Biodistribution in tumour-bearing mice of polycationic, amphoteric and polyanionic branched polypeptides with a poly(l-lysine) backbone labelled with125I and111In: Tumour accumulation less than that of labelled serum proteins

Abstract

The biodistribution has been studied in mice with subcutaneously transplanted solid tumours (mammary carcinoma and melanoma) of synthetic branched-chain polypeptides based on poly(L-lysine). The polypeptides were a poly(L-lysine) backbone with side-chains of three DL-alanine residues (AK, which is polycationic), AK with additional glutamic acid residues at the end of the side-chains (EAK, which is amphoteric) and EAK in which the terminal glutamic acid amino groups had been acetylated (AcEAK, which is polyanionic) or succinylated (SucEAK, which is highly polyanionic). Polypeptides were labelled with 125I by reaction with Bolton and Hunter reagent, or with 111In by chelation to diethylenetriaminepentaacetic acid previously conjugated to them. As controls, natural plasma proteins (immunoglobulin G, albumin and transferrin) were similarly labelled. Over a study period of up to 7 days, even with the polypeptides showing most prolonged blood survival (EAK and AcEAK) there was no particular uptake or retention in tumour tissue, over and above what was seen with control plasma proteins and/or in normal tissues. Overall these findings suggest that any enhanced permeability and retention in tumour tissue, reported by other workers with other synthetic macromolecules, operates poorly with the present polypeptides and/or tumours. Specific tumour targeting, for example with monoclonal antibodies, would seem a better option than non-specific accumulation of macromolecules.