary phases to improve LC-MS of oligonucleotides[J]. Biomed Chromatogr,2021,35(5):e5045.Doi:10.1002/bmc.5045.
[37] ROUSSIS S G, CEDILLO I, RENTEL C. Two-dimensional liquid chromatography-mass spectrometry for the characterization of modified oligonucleotide impurities[J]. Anal Biochem, 2018, 556: 45-52. Doi:10.1016/j.ab.2018.06.019.
[38] HUSSER C, KOLLER E, BRINK A,et al. Studying the biotransformation of phosphorothioate-containing oligonucleotide drugs by LC-MS[J]. Methods Mol Biol, 2019,2036:307-315. Doi:10.1007/978-1-4939-9670-4_18.
[39] POREBSKI P Á, LYNEN F. Combining liquid chromatography with multiplexed capillary gel electrophoresis for offline comprehensive analysis of complex oligonucleotide samples[J]. J Chromatogr A, 2014, 1336: 87-93.
[40] LI F, LÄMMERHOFER M. Impurity profiling of siRNA by two-dimensional liquid chromatography-mass spectrometry with quinine carbamate anion-exchanger and ion-pair reversed-phase chromatography[J]. J Chromatogr A,2021, 1643: 462065.doi:10.1016/j.chroma.2021.462065.

基金

北京市自然科学基金项目资助(7194337)
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