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

• Published in: Pharmaceutical research 2001-09, Vol.18 (9), p.1291-1298
• Main Authors: KONING, Gerben A, MORSELT, Henriëtte W. M, GORTER, Arko, ALLEN, Theresa M, ZALIPSKY, Samuel, KAMPS, Jan A. A. M, SCHERPHOF, Gerrit L
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - pharmacokinetics; Antigens; Antigens, Neoplasm - immunology; Antigens, Surface - immunology; Biological and medical sciences; Cholesterol; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Drug Carriers; Drug Delivery Systems; Drug dosages; General pharmacology; Immunoglobulin G - immunology; Incorporation; Kupffer Cells - metabolism; Lipids; Liposomes - pharmacokinetics; Liver; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Medical sciences; Metastasis; Monoclonal antibodies; Pharmaceutical technology. Pharmaceutical industry; Pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Inbred Strains; Target recognition; Tissue Distribution; Toxicity; Tumor Cells, Cultured
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1013085811044

Compare pharmacokinetics of tumor-directed immunoliposomes in healthy and tumor-bearing rats (hepatic colon cancer metastases). A tumor cell-specific monoclonal antibody was attached to polyethyleneglycol-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 were determined using [3H]cholesteryloleylether or bilayer-anchored 5-fluoro[3H]deoxyuridine-dipalmitate ([3H]FUdR-dP) as a marker. In healthy animals clearance of PEG-(immuno)liposomes was almost log-linear and only slightly affected by antibody attachment; in tumor-bearing animals all liposomes displayed biphasic clearance. In normal and tumor animals blood elimination increased with increasing antibody density; particularly 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 accumulation: uptake per gram tumor tissue (2-4% of dose) was similar to that of liver. Remarkably, this applied to tumor-specific and irrelevant antibody. Increased immunoliposome uptake by trypsin-treated Kupffer cells implicated involvement of high-affinity Fc-receptors on activated macrophages. Tumor growth and immunoliposome characteristics (antibody density and orientation) determine immunoliposome pharmacokinetics. Although with a long-circulating immunoliposome formulation, efficiently retaining the prodrug FUdR-dP, we achieved enhanced uptake by hepatic metastases, this was probably not mediated by specific interaction with the tumor cells, but rather by tumor-associated macrophages.