Uptake of branched polypeptides with poly[L-lys] backbone by bone-marrow culture-derived murine macrophages: the role of the class a scavenger receptor |
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Authors: | Szabó Rita Peiser Leanne Plüddemann Annette Bösze Szilvia Heinsbroek Sigrid Gordon Siamon Hudecz Ferenc |
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Institution: | Research Group of Peptide Chemistry at E?tv?s L. University, Hungarian Academy of Sciences, Budapest 112, POB 32, H-1518 Hungary. |
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Abstract: | Selective delivery of antiparasitic or antibacterial drugs into infected macrophages could be a promising approach for improved therapies. Methotrexate conjugate with branched chain polypeptides exhibited pronounced anti-Leishmania activity in vitro and in vivo as reported here earlier. To identify structural requirements for efficient uptake of branched polypeptides, we have studied murine bone marrow culture-derived macrophages (BMMphi) from 129/ICR mice. We report on the translocation characteristics of structurally closely related compounds labeled with 5(6)-carboxyfluorescein. We found that this process is dependent on experimental conditions (e.g. polypeptide concentration, incubation time, and temperature). Using specific inhibitors as well as macrophages from wild-type and class-A scavenger receptor knockout (SR-A -/-) mice, we demonstrated that SR-A was involved in the endocytosis of some polypeptides depending on their charge. Uptake could be blocked by unlabeled polypeptide, by SR-A inhibitors, and by specific anti-SR-A monoclonal antibody. The polyanionic polypeptide polyLys(Succ-Glu(1.0)-dl-Ala(3.8))] (SuccEAK) with high charge density translocated more efficiently than polyLys(Ac-Glu(1.0)-dl-Ala(3.8))] (AcEAK), which had a lower anionic charge density. On the basis of experimental data presented, SuccEAK can be considered as a potential candidate for the design of a macromolecular carrier for specific drug delivery of bioactive entities into macrophages via SR-A. |
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