Uptake of hyaluronan in hepatic metastases after blocking of liver endothelial cell receptors

To follow the biodistribution of exogenous hyaluronan in tumor-bearing anim als, a total of seventeen inbred rats with hepatic metastases from a coloni c adenocarcinoma received I-125-labelled hyaluronan by intravenous injectio ns. Group I received only labeled hyaluronan (25 mu g), whereas group II re ceived 2.5 mg chondroitin sulphate prior to labeled hyaluronan, to block re ceptor uptake in normal liver endothelial cells. Animals in group III recei ved intravenous, as well as intraperitoneal chondroitin sulphate (2.5 mg), to see if a better and prolonged blocking could be achieved. Radioactivity was visualized by whole body autoradiography, using phosphorimaging and the average radioactivity determined as phosphoimaging density units of the to tal area of hepatic metastases, normal liver, and skeletal muscle by comput er-based image analysis. At 5 h, tumors in groups II and III showed higher uptake (4.8 +/- 1.8, P = .01 and 3.6 +/- 1.1, P = .01, respectively), in co mparison to group I (1.8 +/- 0.6), and the mean normal liver/tumor concentr ation ratio was reduced from 21.4 +/- 10.1 in group I to 5.7 +/- 2.7 in gro up II and 3.5 +/- 1.1 in group III (P = .008 and P = .01, respectively). Our study shows that hyaluronan targets liver metastases of a colon adenoca rcinoma. Furthermore, chondroitin sulphate pretreatment increases tumor upt ake, while uptake at normal receptor sites is significantly reduced. The re sults also suggest that after blocking of normal hyaluronan/chondroitin sul phate receptors in healthy tissue, hyaluronan may be used to deliver drugs to specific hyaluronan receptor-positive sites of pathology.