Effects of insulinlike growth factor binding proteins on insulinlike growth factor-I biodistribution in tumor-bearing nude mice

This study evaluated the biodistribution and tumor targeting ability of rad iolabeled insulinlike growth factor (IGF)-1. Because IGF binding proteins ( IGFBPs) play a critical role in modulating IGF activity, the binding proper ties of I-125-labeled IGF-1 to IGFBPs were investigated in vitro and in viv o. Because a large amount of the IGF-1 was catabolized in vivo, we also stu died the catabolism of IGF-1 by tumor cells in vitro. Methods: I-125-labele d-IGF-1 was prepared using the chloramine T method. The biodistribution of I-125-labeled-IGF-1 in tumor-bearing nude mice was compared between groups injected with I-125-labeled IGF-1 alone or coinjected with unlabeled peptid e. in vitro and in vivo chromatography studies were performed to evaluate t he binding profile to IGFBPs and the degree of catabolites in serum as well as urine. Results: Data indicated that the binding of radiolabeled IGF-1 t o IGFBPs in vitro was dose dependent. However, there was a difference in co mplex formation between the serum and the heparinized plasma. In heparinize d plasma, the radioactivity shifted from a 30- to 50-kDa complex to a 150-k Da complex and to a free ligand, because the binding of heparin with IGFBPs decreased its affinity for IGF-1. In plasma prepared with acid citrate dex trose a binding pattern identical to that of serum was observed. Moreover, there was a binding difference between mouse and rat. The I-125-labeled IGF -1 catabolized very quickly when incubated at 37 degrees C but not at all a t 4 degrees C. In tumor-bearing nude mice, the uptake of radioactivity in n ormal tissues decreased quickly, particularly in the kidneys, in mice coinj ected with unlabeled carrier, the radioactivity in most normal tissues was lower and the tumor uptake higher than in the mice without carrier. Conclus ion: These data confirm that I-125-labeled IGF-1 is avidly bound to IGFBPs, both in vitro and in vivo. By partially saturating this binding with unlab eled peptides, a favorable biodistribution was achieved, including faster c learance from normal tissue and higher tumor uptake, which resulted in bett er tumor-to-nontumor ratios. Nevertheless, the rapid catabolism and release of the radiolabel from tumor tissue result in a suboptimal targeting agent .