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dc.contributor.author
Bapst, Jean-Philippe
dc.contributor.author
Eberle, Alex N.
dc.date.accessioned
2017-11-13T14:15:43Z
dc.date.available
2017-10-06T02:39:46Z
dc.date.available
2017-11-13T14:15:43Z
dc.date.issued
2017-04-26
dc.identifier.issn
1664-2392
dc.identifier.other
10.3389/fendo.2017.00093
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/190941
dc.identifier.doi
10.3929/ethz-b-000190941
dc.description.abstract
A majority of melanotic and amelanotic melanomas overexpress melanocortin type 1 receptors (MC1Rs) for α-melanocyte-stimulating hormone. Radiolabeled linear or cyclic analogs of α-MSH have a great potential as diagnostic or therapeutic tools for the management of malignant melanoma. Compounds such as [111In]DOTA-NAP-amide exhibit high affinity for the MC1R in vitro, good tumor uptake in vivo, but they may suffer from relatively high kidney uptake and retention in vivo. We have shown previously that the introduction of negative charges into radiolabeled DOTA-NAP-amide peptide analogs may enhance their excretion and reduce kidney retention. To address the question of where to place negative charges within the ligand, we have extended these studies by designing two novel peptides, Ac-Nle-Asp-His-d-Phe-Arg-Trp-Gly-Lys(DOTA)-d-Asp-d-Asp-OH (DOTA-NAP-d-Asp-d-Asp) with three negative charges at the C-terminal end (overall net charge of the molecule −2) and DOTA-Gly-Tyr(P)-Nle-Asp-His-d-Phe-Arg-Trp-NH2 (DOTA-Phospho-MSH2-9) with two negative charges in the N-terminal region (net charge −1). The former peptide showed markedly reduced receptor affinity and biological activity by >10-fold compared to DOTA-NAP-amide as reference compound, and the latter peptide displayed similar bioactivity and receptor affinity as the reference compound. The uptake by melanoma tumor tissue of [111In]DOTA-Phospho-MSH2-9 was 7.33 ± 0.47 %ID/g 4 h after injection, i.e., almost equally high as with [111In]DOTA-NAP-amide. The kidney retention was 2.68 ± 0.18 %ID/g 4 h after injection and hence 44% lower than that of [111In]DOTA-NAP-amide. Over an observation period from 4 to 48 h, the tumor-to-kidney ratio of [111In]DOTA-Phospho-MSH2-9 was 35% more favorable than that of the reference compound. In a comparison of DOTA-NAP-d-Asp-d-Asp, DOTA-Phospho-MSH2-9 and DOTA-NAP-amide with five previously published analogs of DOTA-NAP-amide that altogether cover a range of peptides with an overall net charge between +2 and −2, we now demonstrate that a net charge of −1, with the extra negative charges preferably placed in the N-terminal region, has led to the lowest kidney uptake and retention. Charges of +2 or −2 markedly increased kidney uptake and retention. In conclusion, the novel DOTA-Phospho-MSH2-9 may represent a new lead compound for negatively charged linear MC1R ligands that can be further developed into a clinically relevant melanoma targeting radiopeptide.
en_US
dc.language.iso
en
en_US
dc.publisher
Frontiers Research Foundation
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
tumor targeting
en_US
dc.subject
radiolabeled peptide
en_US
dc.subject
net charge
en_US
dc.subject
phosphopeptide
en_US
dc.subject
melanoma
en_US
dc.subject
alpha-melanocyte-stimulating hormone
en_US
dc.subject
tissue distribution
en_US
dc.subject
kidney toxicity
en_US
dc.title
Receptor-Mediated Melanoma Targeting with Radiolabeled alpha-Melanocyte-Stimulating Hormone: Relevance of the Net Change of the Ligand
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
ethz.journal.title
Frontiers in Endocrinology
ethz.journal.volume
8
en_US
ethz.journal.issue
93
en_US
ethz.journal.abbreviated
Front. endocrinol.
ethz.size
11 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Lausanne
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00030 - Bereich Rektorat / Domain Rectorate::02803 - Collegium Helveticum / Collegium Helveticum
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00003 - Schulleitung und Dienste::00030 - Bereich Rektorat / Domain Rectorate::02803 - Collegium Helveticum / Collegium Helveticum
ethz.date.deposited
2017-10-06T02:40:05Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-11-13T14:15:59Z
ethz.rosetta.lastUpdated
2018-02-01T09:31:57Z
ethz.rosetta.versionExported
true
ethz.COinS
ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.atitle=Receptor-Mediated%20Melanoma%20Targeting%20with%20Radiolabeled%20alpha-Melanocyte-Stimulating%20Hormone:%20Relevance%20of%20the%20Net%20Change%20of%20the%20Ligand&rft.jtitle=Frontiers%20in%20Endocrinology&rft.date=2017-04-26&rft.volume=8&rft.issue=93&rft.issn=1664-2392&rft.au=Bapst,%20Jean-Philippe&Eberle,%20Alex%20N.&rft.genre=article&
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