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
- Chinese Journal of Polymer Science Vol. 43, Issue 11, Pages: 2000-2008(2025)
- 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：
- DOI：10.1007/s10118-025-3441-4
  CLC：
- Received：09 June 2025，
  
  Accepted：18 August 2025，
  
  Online First：16 October 2025，
  
  Published：05 November 2025
- 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

DOI：10.1007/s10118-025-3441-4

摘要

Abstract

关键词

Keywords

references