Pharmacokinetics of differently designed immunoliposome formulations in rats with or without hepatic colon cancer metastases

Purpose. Compare pharmacokinetics of tumor-directed immunoliposomes in heal thy and tumor-bearing rats (hepatic colon. cancer metastases). Methods. A tumor cell-specific monoclonal antibody was attached to polyethy leneglycol-stabilized liposomes, either in a random orientation via a lipid anchor (MPB-PEG-liposomes) or uniformly oriented at the distal end of the PEG chains (Hz-PEG-liposomes). Pharmacokinetics and tissue distribution wer e determined using [H-3]cholesteryloleylether or bilayer-anchored 5-fluoro[ H-3]deoxyuridinedipalmitate ([H-3]FUdR-dP) as a marker. Results. In healthy animals clearance of PEG -(immuno)liposomes was almost log-linear and only slightly affected by antibody attachment; in tumor-bear ing animals all liposomes displayed biphasic clearance. In normal and tumor animals blood elimination increased with increasing antibody density; part icularly for the Hz-PEG-liposomes, and was accompanied by increased hepatic uptake, probably due to increased numbers of macrophages induced by tumor growth. The presence of antibodies on the liposomes enhanced tumor accumula tion: uptake per gram tumor tissue (2-4% of dose) was similar to that of li ver, Remarkably, this applied to tumor-specific and irrelevant antibody. In creased immunoliposome uptake by trypsin-treated Kupffer cells implicated i nvolvement of high-affinity Fc-receptors on activated macrophages. Conclusions. Tumor growth and immunoliposome characteristics (antibody dens ity and orientation) determine immunoliposome pharmacokinetics. Although wi th a long-circulating immunoliposome formulation, efficiently retaining the prodrug FUdR-dP, we achieved enhanced uptake by hepatic metastases, this w as probably not mediated by specific interaction with the tumor cells, but rather by tumor-associated macrophages.