THE EFFECT OF CHARGE ON THE BIODISTRIBUTION IN MICE OF BRANCHED POLYPEPTIDES WITH A POLY(L-LYSINE) BACKBONE LABELED WITH I-125, IN-111 OR CR-51

The biodistribution has been assessed in mice of synthetic branched po lypeptides. These were: A poly(L-lysine) backbone with short side chai ns of three DL-alanine residues (AK, which is polycationic); AK with a n additional glutamic acid residue at the end of the branches (EAK, wh ich is amphoteric); EAK whose terminal glutamic acid amino groups had been acetylated (Ac-EAK, which is polyanionic) or succinylated (Suc-EA K, which is highly polyanionic). Each was labelled with gamma emitting radionuclides suitable for use in biodistribution studies (I-125 and Cr-51) or for gamma scintigraphy (In-111). Regardless of the radiolabe l, both EAK and Ac-EAK showed prolonged survival in the blood over a f our hour observation period, while polycationic AK or highly polyanion ic Suc-EAK were rapidly cleared. There were great differences in organ retention of the different radionuclides from any one polypeptide. Wi th AK there were much higher levels of Cr-51 than of In-111 or I-125 i n spleen, liver and lung. With EAK, there were higher levels of Cr-51 than of In-111 or I-125 in liver and spleen, but higher levels of In-1 11 than of Cr-51 or I-125 in kidney. The pattern was similar with Ac-E AK, bur the high kidney level of In-111 seen with EAK was not present. With Suc-EAK, biodistribution of In-111 and Cr-51 were virtually iden tical with very high levels in spleen and liver, which were not seen w ith I-125. This study has shown that only amphoteric or mildly anionic polypeptides survive well in the circulation. Cationic or highly anio nic polypeptides survive poorly, but have different sites of clearance , the former going particularly to spleen, kidney, liver and lung, the latter particularly to spleen and liver. However the apparent site of clearance depends upon the labelling radionuclide. Presumably, this r eflects the handling within organs of the particular radioelement and/ or (in the case of radiometals) the amino acids to which its chelating DTPA was covalently linked.