BACKGROUND: The side effects of cyclosporine (CsA)-including nephrotoxicity and abnormal differentiation of thymocytes developing in the thymus-can be decreased or even avoided using targeted conjugates of CsA, where both targeting moiety and drug are bound to water-soluble polymeric carrier based on N-(2-hydroxypropyl) methacrylamide (HPMA). METHODS: Irradiated, syngeneic bone marrow transplanted-mice (BALB/c and A/Ph) were treated intraperitoneally for 4 weeks with 20 mg/kg of free CsA, HPMA-conjugated CsA, or antibody-targeted HPMA-bound CsA. Immunohistology of the thymus was performed together with two-color flow cytometry to detect the effect of different forms of CsA on individual thymocyte subpopulations. RESULTS: . We have shown that free CsA strongly abrogated T-cell development. The appearance of mature thymocytes expressing CD3(high) is almost completely inhibited (1.8%) after free CsA treatment, whereas these cells are well detectable in controls (22%) and HPMA polymer-bound CsA-treated animals (19%). Immunohistological studies have shown acellular rests of the medulla after free CsA treatment, whereas well-stained medullary thymocytes were detected in controls and after exposure to antibody-targeted HPMA. conjugated CsA. CONCLUSIONS: HPMA-conjugates of CsA are generally more specific in their targeting to T lymphocytes. It was found that nonspecific binding of CsA to erythrocytes and plasma lipoproteins is significantly reduced using anti-CD3 targeted, HPMA polymer-bound CsA In addition, the entry of these macromolecules into the thymus is limited-probably due to the blood-thymus barrier-and HPMA conjugates of CsA, unlike free drug, do not abrogate T-cell development in bone marrow transplanted mice.

Institute of Microbiology Academy of Sciences of the Czech Republic Department of Immunology and Gnotobiology Prague

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