Efficient Preparation of Polypeptides through Accelerated Polymerization of <italic style="font-style: italic">N</italic>-Carboxyanhydrides in Continuous Flow

Yu-Ke Qian; Shao-Bo Feng; Zi-Yuan Song

doi:10.1007/s10118-025-3441-4

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Efficient Preparation of Polypeptides through Accelerated Polymerization of N-Carboxyanhydrides in Continuous Flow

RESEARCH ARTICLE | Updated：2025-10-30

- Efficient Preparation of Polypeptides through Accelerated Polymerization of N-Carboxyanhydrides in Continuous Flow
- Efficient Preparation of Polypeptides through Accelerated Polymerization of N-Carboxyanhydrides in Continuous Flow
- 高分子科学（英文） 2025年43卷第11期页码：2000-2008
- Affiliations：
  
  Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China
- Author bio：
  
  zysong@suda.edu.cn
- Funds：
  
  This work was financially supported by the National Natural Science Foundation of China (No. 22101194), Natural Science Foundation of Jiangsu Province (No. BK20210733), Suzhou Municipal Science and Technology Bureau (No. ZXL2021447), Collaborative Innovation Center of Suzhou Nano Science & Technology, the 111 Project, and Joint International Research Laboratory of Carbon-Based Functional Materials and Devices.;Electronic supplementary information (ESI) is available free of charge in the online version of this article at http://doi.org/10.1007/s10118-025-3441-4.
- DOI：10.1007/s10118-025-3441-4
  中图分类号：
- 收稿：2025-06-09，
  
  录用：2025-08-18，
  
  网络首发：2025-10-16，
  
  纸质出版：2025-11-05
- Accepted：
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Qian, Y. K.; Feng, S. B.; Song, Z. Y. Efficient preparation of polypeptides through accelerated polymerization of N-carboxyanhydrides in continuous flow. Chinese J. Polym. Sci. 2025, 43, 2000–2008

Yu-Ke Qian, Shao-Bo Feng, Zi-Yuan Song. Efficient Preparation of Polypeptides through Accelerated Polymerization of N-Carboxyanhydrides in Continuous Flow[J]. Chinese Journal of Polymer Science, 2025, 43(11): 2000-2008. DOI: 10.1007/s10118-025-3441-4.
Qian, Y. K.; Feng, S. B.; Song, Z. Y. Efficient preparation of polypeptides through accelerated polymerization of N-carboxyanhydrides in continuous flow. Chinese J. Polym. Sci. 2025, 43, 2000–2008 DOI： 10.1007/s10118-025-3441-4.

Yu-Ke Qian, Shao-Bo Feng, Zi-Yuan Song. Efficient Preparation of Polypeptides through Accelerated Polymerization of N-Carboxyanhydrides in Continuous Flow[J]. Chinese Journal of Polymer Science, 2025, 43(11): 2000-2008. DOI: 10.1007/s10118-025-3441-4. DOI：

摘要

Accelerated polymerization of amino acid N-carboxyanhydrides was achieved in flow reactors through the use of cosolvent and a crown ether catalyst

enabling the preparation of various polypeptide materials with high molecular weights (up to 30 kDa) and narrow dispersity in a continuous and scalable manner.

Abstract

The preparation of polypeptide materials in continuous flow reactors shows great potential with improved reproducibility and scalability. However

conventional polypeptide synthesis from the polymerization of

-carboxyanhydride (NCA) is conducted at relatively slow rates

requiring long tubing or ending up with low-molecular-weight polymers. Inspired by recent advances in accelerated NCA polymerization

we report the crown-ether-catalyzed

rapid synthesis of polypeptide materials in cosolvents in flow reactors. The incorporation of low-polarity dichloromethane and the use of catalysts enabled fast conversion of monomers in 30 min

yielding well-defined polypeptides (up to 30 kDa) through a 20-cm tubing reactor. Additionally

random or block copolypeptides were efficiently prepared by incorporating a second NCA monomer. We believe that this work highlights the accelerated polymerization design in flow polymerization processes

offering the continuous production of polypeptide materials.

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references

Deming, T. J. Synthesis of side-chain modified polypeptides. Chem. Rev. 2016 , 116 , 786−808..

Song, Z.; Han, Z.; Lv, S.; Chen, C.; Chen, L.; Yin, L.; Cheng, J. Synthetic polypeptides: from polymer design to supramolecular assembly and biomedical application. Chem. Soc. Rev. 2017 , 46 , 6570−6599..

Cabral, H.; Miyata, K.; Osada, K.; Kataoka, K. Block copolymer micelles in nanomedicine applications. Chem. Rev. 2018 , 118 , 6844−6892..

Song, Z.; Fu, H.; Wang, R.; Pacheco, L. A.; Wang, X.; Lin, Y.; Cheng, J. Secondary structures in synthetic polypeptides from N -carboxyanhydrides: design, modulation, association, and material applications. Chem. Soc. Rev. 2018 , 47 , 7401−7425..

Rasines Mazo, A.; Allison-Logan, S.; Karimi, F.; Chan, N. J. A.; Qiu, W.; Duan, W.; O’Brien-Simpson, N. M.; Qiao, G. G. Ring opening polymerization of α -amino acids: advances in synthesis, architecture and applications of polypeptides and their hybrids. Chem. Soc. Rev. 2020 , 49 , 4737−4834..

Deng, C.; Zhang, Q.; Guo, J.; Zhao, X.; Zhong, Z. Robust and smart polypeptide-based nanomedicines for targeted tumor therapy. Adv. Drug Deliv. Rev. 2020 , 160 , 199−211..

Zhang, Y.; He, P.; Zhang, P.; Yi, X.; Xiao, C.; Chen, X. Polypeptides-drug conjugates for anticancer therapy. Adv. Healthc. Mater. 2021 , 10 , 2001974..

[Liu, Y.; Yin, L. α-Amino acid N -carboxyanhydride (NCA)-derived synthet ic polypeptides for nucleic acids delivery. Adv. Drug Deliv. Rev . 2021 , 171 , 139-163..

Song, Y.; Ding, Y.; Dong, C. M. Stimuli-responsive polypeptide nanoassemblies: Recent progress and applications in cancer nanomedicine. WIREs Nanomed. Nanobiotechnol. 2022 , 14 , e1742..

Wu, Y.; Chen, K.; Wang, J.; Chen, M.; Dai, W.; Liu, R. Recent advances and future developments in the preparation of polypeptides via N -carboxyanhydride (NCA) ring-opening polymerization. J. Am. Chem. Soc. 2024 , 146 , 24189−24208..

Zhao, W.; Lv, Y.; Li, J.; Feng, Z.; Ni, Y.; Hadjichristidis, N. Fast and selective organocatalytic ring-opening polymerization by fluorinated alcohol without a cocatalyst. Nat. Commun. 2019 , 10 , 3590..

Jacobs, J.; Pavlović, D.; Prydderch, H.; Moradi, M. A.; Ibarboure, E.; Heuts, J. P. A.; Lecommandoux, S.; Heise, A. Polypeptide nanoparticles obtained from emulsion polymerization of amino acid N -carboxyanhydrides. J. Am. Chem. Soc. 2019 , 141 , 12522−12526..

Lv, W.; Wang, Y.; Li, M.; Wang, X.; Tao, Y. Precision synthesis of polypeptides via living anionic ring-opening polymerization of N -carboxyanhydrides by tri-thiourea catalysts. J. Am. Chem. Soc. 2022 , 144 , 23622−23632..

Xu, S. Y.; Bai, T. W.; Zheng, B. T.; Li, Z. H.; Ling, J. Histidine N -thiocarboxyanhydride: direct synthesis and polymerization without protection towards well-defined polyhistidine. Chinese J. Polym. Sci . 2025 , 43 , 1311−1319..

Baumgartner, R.; Fu, H.; Song, Z.; Lin, Y.; Cheng, J. Cooperative polymerization of α -helices induced by macromolecular architecture. Nat. Chem. 2017 , 9 , 614−622..

Wu, Y.; Zhang, D.; Ma, P.; Zhou, R.; Hua, L.; Liu, R. Lithium hexamethyldisilazide initiated superfast ring opening polymerization of alpha-amino acid N -carboxyanhydrides. Nat. Commun. 2018 , 9 , 5297..

Hu, Y.; Tian, Z. Y.; Xiong, W.; Wang, D.; Zhao, R.; Xie, Y.; Song, Y. Q.; Zhu, J.; Lu, H. Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N -carboxyanhydride. Natl. Sci. Rev. 2022 , 9 , nwac033..

Song, Z.; Fu, H.; Wang, J.; Hui, J.; Xue, T.; Pacheco, L. A.; Yan, H.; Baumgartner, R.; Wang, Z.; Xia, Y.; Wang, X.; Yin, L.; Chen, C.; Rodríguez-López, J.; Ferguson, A. L.; Lin, Y.; Cheng, J. Synthesis of polypeptides via bioinspired polymerization of in situ purified N -carboxyanhydrides. Proc. Natl. Acad. Sci. U. S. A. 2019 , 116 , 10658−10663..

Grazon, C.; Salas-Ambrosio, P.; Ibarboure, E.; Buol, A.; Garanger, E.; Grinstaff, M. W.; Lecommandoux, S.; Bonduelle, C. Aqueous ring-opening polymerization-induced self-assembly (ROPISA) of N -carboxyanhydrides. Angew. Chem. Int. Ed. 2020 , 59 , 622−626..

Liu, B.; Fang, R.; Li, W.; Wu, X.; Liu, T.; Lin, M.; Sun, J.; Chen, X. Fast catalyst-free synthesis of stereoselective polypeptides via hierarchical chiral assembly. J. Am. Chem. Soc. 2024 , 146 , 16558−16566..

Tinajero-Díaz, E.; Judge, N.; Li, B.; Leigh, T.; Murphy, R. D.; Topham, P. D.; Derry, M. J.; Heise, A. Poly( L -proline)-stabilized polypeptide nanostructures via ring-opening polymerization-induced self-assembly (ROPISA). ACS Macro Lett. 2024 , 13 , 1031−1036..

Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Hitchhiker’s guide to flow chemistry. Chem. Rev. 2017 , 117 , 11796−11893..

Tonhauser, C.; Natalello, A.; Löwe, H.; Frey, H. Microflow technology in polymer synthesis. Macromolecules 2012 , 45 , 9551−9570..

Junkers, T. Precise macromolecular engineering via continuous-flow synthesis techniques. J. Flow Chem. 2017 , 7 , 106−110..

Hu, X.; Zhu, N.; Fang, Z.; Guo, K. Continuous flow ring-opening polymerizations. React. Chem. Eng. 2017 , 2 , 20−26..

Reis, M. H.; Leibfarth, F. A.; Pitet, L. M. Polymerizations in continuous flow: Recent advances in the synthesis of diverse polymeric materials. ACS Macro Lett. 2020 , 9 , 123−133..

Zaquen, N.; Rubens, M.; Corrigan, N.; Xu, J.; Zetterlund, P. B.; Boyer, C.; Junkers, T. Polymer synthesis in continuous flow reactors. Prog. Polym. Sci. 2020 , 107 , 101256..

Liu, Y.; Ou, S.; Wu, J.; Zhao, R.; Hou, R.; Li, X.; Sun, Y.; Li, Y.; Hu, X.; Zhu, N.; Guo, K. Continuous flow ring-opening polymerization and ring-opening metathesis polymerization. Eur. Polym. J. 2024 , 216 , 113288..

Wang, B. B.; Zhang, Z.; Wang, J. T.; Pan, L.; Li, Y. S.; Song, D.-P. High-performance flow chemistry platform for scalable continuous synthesis of branched block copolymers with precise chain structures. Chinese J. Polym. Sci. 2025 , 43 , 457−467..

Otake, Y.; Nakamura, H.; Fuse, S. Rapid and mild synthesis of amino acid N -carboxy anhydrides: basic-to-acidic flash switching in a microflow reactor. Angew. Chem. Int. Ed. 2018 , 57 , 11389−11393..

Honda, T.; Miyazaki, M.; Nakamura, H.; Maeda, H. Controllable polymerization of N -carboxy anhydrides in a microreaction system. Lab Chip 2005 , 5 , 812−818..

Miyazaki, M.; Honda, T.; Nakamura, H.; Maeda, H. Development of a microreactor for amino acid polymerization. Chem. Eng. Technol. 2007 , 30 , 300−304..

Vrijsen, J. H.; Rasines Mazo, A.; Junkers, T.; Qiao, G. G. Accelerated polypeptide synthesis via N -carboxyanhydride ring opening polymerization in continuous flow. Macromol. Rapid Commun. 2020 , 41 , 2000071..

Tian, Z.-Y.; Zhang, Z.; Wang, S.; Lu, H. A moisture-tolerant route to unprotected α / β -amino acid N -carboxyanhydrides and facile synthesis of hyperbranched polypeptides. Nat. Commun. 2021 , 12 , 5810..

Wang, W.; Fu, H.; Lin, Y.; Cheng, J.; Song, Z. Cooperative covalent polymerization of N -carboxyanhydrides: from kinetic studies to efficient synthesis of polypeptide materials. Acc. Mater. Res. 2023 , 4 , 604−615..

Xia, Y.; Song, Z.; Tan, Z.; Xue, T.; Wei, S.; Zhu, L.; Yang, Y.; Fu, H.; Jiang, Y.; Lin, Y.; Lu, Y.; Ferguson, A. L.; Cheng, J. Accelerated polymerization of N -carboxyanhydrides catalyzed by crown ether. Nat. Commun. 2021 , 12 , 732..

Li, Q.; Lan, Y.; Wang, W.; Ji, G.; Li, X.; Song, Z. Polymerization of N -carboxyanhydride in cosolvents: the balance between the polymerization rate and molecular weight control. Macromolecules 2023 , 56 , 7023−7031..

Wang, X.; Song, Z.; Tan, Z.; Zhu, L.; Xue, T.; Lv, S.; Fu, Z.; Zheng, X.; Ren, J.; Cheng, J. Facile synthesis of helical multiblock copolypeptides: minimal side reactions with accelerated polymerization of N -carboxyanhydrides. ACS Macro Lett. 2019 , 8 , 1517−1521..

Lv, S.; Kim, H.; Song, Z.; Feng, L.; Yang, Y.; Baumgartner, R.; Tseng, K.-Y.; Dillon, S. J.; Leal, C.; Yin, L.; Cheng, J. Unimolecular polypeptide micelles via ultrafast polymerization of N -carboxyanhydrides. J. Am. Chem. Soc. 2020 , 142 , 8570−8574..

Ji, G.; Zheng, X.; Hou, X.; Sun, X.; Wang, S.; Li, X.; Cheng, J.; Song, Z. Modulation of polymerization rate of N -carboxyanhydrides in a biphasic system. Chin. Chem. Lett. 2024 , 35 , 108872..

Malkin, A. Y. Shear-induced transitions in colloidal and polymeric liquids. Adv. Colloid Interface Sci. 2021 , 290 , 102381..

Song, Z.; Fu, H.; Baumgartner, R.; Zhu, L.; Shih, K.-C.; Xia, Y.; Zheng, X.; Yin, L.; Chipot, C.; Lin, Y.; Cheng, J. Enzyme-mimetic self-catalyzed polymerization of polypeptide helices. Nat. Commun. 2019 , 10 , 5470..

Corrigan, N.; Almasri, A.; Taillades, W.; Xu, J.; Boyer, C. Controlling molecular weight distributions through photoinduced flow polymerization. Macromolecules 2017 , 50 , 8438−8448..

Reis, M. H.; Varner, T. P.; Leibfarth, F. A. The influence of residence time distribution on continuous-flow polymerization. Macromolecules 2019 , 52 , 3551−3557..

Britton, J.; Jamison, T. F. The assembly and use of continuous flow systems for chemical synthesis. Nat. Protoc. 2017 , 12 , 2423−2446..

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Efficient Preparation of Polypeptides through Accelerated Polymerization of N-Carboxyanhydrides in Continuous Flow

Efficient Preparation of Polypeptides through Accelerated Polymerization of N-Carboxyanhydrides in Continuous Flow

DOI：10.1007/s10118-025-3441-4

摘要

Abstract

关键词

Keywords

references