SiRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA

Jonathan E. Zuckerman, Aaron Gale, Peiwen Wu, Rong Ma, Mark E. Davis

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs.

Original languageEnglish
Pages (from-to)53-64
Number of pages12
JournalNucleic Acid Therapeutics
Volume25
Issue number2
DOIs
StatePublished - 1 Apr 2015

Fingerprint

Glomerular Mesangium
Cyclodextrins
Nanoparticles
Small Interfering RNA
Cytidine Diphosphate
Chronic Renal Insufficiency
Kidney Glomerulus
Mesangial Cells
Gene Silencing
Therapeutics
Transferrin
Mannose
Intravenous Injections
Genes
Tissue

Cite this

Zuckerman, Jonathan E. ; Gale, Aaron ; Wu, Peiwen ; Ma, Rong ; Davis, Mark E. / SiRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA. In: Nucleic Acid Therapeutics. 2015 ; Vol. 25, No. 2. pp. 53-64.
@article{c993fb472b1a48cc892a92ab162f03bc,
title = "SiRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA",
abstract = "There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs.",
author = "Zuckerman, {Jonathan E.} and Aaron Gale and Peiwen Wu and Rong Ma and Davis, {Mark E.}",
year = "2015",
month = "4",
day = "1",
doi = "10.1089/nat.2014.0505",
language = "English",
volume = "25",
pages = "53--64",
journal = "Nucleic Acid Therapeutics",
issn = "2159-3337",
publisher = "Mary Ann Liebert Inc.",
number = "2",

}

SiRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA. / Zuckerman, Jonathan E.; Gale, Aaron; Wu, Peiwen; Ma, Rong; Davis, Mark E.

In: Nucleic Acid Therapeutics, Vol. 25, No. 2, 01.04.2015, p. 53-64.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - SiRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA

AU - Zuckerman, Jonathan E.

AU - Gale, Aaron

AU - Wu, Peiwen

AU - Ma, Rong

AU - Davis, Mark E.

PY - 2015/4/1

Y1 - 2015/4/1

N2 - There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs.

AB - There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs.

UR - http://www.scopus.com/inward/record.url?scp=84961301013&partnerID=8YFLogxK

U2 - 10.1089/nat.2014.0505

DO - 10.1089/nat.2014.0505

M3 - Article

VL - 25

SP - 53

EP - 64

JO - Nucleic Acid Therapeutics

JF - Nucleic Acid Therapeutics

SN - 2159-3337

IS - 2

ER -