TY  - JOUR
AU  - Järveläinen, Harri A
AU  - Schmithals, Christian
AU  - von Harten, Maike
AU  - Kakoschky, Bianca
AU  - Vogl, Thomas J
AU  - Harris, Stephen
AU  - Henson, Claire
AU  - Bullen-Clerkson, Gemma
AU  - Piiper, Albrecht
TI  - Assessment of the Pharmacokinetics, Disposition, and Duration of Action of the Tumour-Targeting Peptide CEND-1.
JO  - International journal of molecular sciences
VL  - 24
IS  - 6
SN  - 1422-0067
CY  - Basel
PB  - Molecular Diversity Preservation International
M1  - DKFZ-2023-00638
SP  - 5700
PY  - 2023
AB  - 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.
KW  - CEND-1 (Other)
KW  - LSTA1 (Other)
KW  - certepetide (Other)
KW  - iRGD peptide (Other)
KW  - pharmacokinetics (Other)
KW  - quantitative radioactivity analysis (QRA) (Other)
KW  - quantitative whole-body autoradiography (QWBA) (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36982773
DO  - DOI:10.3390/ijms24065700
UR  - https://inrepo02.dkfz.de/record/274561
ER  -