Journal
JOURNAL OF CONTROLLED RELEASE
Volume 96, Issue 3, Pages 497-507Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2004.02.020
Keywords
nanoparticles; antisense oligonucleotides; HIV-1; protamine; intracellular processing
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Membrane transport of antisense oligonucleotides (AS-ODN) is an inefficient process which requires special carriers for their intracellular delivery. We have developed a delivery system for AS-ODN and their phosphorothioate analogues (AS-PTO) directed against human immunodeficiency virus type I (HIV-1) tat mRNA for efficient transfection of HIV-1 target cells. Protamine was used to complex AS-ODN and AS-PTO to form nanoparticles with diameters of about 180 nm and surface charges in the range of -18 to +30 mV. Cellular uptake of these nanoparticles was significantly enhanced compared to naked oligonucleotides. A double labeling technique with fluorescently tagged prolamine and AS-ODN was used to follow the intracellular fate of the nanoparticles. Protamine/AS-ODN nanoparticles showed release of the antisense compound leading to specific inhibition of tat mediated HIV-1 transactivation. In contrast, protamine/AS-PTO complexes were stable over 72 h, and failed to release AS-PTO. These results demonstrate that protamine/AS-ODN nanoparticles are useful for future therapeutical application to inhibit viral gene expression. (C) 2004 Elsevier B.V. All rights reserved.
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