Action of polymeric prodrugs based on N-(2-hydroxypropyl)-methacrylamide copolymers. II. Body distribution and T-cell accumulation of free and polymer-bound [ 125i]daunomycin

Abstract

N-(2-hydroxypropyl)methacrylamide copolymers containing oligopeptide side-chains terminated in [ 125I]daunomycin (DNM), and targeting moieties [anti-Thy 1.2 antibodies or nonspecific rabbit gammaglobulin (RGG)], were synthesized. The body distribution of these copolymers after i.v. administration was studied in vivo in an inbred strain of mice (C57L/J). Covalent binding of [ 125I]DNM to an HPMA copolymer containing anti-Thy 1.2 antibodies increased its level in blood 5–20 times and decreased its rate of elimination compared to the free drug. The maximal organ accumulation of [ 125I]DNM bound to the targetable conjugate in the spleen, thymus and liver was detected after 2 hours. Liver accumulation was observed only when the specific anti-Thy 1.2 antibody was replaced with nonspecific RGG in the conjugates. Similar results were obtained when using i.p. administration of the copolymers studied. The accumulation of HPMA copolymer conjugates in thymocytes was studied in vitro. Intracellular radioactivity of thymocytes cultivated in the presence of [ 125I]DNM-HPMA copolymer conjugates with anti-Thy 1.2 antibodies was maximal after 2 hours while the maximum accumulation of free drug was observed after 1 hour. Comparing HPMA copolymers without targeting moieties, the copolymer with biodegradable oligopeptide side-chains (Gly-Phe-Leu-Gly) demonstrated a higher binding and accumulation of radioactivity in the T cells than the copolymer containing nonbiodegradable sidechains (Gly-Gly). The higher hydrophobicity of the former may contribute to the observed phenomenon.