title: Uptake of branched polypeptides with poly[L-lys] backbone by bone-marrow culture-derived murine macrophages: the role of the class a scavenger receptor.
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 poly[Lys(Succ-Glu(1.0)-dl-Ala(3.8))] (SuccEAK) with high charge density translocated more efficiently than poly[Lys(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.
authors.affiliation: Research Group of Peptide Chemistry at Eötvös L. University, Hungarian Academy of Sciences, Budapest 112, POB 32, H-1518 Hungary.
authors.forename: Rita
authors.initials: R
authors.lastname: Szabó
authors.forename: Leanne
authors.initials: L
authors.lastname: Peiser
authors.forename: Annette
authors.initials: A
authors.lastname: Plüddemann
authors.forename: Szilvia
authors.initials: S
authors.lastname: Bösze
authors.forename: Sigrid
authors.initials: S
authors.lastname: Heinsbroek
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
authors.forename: Ferenc
authors.initials: F
authors.lastname: Hudecz
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002463:Cell Membrane Permeability; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics; D011107:Polylysine / Q000737:chemistry / Q000493:pharmacokinetics*; D051117:Scavenger Receptors, Class A / Q000172:deficiency / Q000502:physiology*
chemical_list: D010455:Peptides; D051117:Scavenger Receptors, Class A; D011107:Polylysine