Preclinical evaluation of radiolabelled nimotuzumab, a promising monoclonal antibody targeting the epidermal growth factor receptor.

BACKGROUND: Radiolabelled monoclonal antibodies with affinity towards tumour-associated antigens may enhance the efficacy of cancer treatment with targeted radiotherapy. The humanized antibody nimotuzumab represents a promising vector to deliver radioactivity to tumours overexpressing epidermal growth factor receptor type 1 (ErbB1). We analysed the effect of radiolabelling nimotuzumab on its uptake in cancer cells and its biodistribution profile in preclinical experiments. METHODS: Nimotuzumab was labelled with (131) I by oxidative iodination and with (177) Lu using nimotuzumab conjugates with two different chelators (DTPA and DOTA) and two different spacers (p-SCN-Bn and NHS). For the receptor studies, two cell lines (HaCaT and A431) were used. Biodistribution studies were performed in male Wistar rats. RESULTS: The choice of radiolabel and the manner of its attachment to nimotuzumab had little effect on the internalization of the antibody into ErbB1-expressing cell lines. However, the type of radiolabel, the way in which it was attached to nimotuzumab and the radiolabelling procedure, significantly affected the blood clearance, liver uptake and liver persistence of radiolabelled nimotuzumab. (131) I-nimotuzumab had the longest elimination half-life and the lowest radioactivity uptake in the liver. (177) Lu-labelled nimotuzumab exhibited a shorter elimination half-life, high radioactivity and long-term retention in the liver.

Preclinical pharmacokinetics of radiolabelled hyaluronan.

BACKGROUND: Hyaluronan (HYA) is a high molecular weight glucosaminoglycan with a great perspective for medical applications. Because HYA is widespread in the body, it is difficult to determine the fate of exogenously administered HYA. METHODS: In this study, HYAof different molecular weights (0.1-1 MDa) was labelled with (99m)Tc, and the distribution profiles were determined after administrating the HYA to rats. RESULTS: After the intravenous administration of (99m)Tc-HYA, a rapid decrease in the radioactivity of blood samples was observed, presumably because of (99m)Tc-HYA uptake by the liver; only minimal signs of liver radioactivity washout were detected. After the oral administration of (99m)Tc-HYA, no significant absorption to the central compartment was found. A preliminary study using (14)C-HYA exhibited a different distribution profile than (99m)Tc-HYA because of the different administered dose and the fate of the degradation products. Even with (14)C-HYA, only traces of radioactivity were absorbed after oral administration. CONCLUSION: This paper provides quantitative information regarding the distribution parameters of radiolabelled HYA in preclinical experiments.

Pharmacokinetics of radiolabelled quinlukast in rats.

Pharmacokinetics together with in vivo metabolism and elimination of quinlukast, a potential anti-asthmatic and anti-inflammatory drug, were designed in rats. For this purpose, bile duct cannulated rats and an in situ perfused rat liver preparation were employed. 3H-radiolabelled compound was administered i.v. or loaded to the perfusion medium, respectively. Quinlukast represented the main form of radioactivity determined in plasma; in comparison with the parent drug metabolites were present in lower levels in the systemic circulation. The pharmacokinetic parameters related to the whole animal were calculated from quinlukast rat plasma concentration-time course. The distribution of quinlukast in the body was relatively fast (distribution half-life was approx. 6 min), the elimination half-life exceeded 2h. Binding of quinlukast to rat plasma proteins was very high (approx. 99.7%) and this binding influenced distribution volumes of quinlukast. Both the volume of the central compartment and the volume at a steady state were approx. 115 and 430 ml, respectively. The experiments showed that the biliary clearance was the major route of elimination of this compound from the systemic circulation of rats. In agreement with the determined elimination half-life approx. 42% of the radioactivity was found in the bile, with <0.5% appearing in the urine. The majority of the eliminated radioactivity in the bile was in the form of polar metabolites; only a small part of the parent compound was determined. Two hours after intravenous administration, polar metabolites - but no parent drug - were detected in the urine.