Assessment of the Pharmacokinetics, Disposition, and Duration of Action of the Tumour-Targeting Peptide CEND-1.

Abstract

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.

• Authors: Harri A Järveläinen, Christian Schmithals, Maike von Harten, Bianca Kakoschky, Thomas J Vogl, Stephen Harris, Claire Henson, Gemma Bullen-Clerkson, Albrecht Piiper
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 6 (Mar 16 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36982773 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Peptides

Topics

• Rats
• Mice
• Animals
• Dogs
• Carcinoma, Hepatocellular
• Liver Neoplasms
• Antineoplastic Agents
• Infusions, Intravenous
• Peptides
• Tumor Microenvironment