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.

Tumour-specific activation of a tumour-blood transport improves the diagnostic accuracy of blood tumour markers in mice

“… 21 It revealed favourable pharmacokinetics in humans and no signs of toxicity of iRGD as a monotherapy and in combination with nabpaclitaxel and gemcitabine and suggests that the use of iRGD led to an improved anti-tumour activity in these patients. 50 , 51 , 52 Further clinical trials in patients with pancreatic cancer and other tumour entities are underway to test whether iRGD can improve the efficacy of standard therapy in this and other tumour entities.…”

Advance in Targeted Cancer Therapy and Mechanisms of Resistance

“…Kang et al invented a superparamagnetic iron oxide nanocage, which realized targeted gene therapy based on tumor-specific siRNA and was used to treat osteosarcoma in vivo [18]. Piiper's group demonstrated that a bifunctional cyclic peptide, CEND-1, shows high tumor selectivity and duration in preclinical tumor models of liver cancer and breast cancer in vivo [19], which may provide a tumor-specific delivery system for anticancer drugs. In another study, it was reported that a virus-free gene therapy system can specifically release genetic modifiers in solid tumors without affecting normal tissues in mice, representing an advanced system for applying gene therapy to cancer patients [20].…”