Assessment of the pharmacokinetics, disposition, and duration of action of the tumour-targeting peptide CEND-1

  • CEND-1 (iRGD) is a bifunctional cyclic peptide that can modulate the solid tumour microenvironment, enhancing the delivery and therapeutic index of co-administered anti-cancer agents. This study explored CEND-1’s pharmacokinetic (PK) properties pre-clinically and clinically, and assessed CEND-1 distribution, tumour selectivity and duration of action in pre-clinical tumour models. Its PK properties were assessed after intravenous infusion of CEND-1 at various doses in animals (mice, rats, dogs and monkeys) and patients with metastatic pancreatic cancer. To assess tissue disposition, [3H]-CEND-1 radioligand was administered intravenously to mice bearing orthotopic 4T1 mammary carcinoma, followed by tissue measurement using quantitative whole-body autoradiography or quantitative radioactivity analysis. The duration of the tumour-penetrating effect of CEND-1 was evaluated by assessing tumour accumulation of Evans blue and gadolinium-based contrast agents in hepatocellular carcinoma (HCC) mouse models. The plasma half-life was approximately 25 min in mice and 2 h in patients following intravenous administration of CEND-1. [3H]-CEND-1 localised to the tumour and several healthy tissues shortly after administration but was cleared from most healthy tissues by 3 h. Despite the rapid systemic clearance, tumours retained significant [3H]-CEND-1 several hours post-administration. In mice with HCC, the tumour penetration activity remained elevated for at least 24 h after the injection of a single dose of CEND-1. These results indicate a favourable in vivo PK profile of CEND-1 and a specific and sustained tumour homing and tumour penetrability. Taken together, these data suggest that even single injections of CEND-1 may elicit long-lasting tumour PK improvements for co-administered anti-cancer agents.

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Author:Harri A. JärveläinenORCiD, Jens Christian Johannes SchmithalsGND, Maike von HartenGND, Bianca KakoschkyGND, Thomas J. VoglORCiDGND, Stephen HarrisORCiD, Claire Henson, Gemma Bullen-Clerkson, Albrecht PiiperORCiD
URN:urn:nbn:de:hebis:30:3-868534
DOI:https://doi.org/10.3390/ijms24065700
ISSN:1422-0067
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Document Type:Article
Language:English
Date of Publication (online):2023/03/16
Date of first Publication:2023/03/16
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2024/09/18
Tag:CEND-1; LSTA1; certepetide; iRGD peptide; pharmacokinetics; quantitative radioactivity analysis (QRA); quantitative whole-body autoradiography (QWBA)
Volume:24
Issue:6, art. 5700
Article Number:5700
Page Number:17
First Page:1
Last Page:17
Note:
Funding: Cend Therapeutics, Inc.
Note:
Funding: DrugCendR Australia Pty Ltd.
Note:
Funding: Deutsche Krebshilfe ; 7011950
Note:
Gefördert durch den Open-Access-Publikationsfonds der Goethe-Universität.
HeBIS-PPN:523176767
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - CC BY - Namensnennung 4.0 International