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Pharmacokinetics of Differently Designed Immunoliposome Formulations in Rats with Or Without Hepatic Colon Cancer Metastases

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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.

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Author notes

  1. Gerben A. Koning

    Present address: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, P.O Box 80082, 3508 TB, Utrecht, The Netherlands

Authors and Affiliations

  1. Department of Cell Biology, Groningen University Institute for Drug Exploration (GUIDE), Netherlands

    Gerben A. Koning, Henriëtte W. M. Morselt, Jan A. A. M. Kamps & Gerrit L. Scherphof

  2. Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    Arko Gorter

  3. Department of Pharmacology, University of Alberta, Edmonton, Canada, T6G 2H7

    Theresa M. Allen

  4. ALZA Corporation, Palo Alto, CA, 94303-0802

    Samuel Zalipsky

  5. Faculty of Medical Sciences, University of Groningen, A. Deusinglaan 1, 9713 AV, Groningen, The Netherlands

    Gerben A. Koning

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Koning, G.A., Morselt, H.W.M., Gorter, A. et al. Pharmacokinetics of Differently Designed Immunoliposome Formulations in Rats with Or Without Hepatic Colon Cancer Metastases. Pharm Res 18, 1291–1298 (2001). https://doi.org/10.1023/A:1013085811044

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