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Albumin-based nanoconjugates for targeted delivery of therapeutic oligonucleotides

Paper ID Volume ID Publish Year Pages File Format Full-Text
6385 488 2013 11 PDF Available
Title
Albumin-based nanoconjugates for targeted delivery of therapeutic oligonucleotides
Abstract

Nanoparticle-based delivery has become an important strategy to advance siRNA and antisense oligonucleotides into clinical reality. However, limited biodistribution of nanoparticles and the toxicity of some nanocarriers restrict the wider application of this strategy. To address these issues we aimed to construct oligonucleotide delivery systems which are non-cytotoxic and smaller than typical nanoparticles. Thus, a morpholino oligonucleotide was conjugated to a tumor-targeting RGD peptide, and then, multiple RGD-oligo conjugates were linked to a single molecule of human serum albumin via a reductively responsive linkage. The resultant nanoconjugates showed uniform and monodispersed size distribution with a diameter of 13 nm. A single nanoconjugate molecule contains 15 oligonucleotides as well as 15 targeting ligands on the surface of albumin. The nanoparticle demonstrated 61-fold enhancement in receptor-specific cellular delivery of oligonucleotides in integrin-expressing tumor cells compared to the non-targeted control nanoconjugates and were able to robustly enhance functional activity of the oligonucleotide at low nanomolar concentrations without causing cytotoxicity. Due to their small size, the targeted nanoconjugates could penetrate deeply and distribute throughout 3-D tumor spheroids, whereas the conventional nanoparticles with sizes over 300 nm could only deliver to the cells on the surface of the tumor spheroids. As a result of their greater cellular delivery, smaller size, and lack of cytotoxicity compared to conventional nanoparticles, the multivalent nanoconjugates may provide an effective tool for targeting oligonucleotides to tumors and other diseased tissues.

Keywords
Targeted delivery; Therapeutic oligonucleotides; Albumin; Conjugation
First Page Preview
Albumin-based nanoconjugates for targeted delivery of therapeutic oligonucleotides
Publisher
Database: Elsevier - ScienceDirect
Journal: Biomaterials - Volume 34, Issue 32, October 2013, Pages 7939–7949
Authors
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Subjects
Physical Sciences and Engineering Chemical Engineering Bioengineering