The uptake mechanism of PEGylated DNA polyplexes by the liver influences gene expression

S Khargharia; N J Baumhover; S T Crowley; J Duskey; K G Rice

doi:10.1038/gt.2014.81

Back

The uptake mechanism of PEGylated DNA polyplexes by the liver influences gene expression

Journal article

Open access

Peer reviewed

The uptake mechanism of PEGylated DNA polyplexes by the liver influences gene expression

S Khargharia, N J Baumhover, S T Crowley, J Duskey and K G Rice

Gene therapy, Vol.21(12), pp.1021-1028

12/2014

DOI: 10.1038/gt.2014.81

PMID: 25253445

Files and links (1)

url

https://doi.org/10.1038/gt.2014.81View

Published (Version of record) Open Access

Abstract

Two uptake mechanisms were identified for PEGylated DNA polyplex biodistribution to the liver. At a low polyplex dose, a rapid-uptake mechanism dominates, resulting in 60% capture by liver in 5 min, due to a saturable receptor-mediated process. Rapid-uptake led to the fast metabolism of polyplexes by liver (t1/2 = 2.1 h), correlating with a 1-μg pGL3 polyplex dose losing full transfection competency after 4 h in the liver. Dose escalation of either polyplex or poly(ethylene glycol) (PEG) peptide led to the saturation of rapid-uptake and revealed a delayed-uptake mechanism for polyplexes by liver. Delayed-uptake was characterized by the slower liver accumulation of 40% of the polyplex dose over 40 min, followed by slow metabolism (t1/2 = 15 h) and an extended time (12 h) for a 1-μg pGL3 polyplex dose, remaining fully transfection competent in the liver. The delayed-uptake mechanism is consistent with polyplexes crossing liver fenestrated endothelial cells to reach steady state in the space of Disse. The results describe how to control polyplex biodistribution to liver to avoid rapid-uptake and metabolism, in favor of delayed-uptake, to preserve polyplex transfection competency in the liver for up to 12 h.

Animals

DNA - chemistry

DNA - pharmacokinetics

Endothelial Cells - drug effects

Endothelial Cells - metabolism

Gene Expression

Kupffer Cells - drug effects

Kupffer Cells - metabolism

Liver - drug effects

Liver - metabolism

Mice

Plasmids - genetics

Polyethylene Glycols - chemistry

Polyethylene Glycols - pharmacokinetics

Tissue Distribution

Transfection - methods

Details

Title: Subtitle: The uptake mechanism of PEGylated DNA polyplexes by the liver influences gene expression
Creators: S Khargharia - University of Iowa
N J Baumhover - University of Iowa
S T Crowley - University of Iowa
J Duskey - University of Iowa
K G Rice - University of Iowa
Resource Type: Journal article
Publication Details: Gene therapy, Vol.21(12), pp.1021-1028
DOI: 10.1038/gt.2014.81
PMID: 25253445
NLM abbreviation: Gene Ther
ISSN: 0969-7128
eISSN: 1476-5462
Grant note: T32HL080070 / NHLBI NIH HHS GM097093 / NIGMS NIH HHS T32GM008365 / NIGMS NIH HHS
Language: English
Date published: 12/2014
Academic Unit: Radiology; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Medicinal and Natural Products Chemistry
Record Identifier: 9984366027702771

Metrics

21 Record Views

14 Times Cited - Web of Science