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

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dc.contributor.authorHaddad, Yazan Abdulmajeed Eyadhcs
dc.contributor.authorCharousová, Markétacs
dc.contributor.authorŽivotská, Hanacs
dc.contributor.authorŠplíchal, Zbyněkcs
dc.contributor.authorMerlos Rodrigo, Miguel Ángelcs
dc.contributor.authorMichálková, Hanacs
dc.contributor.authorKřížková, Soňacs
dc.contributor.authorTesařová, Barboracs
dc.contributor.authorRichtera, Lukášcs
dc.contributor.authorVítek, Petrcs
dc.contributor.authorStokowa-Soltys, Kamilacs
dc.contributor.authorHynek, Davidcs
dc.contributor.authorMilosavljević, Vedrancs
dc.contributor.authorRex, Simonacs
dc.contributor.authorHeger, Zbyněkcs
dc.coverage.issue95cs
dc.coverage.volume18cs
dc.date.issued2020-07-13cs
dc.description.abstractBackground: 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.en
dc.formattextcs
dc.format.extent1-20cs
dc.format.mimetypeapplication/pdfcs
dc.identifier.citationJournal of Nanobiotechnology. 2020, vol. 18, issue 95, p. 1-20.en
dc.identifier.doi10.1186/s12951-020-00654-xcs
dc.identifier.issn1477-3155cs
dc.identifier.orcid0000-0002-7844-4336cs
dc.identifier.orcid0000-0001-9027-4002cs
dc.identifier.orcid0000-0003-4900-0020cs
dc.identifier.orcid0000-0002-0479-8369cs
dc.identifier.orcid0000-0002-8288-3999cs
dc.identifier.orcid0000-0002-7318-6470cs
dc.identifier.orcid0000-0003-4122-0694cs
dc.identifier.orcid0000-0002-3915-7270cs
dc.identifier.other164764cs
dc.identifier.researcheridJ-2985-2015cs
dc.identifier.researcheridH-2894-2018cs
dc.identifier.researcheridE-9617-2012cs
dc.identifier.researcheridN-9991-2014cs
dc.identifier.researcheridE-5702-2012cs
dc.identifier.researcheridP-3551-2018cs
dc.identifier.researcheridD-1973-2013cs
dc.identifier.scopus36070488100cs
dc.identifier.scopus12040049600cs
dc.identifier.scopus56115133500cs
dc.identifier.urihttp://hdl.handle.net/11012/195128
dc.language.isoencs
dc.publisherBioMed Centralcs
dc.relation.ispartofJournal of Nanobiotechnologycs
dc.relation.urihttps://jnanobiotechnology.biomedcentral.com/articles/10.1186/s12951-020-00654-xcs
dc.rightsCreative Commons Attribution 4.0 Internationalcs
dc.rights.accessopenAccesscs
dc.rights.sherpahttp://www.sherpa.ac.uk/romeo/issn/1477-3155/cs
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/cs
dc.subjectHoming peptideen
dc.subjectFerritinen
dc.subjectNeuroblastomaen
dc.subjectNorepinephrine transporteren
dc.subjectTargeted therapyen
dc.titleNorepinephrine Transporter-Derived Homing Peptides Enable Rapid Endocytosis of Drug Delivery Nanovehicles into Neuroblastoma Cellsen
dc.type.driverarticleen
dc.type.statusPeer-revieweden
dc.type.versionpublishedVersionen
sync.item.dbidVAV-164764en
sync.item.dbtypeVAVen
sync.item.insts2025.02.03 15:49:59en
sync.item.modts2025.01.17 16:39:59en
thesis.grantorVysoké učení technické v Brně. Středoevropský technologický institut VUT. Chytré nanonástrojecs
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