| Autor: |
Koning, GA, Morselt, HWM, Gorter, A, Allen, TM, Zalipsky, S, Kamps, JAAM, Scherphof, GL |
| Přispěvatelé: |
Groningen University Institute for Drug Exploration (GUIDE), Nanotechnology and Biophysics in Medicine (NANOBIOMED), Vascular Ageing Programme (VAP) |
| Jazyk: |
angličtina |
| Rok vydání: |
2001 |
| Předmět: |
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| Zdroj: |
Pharmaceutical Research, 18(9), 1291-1298. SPRINGER/PLENUM PUBLISHERS |
| ISSN: |
0724-8741 |
| Popis: |
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 [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-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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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