Skip to main content
SpringerLink
Log in

Self-assembly of peptide-based nanostructures: Synthesis and biological activity

  • Review Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

Peptide-based nanostructures have received much attention in the field of drug targeting. In fact, peptides have many advantages such as simplicity of the structure, biocompatibility, and chemical diversity. Moreover, some peptides, which are called cell-penetrating peptides, can cross cellular membranes and carry small molecules, small interfering RNA, or viruses inside live cells. These molecules are often covalently or noncovalently linked to cargoes, thus forming amphiphilic conjugates that can self-assemble. Supramolecular nanostructures formed from peptides are used in nanomedicine as a carrier to protect a drug and to target cancer cells. This review explores aliphatic-chain–conjugated peptides and drug-conjugated peptides that can self-assemble. Special emphasis is placed on the synthesis procedure, nanostructure formation, and biological activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bangham, A. D.; Standish, M. M.; Watkins, J. C. Diffusion of univalent ions across the lamellae of swollen phospholipids. J. Mol. Biol. 1965, 13, 238–252.

    Article  Google Scholar 

  2. Allen, T. M.; Cullis, P. R. Liposomal drug delivery systems: From concept to clinical applications. Adv. Drug Deliv. Rev. 2013, 65, 36–48.

    Article  Google Scholar 

  3. Croy, S. R.; Kwon, G. S. Polymeric micelles for drug delivery. Curr. Pharm. Des. 2006, 12, 4669–4684.

    Article  Google Scholar 

  4. Mandal, A.; Bisht, R.; Rupenthal, I. D.; Mitra, A. K. Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies. J. Control. Release 2017, 248, 96–116.

    Article  Google Scholar 

  5. Panahi, Y.; Farshbaf, M.; Mohammadhosseini, M.; Mirahadi, M.; Khalilov, R.; Saghfi, S.; Akbarzadeh, A. Recent advances on liposomal nanoparticles: Synthesis, characterization and biomedical applications. Artif. Cells Nanomed. Biotechnol. 2017, 45, 788–799.

    Article  Google Scholar 

  6. Mehrabi, M.; Esmaeilpour, P.; Akbarzadeh, A.; Saffari, Z.; Farahnak, M.; Farhangi, A.; Chiani, M. Efficacy of PEGylated liposomal etoposide nanoparticles on breast cancer cell lines. Turk. J. Med. Sci. 2016, 46, 567–571.

    Article  Google Scholar 

  7. Vahed Zununi, S.; Salehi, R.; Davaran, S.; Sharifi, S. Liposome-based drug co-delivery systems in cancer cells. Mater. Sci. Eng. C 2017, 71, 1327–1341.

    Article  Google Scholar 

  8. Venev, S. V.; Reineker, P.; Potemkin, I. I. Direct and inverse micelles of diblock copolymers with a polyelectrolyte block: Effect of equilibrium distribution of counterions. Macromolecules 2010, 43, 10735–10742.

    Article  Google Scholar 

  9. Gennes, P. G. Scaling Concepts in Polymer Physics; Cornell University Press: Ithaca, NY, 1979.

    Google Scholar 

  10. Birshtein, T. M.; Zhulina, E. B. Scaling theory of supermolecular structures in block copolymer-solvent systems: 1. Model of micellar structures. Polymer 1989, 30, 170–177.

    Article  Google Scholar 

  11. Jain, S.; Bates, F. S. On the origins of morphological complexity in block copolymer surfactants. Science 2003, 300, 460–464.

    Article  Google Scholar 

  12. Israelachvili, J. N.; Mitchell, D. J.; Ninham, B. W. Theory of self-assembly of hydrocarbon amphiphiles into micelles and bilayers. J. Chem. Soc. Faraday Trans. 2 1976, 72, 1525–1568.

    Article  Google Scholar 

  13. Israelachvili, J. N. Thermodynamic and geometric aspects of amphiphile aggregation into micelles, vesicles and bilayers and the interactions between them. In Physics of Amphiphiles: Micelles, Vesicles and Microemulsions: Proceedings of the International School of Physics, Enrico Fermi, Course Xc. Degiorgio, V.; Corti, M., Eds.; Elsevier Science Ltd: Amsterdam, 1985; pp 24–58.

    Google Scholar 

  14. Israelachvili, J. N. 20-Soft and biological structures. In Intermolecular and Surface Forces. 3rd Ed. Israelachvili, J. N., Ed.; Academic Press: San Diego, 2011; pp 535–576.

    Google Scholar 

  15. Holmberg, K.; Jönsson, B.; Kronberg, B.; Lindman, B. Front matter. In Surfactants and Polymers in Aqueous Solution. 2nd ed. Holmberg, K.; Jönsson, B.; Kronberg, B.; Lindman, B., Eds.; John Wiley & Sons, Ltd: Chichester, 2003.

    Google Scholar 

  16. Lepeltier, E.; Bourgaux, C.; Maksimenko, A.; Meneau, E.; Rosilio, V.; Sliwinski, E.; Zouhiri, F.; Desmaële, D.; Couvreur, P. Self-assembly of polyisoprenoyl gemcitabine conjugates: Influence of supramolecular organization on their biological activity. Langmuir 2014, 30, 6348–6357.

    Article  Google Scholar 

  17. Naik, S. S.; Savin, D. A. Poly(Z-lysine)-based organogels: Effect of interfacial frustration on gel strength. Macromolecules 2009, 42, 7114–7121.

    Article  Google Scholar 

  18. Nowak, A. P.; Breedveld, V.; Pakstis, L.; Ozbas, B.; Pine, D. J.; Pochan, D.; Deming, T. J. Rapidly recovering hydrogel scaffolds from self-assembling diblock copolypeptide amphiphiles. Nature 2002, 417, 424–428.

    Article  Google Scholar 

  19. Holowka, E. P.; Pochan, D. J.; Deming, T. J. Charged polypeptide vesicles with controllable diameter. J. Am. Chem. Soc. 2005, 127, 12423–12428.

    Article  Google Scholar 

  20. Denisov, I. G.; Grinkova, Y. V.; Lazarides, A. A.; Sligar, S. G. Directed self-assembly of monodisperse phospholipid bilayer nanodiscs with controlled size. J. Am. Chem. Soc. 2004, 126, 3477–3487.

    Article  Google Scholar 

  21. Sigg, S. J.; Postupalenko, V.; Duskey, J. T.; Palivan, C. G.; Meier, W. Stimuli-responsive codelivery of oligonucleotides and drugs by self-assembled peptide nanoparticles. Biomacromolecules 2016, 17, 935–945.

    Article  Google Scholar 

  22. Yao, C.; Liu, J. Y.; Wu, X.; Tao, Z. G.; Gao, Y.; Zhu, Q. G.; Li, J. F.; Zhang, L. J.; Hu, C. L.; Gu, F. F. et al. Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgenindependent prostate cancer therapy. J. Control. Release 2016, 232, 203–214.

    Article  Google Scholar 

  23. Tai, Z. G.; Wang, X. Y.; Tian, J.; Gao, Y.; Zhang, L. J.; Yao, C.; Wu, X.; Zhang, W.; Zhu, Q. G.; Gao, S. Biodegradable stearylated peptide with internal disulfide bonds for efficient delivery of siRNA in vitro and in vivo. Biomacromolecules 2015, 16, 1119–1130.

    Article  Google Scholar 

  24. Hartgerink, J. D.; Beniash, E.; Stupp, S. I. Peptide-amphiphile nanofibers: A versatile scaffold for the preparation of selfassembling materials. Proc. Natl. Acad. Sci. USA 2002, 99, 5133–5138.

    Article  Google Scholar 

  25. Mata, A.; Geng, Y. B.; Henrikson, K. J.; Aparicio, C.; Stock, S. R.; Satcher, R. L.; Stupp, S. I. Bone regeneration mediated by biomimetic mineralization of a nanofiber matrix. Biomaterials 2010, 31, 6004–6012.

    Article  Google Scholar 

  26. Mammadov, R.; Mammadov, B.; Toksoz, S.; Aydin, B.; Yagci, R.; Tekinay, A. B.; Guler, M. O. Heparin mimetic peptide nanofibers promote angiogenesis. Biomacromolecules 2011, 12, 3508–3519.

    Article  Google Scholar 

  27. Standley, S. M.; Toft, D. J.; Cheng, H.; Soukasene, S.; Chen, J.; Raja, S. M.; Band, V.; Band, H.; Cryns, V. L.; Stupp, S. I. Induction of cancer cell death by self-assembling nanostructures incorporating a cytotoxic peptide. Cancer Res. 2010, 70, 3020–3026.

    Article  Google Scholar 

  28. Missirlis, D.; Krogstad, D. V.; Tirrell, M. Internalization of p5314-29 peptide amphiphiles and subsequent endosomal disruption results in SJSA-1 cell death. Mol. Pharmaceutics 2010, 7, 2173–2184.

    Article  Google Scholar 

  29. Missirlis, D.; Khant, H.; Tirrell, M. Mechanisms of peptide amphiphile internalization by SJSA-1 cells in vitro. Biochemistry 2009, 48, 3304–3314.

    Article  Google Scholar 

  30. Anderson, J. M.; Kushwaha, M.; Tambralli, A.; Bellis, S. L.; Camata, R. P.; Jun, H. W. Osteogenic differentiation of human mesenchymal stem cells directed by extracellular matrixmimicking ligands in a biomimetic self-assembled peptide amphiphile nanomatrix. Biomacromolecules 2009, 10, 2935–2944.

    Article  Google Scholar 

  31. Black, M.; Trent, A.; Kostenko, Y.; Lee, J. S.; Olive, C.; Tirrell, M. Self-assembled peptide amphiphile micelles containing a cytotoxic t-cell epitope promote a protective immune response in vivo. Adv. Mater. 2012, 24, 3845–3849.

    Article  Google Scholar 

  32. Webber, M. J.; Tongers, J.; Newcomb, C. J.; Marquardt, K. T.; Bauersachs, J.; Losordo, D. W.; Stupp, S. I. Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair. Proc. Natl. Acad. Sci. USA 2011, 108, 13438–13443.

    Article  Google Scholar 

  33. Boato, F.; Thomas, R. M.; Ghasparian, A.; Freund-Renard, A.; Moehle, K.; Robinson, J. A. Synthetic virus-like particles from self-assembling coiled-coil lipopeptides and their use in antigen display to the immune system. Angew. Chem., Int. Ed. 2007, 46, 9015–9018.

    Article  Google Scholar 

  34. Tang, Q.; Cao, B.; Wu, H. Y.; Cheng, G. Cholesterol-peptide hybrids to form liposome-like vesicles for gene delivery. PLoS One 2013, 8, e54460.

    Article  Google Scholar 

  35. Matsubara, T.; Shibata, R.; Sato, T. Binding of hemagglutinin and influenza virus to a peptide-conjugated lipid membrane. Front. Microbiol. 2016, 7, 468.

    Article  Google Scholar 

  36. Peters, D.; Kastantin, M.; Kotamraju, V. R.; Karmali, P. P.; Gujraty, K.; Tirrell, M.; Ruoslahti, E. Targeting atherosclerosis by using modular, multifunctional micelles. Proc. Natl. Acad. Sci. USA 2009, 106, 9815–9819.

    Article  Google Scholar 

  37. Tornoe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem. 2002, 67, 3057–3064.

    Article  Google Scholar 

  38. Beniash, E.; Hartgerink, J. D.; Storrie, H.; Stendahl, J. C.; Stupp, S. I. Self-assembling peptide amphiphile nanofiber matrices for cell entrapment. Acta Biomater. 2005, 1, 387–397.

    Article  Google Scholar 

  39. Matson, J. B.; Newcomb, C. J.; Bitton, R.; Stupp, S. I. Nanostructure-templated control of drug release from peptide amphiphile nanofiber gels. Soft Matter 2012, 8, 3586–3595.

    Article  Google Scholar 

  40. Cui, H. G.; Muraoka, T.; Cheetham, A. G.; Stupp, S. I. Selfassembly of giant peptide nanobelts. Nano Lett. 2009, 9, 945–951.

    Article  Google Scholar 

  41. Trent, A.; Ulery, B. D.; Black, M. J.; Barrett, J. C.; Liang, S. M.; Kostenko, Y.; David, N. A.; Tirrell, M. V. Peptide amphiphile micelles self-adjuvant group a streptococcal vaccination. AAPS J. 2015, 17, 380–388.

    Article  Google Scholar 

  42. Matsubara, T.; Iijima, K.; Yamamoto, N.; Yanagisawa, K.; Sato, T. Density of GM1 in nanoclusters is a critical factor in the formation of a spherical aßsembly of amyloid ß-protein on synaptic plasma membranes. Langmuir 2013, 29, 2258–2264.

    Article  Google Scholar 

  43. Iijima, K.; Soga, N.; Matsubara, T.; Sato, T. Observations of the distribution of GM3 in membrane microdomains by atomic force microscopy. J. Colloid Interface Sci. 2009, 337, 369–374.

    Article  Google Scholar 

  44. Pakalns, T.; Haverstick, K. L.; Fields, G. B.; McCarthy, J. B.; Mooradian, D. L.; Tirrell, M. Cellular recognition of synthetic peptide amphiphiles in self-assembled monolayer films. Biomaterials 1999, 20, 2265–2279.

    Article  Google Scholar 

  45. Ma, W.; Cheetham, A. G.; Cui, H. G. Building nanostructures with drugs. Nano Today 2016, 11, 13–30.

    Article  Google Scholar 

  46. Gewirtz, D. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem. Pharmacol. 1999, 57, 727–741.

    Article  Google Scholar 

  47. Dreher, M. R.; Raucher, D.; Balu, N.; Colvin Michael, O.; Ludeman, S. M.; Chilkoti, A. Evaluation of an elastin-like polypeptide-doxorubicin conjugate for cancer therapy. J. Control. Release 2003, 91, 31–43.

    Article  Google Scholar 

  48. Furgeson, D. Y.; Dreher, M. R.; Chilkoti, A. Structural optimization of a ‘smart’ doxorubicin–polypeptide conjugate for thermally targeted delivery to solid tumors. J. Control. Release 2006, 110, 362–369.

    Article  Google Scholar 

  49. MacKay, A. J.; Chen, M. N.; McDaniel, J. R.; Liu, W. G.; Simnick, A. J.; Chilkoti, A. Self-assembling chimeric polypeptide–doxorubicin conjugate nanoparticles that abolish tumours after a single injection. Nat. Mater. 2009, 8, 993–999.

    Article  Google Scholar 

  50. Mastria, E. M.; Chen, M. N.; McDaniel, J. R.; Li, X. H.; Hyun, J.; Dewhirst, M. W.; Chilkoti, A. Doxorubicinconjugated polypeptide nanoparticles inhibit metastasis in two murine models of carcinoma. J. Control. Release 2015, 208, 52–58.

    Article  Google Scholar 

  51. Cheng, H.; Zhu, J. Y.; Xu, X. D.; Qiu, W. X.; Lei, Q.; Han, K.; Cheng, Y. J.; Zhang, X. Z. Activable cell-penetrating peptide conjugated prodrug for tumor targeted drug delivery. Appl. Mater. Interfaces 2015, 7, 16061–16069.

    Article  Google Scholar 

  52. Shi, N. Q.; Gao, W.; Xiang, B.; Qi, X. R. Enhancing cellular uptake of activable cellpenetrating peptide–doxorubicin conjugate by enzymatic cleavage. Int. J. Nanomedicine 2012, 7, 1613–1621.

    Google Scholar 

  53. Yang, Y. F.; Yang, Y.; Xie, X. Y.; Cai, X.S.; Zhang, H.; Gong, W.; Wang, Z. Y.; Mei, X. G. PEGylated liposomes with NGR ligand and heat-activable cell penetrating peptidedoxorubicin conjugate for tumor-specific therapy. Biomaterials 2014, 35, 4368–4381.

    Article  Google Scholar 

  54. Liang, J. F.; Yang, V. C. Synthesis of doxorubicin-peptide conjugate with multidrug resistant tumor cell killing activity. Bioorg. Med. Chem. Lett. 2005, 15, 5071–5075.

    Article  Google Scholar 

  55. Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. Plant antitumor agents. VI. Isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J. Am. Chem. Soc. 1971, 93, 2325–2327.

    Article  Google Scholar 

  56. Tian, R.; Wang, H. M.; Niu, R. F.; Ding, D. Drug delivery with nanospherical supramolecular cell penetrating peptidetaxol conjugates containing a high drug loading. J. Colloid Interface Sci. 2015, 453, 15–20.

    Article  Google Scholar 

  57. Dubikovskaya, E. A.; Thorne, S. H.; Pillow, T. H.; Contag, C. H.; Wender, P. A. Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters. Proc. Natl. Acad. Sci. USA 2008, 105, 12128–12133.

    Article  Google Scholar 

  58. Thomas, C. J.; Rahier, N. J.; Hecht, S. M. Camptothecin: Current perspectives. Bioorg. Med. Chem. 2004, 12, 1585–1604.

    Article  Google Scholar 

  59. Choi, H.; Jeena, M. T.; Palanikumar, L.; Jeong, Y.; Park, S.; Lee, E.; Ryu, J. H. The HA-incorporated nanostructure of a peptide–drug amphiphile for targeted anticancer drug delivery. Chem. Commun. 2016, 52, 5637–5640.

    Article  Google Scholar 

  60. Peng, M. Y.; Qin, S. Y.; Jia, H. Z.; Zheng, D. W.; Rong, L.; Zhang, X. Z. Self-delivery of a peptide based prodrug for tumor-targeting therapy. Nano Res. 2015, 9, 663–673.

    Article  Google Scholar 

  61. Ossipov, D. A. Nanostructured hyaluronic acid-based materials for active delivery to cancer. Expert Opinion Drug Deliv. 2010, 7, 681–703.

    Article  Google Scholar 

  62. Fish, R. H.; Jaouen, G. Bioorganometallic chemistry: Structural diversity of organometallic complexes with bioligands and molecular recognition studies of several supramolecular hosts with biomolecules, alkali-metal ions, and organometallic pharmaceuticals. Organometallics 2003, 22, 2166–2177.

    Article  Google Scholar 

  63. Fouda, M. F. R.; Abd-Elzaher, M. M.; Abdelsamaia, R. A.; Labib, A. A. On the medicinal chemistry of ferrocene. Appl. Organomet. Chem. 2007, 21, 613–625.

    Article  Google Scholar 

  64. Adhikari, B.; Singh, C.; Shah, A.; Lough, A. J.; Kraatz, H. B. Amino acid chirality and ferrocene conformation guided self-assembly and gelation of ferrocene-peptide conjugates. Chem.-Eur. J. 2015, 21, 11560–11572.

    Article  Google Scholar 

  65. Miklán, Z.; Szabó, R.; Zsoldos-Mády, V.; Reményi, J.; Bánóczi, Z.; Hudecz, F. New ferrocene containing peptide conjugates: Synthesis and effect on human leukemia (HL-60) cells. Biopolymers 2007, 88, 108–114.

    Article  Google Scholar 

  66. Huang, X.; Brazel, C. S. On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. J. Control. Release 2001, 73, 121–136.

    Article  Google Scholar 

  67. Ma, C. Y.; Yin, G. F.; You, F.; Wei, Y.; Huang, Z. B.; Chen, X. C.; Yan, D. H. A specific cell-penetrating peptide induces apoptosis in SKOV3 cells by down-regulation of Bcl-2. Biotechnol. Lett. 2013, 35, 1791–1797.

    Article  Google Scholar 

  68. Gao, H. L.; Zhang, Q. Y.; Yang, Y. T.; Jiang, X. G.; He, Q. Tumor homing cell penetrating peptide decorated nanoparticles used for enhancing tumor targeting delivery and therapy. Int. J. Pharm. 2015, 478, 240–250.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Micro & Nanomédecines Translationnelles-MINT, UNIV Angers, INSERM U1066, CNRS UMR 6021, UBL Université Bretagne Loire, Angers, F-49933, France

    Léna Guyon, Elise Lepeltier & Catherine Passirani

Authors
  1. Léna Guyon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elise Lepeltier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catherine Passirani
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elise Lepeltier.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guyon, L., Lepeltier, E. & Passirani, C. Self-assembly of peptide-based nanostructures: Synthesis and biological activity. Nano Res. 11, 2315–2335 (2018). https://doi.org/10.1007/s12274-017-1892-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-017-1892-9

Keywords

Search

Navigation