Uptake of of branched polypeptides with poly[L-Lys] backbone by bone-marrow derived murine macrophages: The role of the class A scavenger

Szabó, Rita and Peiser, Leanne and Plüddemann, Annette and Bősze, Szilvia and Heinsbroek, Sigrid and Gordon, Siamon and Hudecz, Ferenc (2005) Uptake of of branched polypeptides with poly[L-Lys] backbone by bone-marrow derived murine macrophages: The role of the class A scavenger. Bioconjugate Chemistry, 16. pp. 1442-1450. ISSN 1043-1802 (print), 1520-4812 (online)

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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 (BMM\phi) 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 poly[Lys(Succ-Glu1.0-DL-Ala3.8)] (SuccEAK) with high charge density translocated more efficiently than poly[Lys(Ac-Glu1.0-DL-Ala3.8)] (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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