Preparation and Characterization of Doxorubicin-Loaded Sterically Stabilized Immunoliposomes |
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Authors: | Emanuel Noam Kedar Eli Bolotin Elijah M. Smorodinsky Nechama I. Barenholz Yechezkel |
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Affiliation: | (1) The Lantenbery Center for General and Tumor Immunology, The Hebrew University, Hadassah Medical School, Jerusalem, 91120, Israel;(2) Department of Biochemistry, The Hebrew University, Hadassah Medical School, Jerusalem, 91120, Israel;(3) Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 69978, Israel |
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Abstract: | Purpose. To compare the performance of sterically stabilized, doxorubicin-loaded liposomes with and without surface attached specific antibodies (D-SSIL and D-SSL, respectively).Methods. Small ( 120 nm) unilamellar liposomes were prepared composed of hydrogenated soy phosphatidylcholine, hydrogenated phosphatidylethanolamine (HPE), cholesterol, and 2000Da polyethylene glycol (2000PEG) attached to the primary amino group of distearoyl phosphatidylethanolamine. Doxorubicin was remote-loaded into these liposomes by an ammonium sulfate gradient to form the D-SSL. Monoclonal IgG3 NI32/2 antibodies directed against a polyoma virus tumor-associated antigen expressed on A9 etc 102 murine fibrosarcoma cells were attached to the D-SSL HPE via a thioether bond to form the D-SSIL-32/2. A control of nonspecific D-SSIL was prepared by attaching nonspecific IgG3-enriched immunoglobulins to D-SSL. All liposomes were physically and chemically characterized and then tested in vitro for tumor cell binding, specificity, and uptake by macrophages; and in vivo for the drug plasma pharmacokinetics after intravenous administration in mice.Results. (i) The attachment of antibodies to D-SSL did not impair their chemical or physical stability and had a minimal effect on their size and level of loaded drug, (ii) The combination of specific antibodies and 2000PEG grafted in the liposomes improved the specific binding to relevant target cells by reducing the level of unspecific binding to nonrelevant cells. (iii) D-SSIL retained the prolonged circulation and slow clearance typical of SSL lacking the antibodies.Conclusions. Sterically stabilized immunoliposomes exhibited stability, ability to recognize target cells, and prolonged circulation time. This study also shows that it is feasible to prepare them in pharmaceutically acceptable dosage form. Thus, further investigation for tumor targeting and efficacy is warranted. |
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Keywords: | sterically stabilized immunoliposomes targeting doxorubicin immunospecificity tumor cells |
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