Temperature-sensitive Micelles as Artificial Chaperones for Insulin Protection

Jia-Wen Chen; Yan Xiao; Mei-Dong Lang

doi:10.1007/s10118-024-3244-z

Your Location：

Home >

Browse articles >

Temperature-sensitive Micelles as Artificial Chaperones for Insulin Protection

RESEARCH ARTICLE | Updated：2025-01-23

- Temperature-sensitive Micelles as Artificial Chaperones for Insulin Protection
- Chinese Journal of Polymer Science Vol. 43, Issue 2, Pages: 350-359(2025)
- Affiliations：
  
  Shanghai Key Laboratory of Advanced Polymeric Materials, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China
- Author bio：
  
  yxiao@ecust.edu.cn (Y.X.)
  mdlang@ecust.edu.cn (M.D.L.)
- Funds：
- DOI：10.1007/s10118-024-3244-z
  CLC：
- Received：13 September 2024，
  
  Revised：2024-09-29，
  
  Accepted：30 September 2024，
  
  Online First：25 November 2024，
  
  Published：01 February 2025
- Accepted：
Scan QR Code
Chen, J. W.; Xiao, Y.; Lang, M. D. Temperature-sensitive micelles as artificial chaperones for insulin protection. Chinese J. Polym. Sci. 2025, 43, 350–359

Jia-Wen Chen, Yan Xiao, Mei-Dong Lang. Temperature-sensitive Micelles as Artificial Chaperones for Insulin Protection[J]. Chinese Journal of Polymer Science, 2025, 43(2): 350-359.
Chen, J. W.; Xiao, Y.; Lang, M. D. Temperature-sensitive micelles as artificial chaperones for insulin protection. Chinese J. Polym. Sci. 2025, 43, 350–359 DOI： 10.1007/s10118-024-3244-z.

Jia-Wen Chen, Yan Xiao, Mei-Dong Lang. Temperature-sensitive Micelles as Artificial Chaperones for Insulin Protection[J]. Chinese Journal of Polymer Science, 2025, 43(2): 350-359. DOI： 10.1007/s10118-024-3244-z.

摘要

A series of temperature-sensitive polycaprolactone copolymers were designed and prepared. The binding ability of the micelles to proteins can be modulated by changing the temperature

which in turn enables long-term storage and high-temperature protection of proteins.

Abstract

Insulin is an essential and versatile protein taking part in the control of blood glucose levels and protein anabolism. However

under prolonged storage or high temperature stress

insulin tends to unfold and aggregate into toxic amyloid fibrils

leading to loss of physiological function. Inspired by natural chaperones

a series of temperature-sensitive polycaprolactone-based micelles were designed to prevent insulin from deactivation. The micelles were fabricated through the self-assembly of amphiphilic copolymers of methoxy poly(ethylene glycol)-poly(4-diethylformamide caprolactone-

-caprolactone) (mPEG

-P(DECL-

-CL))

which had a regular spherical morphology with particle sizes of about 100 nm. In addition

the lower critical solution temperature (LCST) of the micelles could be tuned to 9 and 29 °C by changing the ratio of DECL to CL. Benefiting from the temperature-sensitivity of DECL segment

the binding ability of micelles to insulin could be modulated by changing the temperature. Above LCST

micelles effectively inhibited insulin aggregation and protected it f

rom thermal inactivation due to the strong binding ability between the hydrophobic segment DECL and insulin. Below LCST

DECL segment returned to hydrophilic and bound weakly with insulin

leading to the release of insulin and assisting in its recovery of secondary structure. Thus

these temperature-sensitive micelles provided an effective strategy for insulin protection.

关键词

Keywords

references

Ma, F. H.; Li, C.; Liu, Y.; Shi, L. Mimicking molecular chaperones to regulate protein folding. Adv. Mater. 2020 , 32 , e1805945..

Zhang, Q.; Zhang, J.; Song, J.; Liu, Y.; Ren, X.; Zhao, Y. Protein-based nanomedicine for therapeutic benefits of cancer. ACS Nano 2021 , 15 , 8001−8038..

Zou, Q.; Chang, R.; Yan, X. Self-assembling proteins for design of anticancer nanodrugs. Chem. Asian J. 2020 , 15 , 1405−1419..

Dutta, K.; Hu, D.; Zhao, B.; Ribbe, A. E.; Zhuang, J.; Thayumanavan, S. Templated self-assembly of a covalent polymer network for intracellular protein delivery and traceless release. J. Am. Chem. Soc. 2017 , 139 , 5676−5679..

Loveday, S. M. Food proteins: technological, nutritional, and sustainability attributes of traditional and emerging proteins. Annu. Rev. Food Sci. T. 2019 , 10 , 311−339..

Chalamaiah, M.; Yu, W.; Wu, J. Immunomodulatory and anticancer protein hydrolysates (peptides) from food proteins: a review. Food Chem. 2018 , 245 , 205−222..

Tomadoni, B.; Capello, C.; Valencia, G. A.; Gutiérrez, T. J. Self-assembled proteins for food applications: a review. Trends Food Sci. Technol. 2020 , 101 , 1−16..

Dutta, K.; Das, R.; Ling, J.; Monibas, R. M.; Carballo-Jane, E.; Kekec, A.; Feng, D. D.; Lin, S.; Mu, J.; Saklatvala, R.; Thayumanavan, S.; Liang, Y. In situ forming injectable thermoresponsive hydrogels for controlled delivery of biomacromolecules. ACS Omega 2020 , 5 , 17531−17542..

Xin, X.; Xu, Y.; Shi, H.; Liu, X. General method to stabilize mesophilic proteins in hyperthermal water. iScience 2021 , 24 , 102503..

Messina, M. S.; Ko, J. H.; Yang, Z.; Strouse, M. J.; Houk, K. N.; Maynard, H. D. Effect of trehalose polymer regioisomers on protein stabilization. Polym. Chem. 2017 , 8 , 4781−4788..

Feller, G. Protein folding at extreme temperatures: Current issues. Semin. Cell Dev. Biol. 2018 , 84 , 129−137..

Abbas Syed, Q.; Hassan, A.; Sharif, S.; Ishaq, A.; Saeed, F.; Afzaal, M.; Hussain, M.; Anjum, F. M. Structural and functional properties of milk proteins as affected by heating, high pressure, Gamma and ultraviolet irradiation: a review. Int. J. Food Prop. 2021 , 24 , 871−884..

Metwalli, A. A. M.; de Jongh, H. H. J.; van Boekel, M. A. J. S. Heat inactivation of bovine plasmin. Int. Dairy J. 1998 , 8 , 47−56..

Cappelletti, V.; Hauser, T.; Piazza, I.; Pepelnjak, M.; Malinovska, L.; Fuhrer, T.; Li, Y.; Dörig, C.; Boersema, P.; Gillet, L.; Grossbach, J.; Dugourd, A.; Saez-Rodriguez, J.; Beyer, A.; Zamboni, N.; Caflisch, A.; de Souza, N.; Picotti, P. Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ . Cell. 2021 , 184 , 545−559..

Zeeshan, F.; Tabbassum, M.; Kesharwani, P. Investigation on secondary structure alterations of protein drugs as an indicator of their biological activity upon thermal exposure. Protein J. 2019 , 38 , 551−564..

Li, S. S.; Li, B. Q.; Liu, J. J.; Lu, S. H.; Zhai, H. L. Tchebichef image moment approach to the prediction of protein secondary structures based on circular dichroism. Proteins. 2018 , 86 , 751−758..

Li, X.; Lu, C.; Xia, W.; Quan, G.; Huang, Y.; Bai, X.; Yu, F.; Xu, Q.; Qin, W.; Liu, D.; Pan, X. Poly(L-glutamic acid)-based brush copolymers: fabrication, self-assembly, and evaluation as efficient nanocarriers for cationic protein drug delivery. AAPS PharmSciTech. 2020 , 21 , 78..

Wu, G.; Li, C.; Liu, X.; Lv, J.; Ding, Y.; Liu, Y.; Liu, Y.; Huang, F.; Shi, L.; An, Y.; Ma, R. Glucose-responsive complex micelles for self-regulated delivery of insulin with effective protection of insulin and enhanced hypoglycemic activity in vivo . Colloid. Surface B 2019 , 180 , 376−383..

Jain, A. K.; Chalasani, K. B.; Khar, R. K.; Ahmed, F. J.; Diwan, P. V. Muco-adhesive multivesicular liposomes as an effective carrier for transmucosal insulin delivery. J. Drug Target. 2007 , 15 , 417−427..

Kuskov, A. N.; Kulikov, P. P.; Goryachaya, A. V.; Tzatzarakis, M. N.; Tsatsakis, A. M.; Velonia, K.; Shtilman, M. I. Self-assembled amphiphilic poly- N -vinylpyrrolidone nanoparticles as carriers for hydrophobic drugs: stability aspects. J. Appl. Polym. Sci. 2018 , 135 , 45637..

Mirchandani, Y.; Patravale, V. B.; S, B. Solid lipid nanoparticles for hydrophilic drugs. J. Control. Rel. 2021 , 335 , 457−464..

Gelb, M. B.; Messina, K. M. M.; Vinciguerra, D.; Ko, J. H.; Collins, J.; Tamboline, M.; Xu, S.; Ibarrondo, F. J.; Maynard, H. D. Poly(trehalose methacrylate) as an excipient for insulin stabilization: mechanism and safety. ACS Appl. Mater. Interfaces 2022 , 14 , 37410−37423..

Pathak, B. K.; Das, D.; Bhakta, S.; Chakrabarti, P.; Sengupta, J. Resveratrol as a nontoxic excipient stabilizes insulin in a bioactive hexameric form. J. Comput. Aid. Mol. Des. 2020 , 34 , 915−927..

Pelegri-O’Day, E. M.; Bhattacharya, A.; Theopold, N.; Ko, J. H.; Maynard, H. D. Synthesis of zwitterionic and trehalose polymers with variable degradation rates and stabilization of insulin. Biomacromolecules 2020 , 21 , 2147−2154..

Castañeda Ruiz, A. J.; Shetab Boushehri, M. A.; Phan, T.; Carle, S.; Garidel, P.; Buske, J.; Lamprecht, A. Alternative excipients for protein stabilization in protein therapeutics: overcoming the limitations of polysorbates. Pharmaceutics . 2022 ..

Brovč, E. V.; Mravljak, J.; Šink, R.; Pajk, S. Rational design to biologics development: the polysorbates point of view. Int. J. Pharm. 2020 , 581 , 119285..

Hu, X.; Zhang, X.; Chen, D.; Li, N.; Hemar, Y.; Yu, B.; Tang, S.; Sun, Y. How much can we trust polysorbates as food protein stabilizers: the case of bovine casein. Food Hydrocolloids 2019 , 96 , 8 1−92..

Brovč, E. V.; Mravljak, J.; Šink, R.; Pajk, S. Degradation of polysorbates 20 and 80 catalysed by histidine chloride buffer. Eur. J. Pharm. Biopharm. 2020 , 154 , 236−245..

Dwivedi, M.; Buske, J.; Haemmerling, F.; Blech, M.; Garidel, P. Acidic and alkaline hydrolysis of polysorbates under aqueous conditions: towards understanding polysorbate degradation in biopharmaceutical formulations. Eur. J. Pharm. Sci. 2020 , 144 , 105211..

Lang, B. J.; Prince, T. L.; Okusha, Y.; Bunch, H.; Calderwood, S. K. Heat shock proteins in cell signaling and cancer. BBA. Mol. Cell Res. 2022 , 1869 , 119187..

Shan, Q.; Ma, F.; Wei, J.; Li, H.; Ma, H.; Sun, P. Physiological functions of heat shock proteins. Curr. Protein Pept. Sci. 2020 , 21 , 751−760..

Kim, J. Y.; Han, Y.; Lee, J. E.; Yenari, M. A. The 70-kDa heat shock protein (Hsp70) as a therapeutic target for stroke. Expert Opin. Ther. Tar. 2018 , 22 , 191−199..

Lu, J.; Zhang, X.; Wu, Y.; Sheng, Y.; Li, W.; Wang, W. Energy landscape remodeling mechanism of Hsp70-chaperone-accelerated protein folding. Biophys. J. 2021 , 120 , 1971−1983..

Rowles, J. E.; Keane, K. N.; Gomes Heck, T.; Cruzat, V.; Verdile, G.; Newsholme, P. Are heat shock proteins an important link between type 2 diabetes and Alzheimer Disease? Int. J. Mol. Sci . 2020 ..

Mogk, A.; Ruger-Herreros, C.; Bukau, B. Cellular functions and mechanisms of action of small heat shock proteins. Annu. Rev. Microbiol. 2019 , 73 , 89−110..

Li, C.; Liu, X.; Zhang, Y.; Lv, J.; Huang, F.; Wu, G.; Liu, Y.; Ma, R.; An, Y.; Shi, L. Nanochaperones mediated delivery of insulin. Nano Lett. 2020 , 20 , 1755−1765..

Kabir, A.; Ahmed, M. Elucidating the role of thermal flexibility of hydrogels in protein refolding. ACS Appl. Bio Mater. 2020 , 3 , 4253−4262..

Wang, H.; Li, A.; Yan g, M.; Zhao, Y.; Shi, L.; Ma, R. Self-assembled nanochaperones enable the disaggregation of amyloid insulin fibrils. Sci. China Chem. 2021 , 65 , 353−362..

Beierle, J. M.; Yoshimatsu, K.; Chou, B.; Mathews, M. A.; Lesel, B. K.; Shea, K. J. Polymer nanoparticle hydrogels with autonomous affinity switching for the protection of proteins from thermal stress. Angew. Chem. Int. Ed. 2014 , 53 , 9275−9279..

Wen, L.; Zhang, S.; Xiao, Y.; He, J.; Zhu, S.; Zhang, J.; Wu, Z.; Lang, M. Organocatalytic ring-opening polymerization toward poly( γ -amide- ε -caprolactone)s with tunable lower critical solution temperatures. Macromolecules 2020 , 53 , 5096−5104..

Deng, Y.; Li, X.; Zhang, Q.; Luo, Z.; Han, C.; Dong, S. LCST phase behavior of benzo-21-crown-7 with different alkyl chains. Beilstein J. Org. Chem. 2019 , 15 , 437−444..

Barman, R.; Rajdev, P.; Mondal, T.; Dey, P.; Ghosh, S. Amphiphilic alternating copolymers with an adjustable lower critical solution temperature (LCST) and correlation with nonspecific protein adsorption. ACS Appl. Polym. Mater. 2022 , 4 , 5261−5268..

Lu, C.; Guo, S.; Liu, L.; Zhang, Y.; Li, Z.; Gu, J. Aggregation behavior of MPEG-PCL diblock copolymers in aqueous solutions and morphologies of the aggregates. J. Polym. Sci., Part B: Polym. Phys. 2006 , 44 , 3406−3417..

Yue, G. L.; Cui, Q. L.; Zhang, Y. X.; Wang, E. J.; Wu, F. P. Thermo-responsive block copolymers based on linear-type poly(ethylene glycol): tunable LCST within the physiological range. Chinese J. Polym. Sci. 2012 , 30 , 770−776..

Views

174

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

Microenvironment Responsive Polymeric Nitric Oxide Releasing Micelles for Enhancing Eradication of Methicillin-resistant Staphylococcus aureus Biofilm

Nanochaperones Based on Hydrophobic Interaction and Coordination Inhibit Protein Misfolding and Fibrillation

Glucose-sensitive Membrane with PBA-based Contraction-type Linear Polymer as Chemical Valves Prepared by Surface Grafting

On-demand Peelable UV-curable Adhesives with Superior Bonding Strength: Rational Molecular Engineering of Cohesion-adhesion Synergy

Silk Sericin-inspired Poly-β-homoserine for Protein Protection

Related Author

Peng Li

Dan Xing

Zhi-Heng Yang

Yu-Tong Yang

Gang-Feng Li

Zheng-Xin Ma

Hui-Fang Ma

Ru-Jiang Ma

Related Institution

State Key Laboratory of Flexible Electronics (LoFE) & Institute of Flexible Electronics (IFE), Shaanxi Key Laboratory of Flexible Electronics & MIIT Key Laboratory of Flexible Electronics (KLoFE), Xi'an Institute of Biomedical Materials and Engineering (IBME), Northwestern Polytechnical University (NPU)

State Key Laboratory of Molecular Engineering of Polymers, Fudan University

Henan Institute of Flexible Electronics (HIFE) and School of Flexible Electronics (SoFE), Henan University

Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University

Haihe Laboratory of Sustainable Chemical Transformations

⁰