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

Abstract

PURPOSE:

Compare pharmacokinetics of tumor-directed immunoliposomes in healthy and tumor-bearing rats (hepatic colon cancer metastases).

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: G A Koning, H W Morselt, A Gorter, T M Allen, S Zalipsky, J A Kamps, G L Scherphof
• Journal: Pharmaceutical research (Pharm Res) Vol. 18 Issue 9 Pg. 1291-8 (Sep 2001) ISSN: 0724-8741 [Print] United States
• PMID: 11683242 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• Antigens, Surface
• Drug Carriers
• Immunoglobulin G
• Liposomes

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, chemistry, pharmacokinetics)
• Antigens, Neoplasm (immunology)
• Antigens, Surface (immunology)
• Colonic Neoplasms (metabolism, pathology)
• Drug Carriers
• Drug Delivery Systems
• Immunoglobulin G (immunology)
• Kupffer Cells (metabolism)
• Liposomes (pharmacokinetics)
• Liver Neoplasms (metabolism, secondary)
• Rats
• Rats, Inbred Strains
• Tissue Distribution
• Tumor Cells, Cultured