Dataset Information

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.

SUBMITTER: Ming X

PROVIDER: S-EPMC3810404 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Albumin-based nanoconjugates for targeted delivery of therapeutic oligonucleotides.

Ming Xin X Carver Kyle K Wu Lin L

Biomaterials 20130719 32

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 ...[more]

PMID: 23876758

Similar Datasets

Project description:Synthetic nucleic acids have shown great potential in the treatment of various diseases. Nevertheless, the selective delivery to a target tissue has proved challenging. The coupling of nucleic acids to targeting peptides, proteins, and antibodies has been explored as an approach for their selective tissue delivery. Nevertheless, the preparation of covalently coupled peptides and proteins that can also undergo intracellular release as well as deliver more than one copy of the nucleic acid has proved challenging. Recently, we have developed a novel method for the rapid noncovalent conjugation of nucleic acids to targeting single chain antibodies (scFv) using chemically self-assembled nanostructures (CSANs). CSANs have been prepared by the self-assembly of two dihydrofolate reductase molecules (DHFR(2)) and a targeting scFv in the presence of bis-methotrexate (bis-MTX). The valency of the nanorings can be tuned from one to eight subunits, depending on the length and composition of the linker between the dihydrofolate reductase molecules. To explore their potential for the therapeutic delivery of nucleic acids as well as the ability to expand the capabilities of CSANs by incorporating smaller cyclic targeting peptides, we prepared DHFR(2) proteins fused through a flexible peptide linker to cyclic-RGD, which targets ?v?3 integrins, and a bis-MTX chemical dimerizer linked to an antisense oligonucleotide (bis-MTX-ASO) that has been shown to silence expression of eukaryotic translation initiation factor 4E (eIF4E). Monomeric and multimeric cRGD-CSANs were then prepared with bis-MTX-ASO and shown to undergo endocytosis in the breast cancer cell line, MDA-MB-231, which overexpresses ?v?3. The bis-MTX-ASO was shown to undergo endosomal escape resulting in the knock down of eIF4E with at least the same efficiency as ASO delivered by oligofectamine. The modularity, flexibility, and common method of conjugation may prove to be a useful general approach for the targeted delivery of ASOs, as well as other nucleic acids to cells.

Dataset Information

Albumin-based nanoconjugates for targeted delivery of therapeutic oligonucleotides.

Publications

Albumin-based nanoconjugates for targeted delivery of therapeutic oligonucleotides.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets