Apolipoprotein A-I coating of protamine-oligonucleotide nanoparticles increases particle uptake and transcytosis in an in vitro model of the blood-brain barrier.
Drug delivery to the brain is severely restricted by formation of tight junctions between adjacent brain capillary endothelial cells (BCEC). In the present study we have evaluated the effects of protamine-oligonucleotide nanoparticles (proticles) on the functional properties of primary porcine BCEC and characterized uptake and transcytosis of proticles by these cells. Proticles had no adverse effects on BCEC properties relevant to blood-brain barrier (BBB) function. Transcytosis of (125)I-labeled proticles across polarized BCEC cultures occurred in a time- and concentration-dependent manner. As apolipoproteins were suggested to enhance cellular proticle uptake, proticle coating was performed with apoA-I, the major apolipoprotein component of high density lipoproteins. Adsorption of apoA-I on the surface of proticles resulted in significantly improved uptake and transcytosis properties as compared to uncoated proticles. ApoA-I coating enhanced proticle delivery to astrocytes in an in vitro model of the BBB almost twofold. Blocking of scavenger receptor class B, type I (the prime receptor for high density lipoprotein/apoA-I that is expressed on BCEC) reduced transcytosis of apoA-I-coated proticles to levels observed for uncoated proticles. Our data indicate that apoA-I-coating of proticles could be a feasible targeting technology to improve delivery across the BBB.
Kratzer
Ingrid
I
Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria.
Wernig
Karin
K
Panzenboeck
Ute
U
Bernhart
Eva
E
Reicher
Helga
H
Wronski
Robert
R
Windisch
Manfred
M
Hammer
Astrid
A
Malle
Ernst
E
Zimmer
Andreas
A
Sattler
Wolfgang
W
D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000166:cytology; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000302:isolation & purification; D053758:Nanoparticles; D009841:Oligonucleotides / Q000494:pharmacology*; D010316:Particle Size; D011479:Protamines / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013552:Swine; D013778:Tetrazolium Salts; D013844:Thiazoles
D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D009841:Oligonucleotides; D011479:Protamines; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue