Pharmacokinetics of differently designed immunoliposome formulations in rats with or without hepatic colon cancer metastases.
OBJECTIVE
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.
Koning
G A
GA
Department of Cell Biology, Groningen University Institute for Drug Exploration, Faculty of Medical Sciences, University of Groningen, The Netherlands.
Morselt
H W
HW
Gorter
A
A
Allen
T M
TM
Zalipsky
S
S
Kamps
J A
JA
Scherphof
G L
GL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D000951:Antigens, Neoplasm / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D007074:Immunoglobulin G / Q000276:immunology; D007728:Kupffer Cells / Q000378:metabolism; D008081:Liposomes / Q000493:pharmacokinetics*; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D004337:Drug Carriers; D007074:Immunoglobulin G; D008081:Liposomes