Publication detail

Norepinephrine Transporter-Derived Homing Peptides Enable Rapid Endocytosis of Drug Delivery Nanovehicles into Neuroblastoma Cells

HADDAD, Y. CHAROUSOVÁ, M. ŽIVOTSKÁ, H. ŠPLÍCHAL, Z. MERLOS RODRIGO, M. MICHÁLKOVÁ, H. KŘÍŽKOVÁ, S. TESAŘOVÁ, B. RICHTERA, L. VÍTEK, P. STOKOWA-SOLTYS, K. HYNEK, D. MILOSAVLJEVIĆ, V. REX, S. HEGER, Z.

Original Title

Norepinephrine Transporter-Derived Homing Peptides Enable Rapid Endocytosis of Drug Delivery Nanovehicles into Neuroblastoma Cells

Type

journal article in Web of Science

Language

English

Original Abstract

Background: Currently, the diagnosis and treatment of neuroblastomas-the most frequent solid tumors in children-exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides. Results: The peptides (seq.GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, one unique binding site has marked the sequence and structural similarities of both peptides, while most of the contribution to the interaction was attributed to the electrostatic energy of Asn and Arg (< - 228 kJ/mol). The peptides were comprehensively characterized by computational and spectroscopic methods showing similar to 21% beta-sheets/aggregation for GASNGINAYL and similar to 27% alpha-helix for SLWERLAYGI. After decorating 12-nm ferritin-based nanovehicles with cysteinated peptides, both peptides exhibited high potential for use in actively targeted neuroblastoma nanotherapy with exceptional in vitro biocompatibility and stability, showing minor yet distinct influences of the peptides on the global expression profiles. Upon binding to hNET with fast binding kinetics, GASNGINAYLC peptides enabled rapid endocytosis of ferritins into neuroblastoma cells, leading to apoptosis due to increased selective cytotoxicity of transported payload ellipticine. Peptide-coated nanovehicles significantly showed higher levels of early apoptosis after 6 h than non-coated nanovehicles (11% and 7.3%, respectively). Furthermore, targeting with the GASNGINAYLC peptide led to significantly higher degree of late apoptosis compared to the SLW-ERLAYGIC peptide (9.3% and 4.4%, respectively). These findings were supported by increased formation of reactive oxygen species, down-regulation of survivin and Bcl-2 and up-regulated p53. Conclusion: This novel homing nanovehicle employing GASNGINAYLC peptide was shown to induce rapid endocytosis of ellipticine-loaded ferritins into neuroblastoma cells in selective fashion and with successful payload. Future homing peptide development via lead optimization and functional analysis can pave the way towards efficient peptide-based active delivery of nanomedicines to neuroblastoma cells.

Keywords

Homing peptide; Ferritin; Neuroblastoma; Norepinephrine transporter; Targeted therapy

Authors

HADDAD, Y.; CHAROUSOVÁ, M.; ŽIVOTSKÁ, H.; ŠPLÍCHAL, Z.; MERLOS RODRIGO, M.; MICHÁLKOVÁ, H.; KŘÍŽKOVÁ, S.; TESAŘOVÁ, B.; RICHTERA, L.; VÍTEK, P.; STOKOWA-SOLTYS, K.; HYNEK, D.; MILOSAVLJEVIĆ, V.; REX, S.; HEGER, Z.

Released

13. 7. 2020

Publisher

BioMed Central

ISBN

1477-3155

Periodical

Journal of Nanobiotechnology

Year of study

18

Number

95

State

United Kingdom of Great Britain and Northern Ireland

Pages from

1

Pages to

20

Pages count

20

URL

https://jnanobiotechnology.biomedcentral.com/articles/10.1186/s12951-020-00654-x

Full text in the Digital Library

http://hdl.handle.net/11012/195128

BibTex

@article{BUT164764,
  author="Yazan Abdulmajeed Eyadh {Haddad} and Markéta {Charousová} and Hana {Životská} and Zbyněk {Šplíchal} and Miguel Ángel {Merlos Rodrigo} and Hana {Michálková} and Soňa {Křížková} and Barbora {Tesařová} and Lukáš {Richtera} and Petr {Vítek} and Kamila {Stokowa-Soltys} and David {Hynek} and Vedran {Milosavljević} and Simona {Rex} and Zbyněk {Heger}",
  title="Norepinephrine Transporter-Derived Homing Peptides Enable Rapid Endocytosis of Drug Delivery Nanovehicles into Neuroblastoma Cells",
  journal="Journal of Nanobiotechnology",
  year="2020",
  volume="18",
  number="95",
  pages="1--20",
  doi="10.1186/s12951-020-00654-x",
  issn="1477-3155",
  url="https://jnanobiotechnology.biomedcentral.com/articles/10.1186/s12951-020-00654-x"
}