Uptake of branched polypeptides with poly[L-lys] backbone by bone-marrow culture-derived murine macrophages: the role of the class a scavenger receptor.
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.
Szabó
Rita
R
Research Group of Peptide Chemistry at Eötvös L. University, Hungarian Academy of Sciences, Budapest 112, POB 32, H-1518 Hungary.
Peiser
Leanne
L
Plüddemann
Annette
A
Bösze
Szilvia
S
Heinsbroek
Sigrid
S
Gordon
Siamon
S
Hudecz
Ferenc
F
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*
D010455:Peptides; D051117:Scavenger Receptors, Class A; D011107:Polylysine