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 (t 1/2 =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 (t 1/2 =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.

The uptake mechanism of PEGylated DNA polyplexes by the liver influences gene expression / Khargharia, S.; Baumhover, N. J.; Crowley, S. T.; Duskey, J.; Rice, K. G.. - In: GENE THERAPY. - ISSN 0969-7128. - 21:12(2014), pp. 1021-1028. [10.1038/gt.2014.81]

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

Duskey J.;
2014

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 (t 1/2 =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 (t 1/2 =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.
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12
1021
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The uptake mechanism of PEGylated DNA polyplexes by the liver influences gene expression / Khargharia, S.; Baumhover, N. J.; Crowley, S. T.; Duskey, J.; Rice, K. G.. - In: GENE THERAPY. - ISSN 0969-7128. - 21:12(2014), pp. 1021-1028. [10.1038/gt.2014.81]
Khargharia, S.; Baumhover, N. J.; Crowley, S. T.; Duskey, J.; Rice, K. G.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1205665
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