Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Facile synthesis of amphiphilic AB3 and A3B miktoarm PeptoMiktoStars

Polymer Journal volume 52, pages 119–132 (2020)Cite this article

Subjects

Abstract

Amphiphilic miktoarm star copolymers have a unique internal structure and many attractive properties with respect to solution self-assembly, such as a high density of internal and peripheral functionalities, low CMC values, and high loading efficiency. However, compared to their linear analogs, the complex architecture demands asymmetric polymer arms emanating from a single core, which poses a significant synthetic challenge. Herein, we demonstrate an approach for the synthesis of polypept(o)ide-based AB3- and A3B-type miktoarm PeptoStars consisting of polypeptidic poly(γ-benzyl-l-glutamate (pGlu(OBn)) as the hydrophobic A arm and polypeptoidic polysarcosine (pSar) as the hydrophilic B arm. These structures, which are completely derived from endogenous amino acids, were realized by the core-first method using a tetrafunctional initiator and the corresponding N-carboxyanhydrides (NCAs) via a controlled, living nucleophilic ring-opening polymerization (ROP). The asymmetric architecture was achieved through an orthogonal protecting group strategy with multiple protection/deprotection steps. Characterization via 1H NMR-, 1H DOSY-spectroscopy, and size-exclusion chromatography (SEC) indicate the presence of well-formed miktoarm PeptoStars with low dispersities (Đ = 1.09–1.14), the precise control over the degree of polymerization and Poisson-like molecular weight distributions.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Scheme 1
Scheme 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Aghajanzadeh M, Zamani M, Rostamizadeh K, Sharafi A. The role of miktoarm star copolymers in drug delivery systems. J Macromol Sci Part A Pure Appl Chem. 2018;55:559–71.

    CAS  Google Scholar 

  2. Guo Y, Pan C & Wang J. Block and star block copolymers by mechanism transformation. VI. Synthesis and characterization of A4B4 miktoarm star copolymers consisting of polystyrene and polytetrahydrofuran prepared by cationic ring-opening polymerization and atom transfer radical polymerization. J Polym Sci A: Polym Chem. 2001;39:2134–42.

  3. Hadjichristidis N, Iatrou H, Pitsikalis M, Mays J. Macromolecular architectures by living and controlled/living polymerizations. Prog Polym Sci. 2006;31:1068–132.

    CAS  Google Scholar 

  4. Zhang L, Zhang W, Zhou N, Zhu J, Zhang Z, Cheng Z, et al. Preparation and characterization of linear and miktoarm star side-chain liquid crystalline block copolymers with p-methoxyazobenzene moieties via a combination of ATRP and ROP. J Macromol Sci Part A. 2009;46:876–85.

    CAS  Google Scholar 

  5. Altintas O, Vogt AP, Barner-Kowollik C, Tunca U. Constructing star polymers via modular ligation strategies. Polym Chem. 2012;3:34–45.

    CAS  Google Scholar 

  6. Schäfer O, Klinker K, Braun L, Huesmann D, Schultze J, Koynov K, et al. Combining orthogonal reactive groups in block copolymers for functional nanoparticle synthesis in a single step. ACS Macro Lett. 2017;6:1140–5.

    Google Scholar 

  7. Ding J, Chen L, Xiao C, Chen L, Chen L. Micelles for controlled drug delivery. Chem Commun. 2014;50:11274–90.

    CAS  Google Scholar 

  8. Kataoka K, Harada A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev. 2012;64:37–48.

    Google Scholar 

  9. Kataoka K, Harada A, Nagasaki Y. Block copolymer micelles for drug delivery: design, characterization and biological significance. Adv Drug Deliv Rev. 2001;47:113–31.

    CAS  PubMed  Google Scholar 

  10. Barz M, Luxenhofer R, Zentel R, Vicent MJ. Overcoming the PEG-addiction: well-defined alternatives to PEG, from structure-property relationships to better defined therapeutics. Polym Chem. 2011;2:1900–18.

    CAS  Google Scholar 

  11. Sun Q, Barz M, De Geest BG, Diken M, Hennink WE, Kiessling F, et al. Nanomedicine and macroscale materials in immuno-oncology. Chem Soc Rev. 2019;48:351–81.

    CAS  PubMed  Google Scholar 

  12. Talelli M, Barz M, Rijcken CJF, Kiessling F, Hennink WE & Lammers T. Core-crosslinked polymeric micelles: principles, preparation, biomedical applications and clinical translation. Nano Today. 2015;10:93–117.

  13. Soliman GM, Sharma A, Maysinger D, Kakkar A. Dendrimers and miktoarm polymers based multivalent nanocarriers for efficient and targeted drug delivery. Chem Commun. 2011;47:9572–87.

    CAS  Google Scholar 

  14. Deng Y, Zhang S, Lu G, Huang X. Constructing well-defined star graft copolymers. Polym Chem. 2013;4:1289–99.

    CAS  Google Scholar 

  15. Khanna K, Varshney S, Kakkar A. Miktoarm star polymers: advances in synthesis, self-assembly, and applications. Polym Chem. 2010;1:1171–85.

    CAS  Google Scholar 

  16. Yoon K, Kang HC, Li L, Cho H, Park MK, Lee E, et al. Amphiphilic poly(ethylene glycol)-poly(ε-caprolactone) AB 2 miktoarm copolymers for self-assembled nanocarrier systems: synthesis, characterization, and effects of morphology on antitumor activity. Polym Chem. 2015;6:531–42.

    CAS  Google Scholar 

  17. Yin H, Kang SW, Bae YH. Polymersome formation from AB2 type 3-miktoarm star copolymers. Macromolecules. 2009;42:7456–64.

    CAS  Google Scholar 

  18. Li Z, Kesselman E, Talmon Y, Hillmyer MA, Lodge TP. Multicompartment micelles from ABC miktoarm stars in water. Science. 2004;306:98–101.

    CAS  PubMed  Google Scholar 

  19. Moquin A, Sharma A, Cui Y, Lau A, Maysinger D, Kakkar A, et al. Asymmetric AB3 Miktoarm star polymers: synthesis, self-assembly, and study of micelle stability using AF 4 for efficient drug delivery. Macromol Biosci. 2015;15:1744–54.

    CAS  PubMed  Google Scholar 

  20. Alkilany AM, Zhu L, Weller H, Mews A, Parak WJ, Barz M. et al. Ligand density on nanoparticles: a parameter with critical impact on nanomedicine. Adv Drug Deliv Rev. 2019. https://doi.org/10.1016/j.addr.2019.05.010.

    CAS  PubMed  Google Scholar 

  21. Wang M, Zhang X, Peng H, Zhang M, Zhang X, Liu Z, et al. Optimization of amphiphilic miktoarm star copolymers for anticancer drug delivery. ACS Biomater Sci Eng. 2018;4:2903–10.

    CAS  Google Scholar 

  22. Xu F, Wu D, Huang Y, Mai Y. Multi-dimensional self-assembly of a dual-responsive abc miktoarm star terpolymer. ACS Macro Lett. 2017;6:426–30.

    CAS  Google Scholar 

  23. Kimura S, Kidchob T, Imanishi Y. Controlled release from amphiphilic polymer aggregates. Polym Adv Technol. 2001;12:85–95.

    CAS  Google Scholar 

  24. Birke A, Huesmann D, Kelsch A, Weilba M, Xie J, Bros M, et al. Polypeptoid-block-polypeptide copolymers: synthesis, characterization, and application of amphiphilic block copolypept(o)ides in drug formulations and miniemulsion techniques. Biomacromolecules. 2014;15:548–57.

    CAS  PubMed  Google Scholar 

  25. Heller P, Birke A, Huesmann D, Weber B, Fischer K, Reske-kunz A, et al. Introducing peptoplexes: polylysine- block—polysarcosine based polyplexes for transfection of HEK 293T cells. Macromol Biosci. 2014;14:1380–95.

    CAS  PubMed  Google Scholar 

  26. Klinker K, Barz M. Polypept(o)ides: hybrid systems based on polypeptides and polypeptoids. Macromol Rapid Commun. 2015;36:1943–57.

    CAS  PubMed  Google Scholar 

  27. Klinker K, Schäfer O, Huesmann D, Bauer T, Capeloa L, Braun L, et al. Secondary-structure-driven self-assembly of reactive polypept(o)ides: controlling size, shape, and function of angewandte. Angew Chem. 2017;56:9608–13.

    CAS  Google Scholar 

  28. Hörtz C, Birke A, Kaps L, Decker S, Wächtersbach E, Fischer K, et al. Cylindrical brush polymers with polysarcosine side chains: a novel biocompatible carrier for biomedical applications. Macromol Symp. 2015;48:2074–86.

    Google Scholar 

  29. Huesmann D, Sevenich A, Weber B, Barz M. A head-to-head comparison of poly (sarcosine) and poly (ethylene glycol) in peptidic, amphiphilic block copolymers. Polymers. 2015;67:240–8.

    CAS  Google Scholar 

  30. Chen X, Ferrigno R, Yang J, Whitesides GM. Redox properties of cytochrome c adsorbed on self-assembled monolayers: a probe for protein conformation and orientation. Langmuir. 2002;18:7009–15.

    CAS  Google Scholar 

  31. Matsui H, Tada Y, Fushimi R, Fujita S, Ito M, Kawabe T, et al. Novel class of nanofiber hydrogels based on the biodegradable amphiphilic copolymers poly(sarcosine) and poly(L-lactic acid) and prepared using alcohols. Mater Today Commun. 2017;11:156–62.

    CAS  Google Scholar 

  32. Birke A, Ling J, Barz M. Polysarcosine-containing copolymers: synthesis, characterization, self-assembly, and applications. Prog Polym Sci. 2018;81:163–208.

    CAS  Google Scholar 

  33. Weber B, Birke A, Fischer K, Schmidt M, Barz M. Solution properties of polysarcosine: from absolute and relative molar mass determinations to complement activation. Macromolecules. 2018;51:2653–61.

    CAS  Google Scholar 

  34. Chapman RG, Ostuni E, Takayama S, Holmlin RE, Yan L, Whitesides GM. Surveying for surfaces that resist the adsorption of proteins. J Am Chem Soc 2000;122:8303–4.

    CAS  Google Scholar 

  35. Lau KHA, Ren C, Sileika TS, Park SH, Szleifer I, Messersmith PB. Surface-grafted polysarcosine as a peptoid antifouling polymer brush. Langmuir. 2012;28:16099–107.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Schneider M, Tang Z, Richter M, Marschelke C, Wegener E, Amin I, et al. Patterned polypeptoid brushes. Macromol Biosci. 2015;16:75–81.

    PubMed  Google Scholar 

  37. Fokina A, Klinker K, Braun L, Jeong BG, Bae WK, Barz M, et al. Multidentate polysarcosine-based ligands for water-soluble quantum dots. Macromolecules. 2016;49:3663–71.

    CAS  Google Scholar 

  38. Negwer I, Best A, Schinnerer M, Schäfer O, Capeloa L, Wagner M, et al. Monitoring drug nanocarriers in human blood by near-infrared fluorescence correlation spectroscopy. Nat Commun. 2018;9:5306.

    PubMed  PubMed Central  Google Scholar 

  39. Oya M, Katakai R, & Nakai H, Chem Lett. 1973;2:1143–4.

  40. Fetsch C, Grossmann A, Holz L, Nawroth JF, Luxenhofer R. Polypeptoids from N-substituted glycine N-carboxyanhydrides: hydrophilic, hydrophobic, and amphiphilic polymers with poisson distribution. Macromolecules. 2011;44:6746–58.

    CAS  Google Scholar 

  41. Kricheldorf HR, Bösinger K. Mechanismus der NCA-Polymerisation, Über die Amin katalysierte Polymerisation von Sarkosin -NCA und -NTA. Makromol Chem. 1976;177:1243–58.

    CAS  Google Scholar 

  42. Dimitrov I & Schlaad H. Synthesis of nearly monodisperse polystyrene—polypeptide block copolymers via polymerisation of N-carboxyanhydrides. Chem Commun. 2003;23:2944–5.

  43. Heller P, Hobernik D, Lächelt U, Schinnerer M, Weber B, Schmidt M, et al. Combining reactive triblock copolymers with functional cross-linkers: a versatile pathway to disulfide stabilized-polyplex libraries and their application as pDNA vaccines. J Control Release. 2017;258:146–60.

    CAS  PubMed  Google Scholar 

  44. Holm R, Weber B, Heller P, Klinker K, Westmeier D, Docter D, et al. Synthesis and characterization of stimuli-responsive star-like polypept(o)ides: introducing biodegradable peptostars. Macromol Biosci. 2017;17:1–14.

    Google Scholar 

  45. Holm R, Douverne M, Weber B, Bauer T, Best A, Ahlers P, et al. Impact of branching on the solution behavior and serum stability of starlike block copolymers. Biomacromolecules. 2019;20:375–88.

    CAS  PubMed  Google Scholar 

  46. Kricheldorf HR, Kreiser-Saunders I, Stricker A. Polylactones 48. SnOct2-initiated polymerizations of lactide: a mechanistic study. Macromolecules. 2000;33:702–9.

    CAS  Google Scholar 

  47. Frisch H, Nie Y, Raunser S, Besenius P. PH-regulated selectivity in supramolecular polymerizations: switching between co- and homopolymers. Chem Eur J. 2015;21:3304–9.

    CAS  PubMed  Google Scholar 

  48. Frisch H, Spitzer D, Haase M, Basché T, Voskuhl J, Besenius P. Probing the self-assembly and stability of oligohistidine based rod-like micelles by aggregation induced luminescence. Org Biomol Chem. 2016;14:5574–9.

    CAS  PubMed  Google Scholar 

  49. Fetsch C, Luxenhofer R. Thermal properties of aliphatic polypeptoids. Polymers 2013;5:112–27.

    Google Scholar 

  50. Sulistio A, Gurr PA, Blencowe A, Qiao GG. Peptide-based star polymers: the rising star in functional polymers. Aust J Chem. 2012;65:978–84.

    CAS  Google Scholar 

  51. Shi Y, Lammers T, Storm G, Hennink WE. Physico-chemical strategies to enhance stability and drug retention of polymeric micelles for tumor-targeted drug delivery. Macromol Biosci. 2017;17:1–11.

    Google Scholar 

  52. Habraken GJM, Wilsens KHRM, Koning CE, Heise A. Optimization of N-carboxyanhydride (NCA) polymerization by variation of reaction temperature and pressure. Polym Chem. 2011;2:1322–30.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Organic Chemistry, Johannes Gutenberg-Universität Mainz, Duesbergweg 10-14, 55128, Mainz, Germany

    David Schwiertz & Matthias Barz

Authors
  1. David Schwiertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Regina Holm
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthias Barz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthias Barz.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schwiertz, D., Holm, R. & Barz, M. Facile synthesis of amphiphilic AB3 and A3B miktoarm PeptoMiktoStars. Polym J 52, 119–132 (2020). https://doi.org/10.1038/s41428-019-0269-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41428-019-0269-1

Search

Advanced search

Quick links