Transient Depletion of Kupffer Cells Leads to Enhanced Transgene Expression in Rat Liver Following Retrograde Intrabiliary Infusion of Plasmid DNA and DNA Nanoparticles

Abstract

In this report, we have demonstrated that by temporarily removing Kupffer cells (KCs), the transgene expression levels mediated by retrograde intrabiliary infusion (RII) of plasmid DNA, polyethylenimine-DNA, and chitosan nanoparticles were enhanced by 1,927-, 131-, and 23,450-fold, respectively, in comparison with the respective groups without KC removal. KC removal also led to significantly prolonged transgene expression in the liver that received all three carriers. This increased transgene expression was correlated with significantly reduced serum tumor necrosis factor-a level as an indicator for KC activation. These results suggest that KC activation is a significant contributing factor to the lowered transgene expression by polycation-DNA nanoparticles delivered by RII. More importantly, the combination of RII and transient removal of KCs may be adopted as an effective approach to achieving high and persistent transgene expression in the liver mediated by nonviral nanoparticles.

Structure–Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery

“…administration of plasmid DNA and lipoplexes activates the innate immune response. Intrabiliary administration of plasmid DNA, chitosan-DNA and PEI-DNA also significantly increases (10-fold) serum concentration of TNF-α . The realization that adenovirus is primarily taken up by Kupffer cells via scavenger receptors, and that higher doses of the adenovirus (10) leads to Kupffer cell death and the release of serum lactate dehydrogenase, prompted the use of preadministered Poly-I to inhibit adenovirus accumulation in Kupffer cells and to improve hepatocyte transfection .…”

PEG-Peptide Inhibition of Scavenger Receptor Uptake of Nanoparticles by the Liver

“…administration of plasmid DNA and lipoplexes 41 also activates the innate immune response, as does intrabiliary administration of plasmid DNA, chitosan-DNA and PEI-DNA which significantly increase the serum concentration of TNF-α 10−fold. 42 The realization that adenovirus is primarily taken up by Kupffer cells via scavenger receptors, and that higher doses of adenovirus (10 12 ) leads to Kupffer cell death and the release of serum lactate dehydrogenase, 6 prompted the use of pre-administered Poly-I to inhibit adenovirus accumulation in Kupffer cells and to improve hepatocyte transfection. 5 While Poly-I is reportedly not toxic to mice, co-administration of Poly-I with adenovirus decreases the lethal threshold for adenovirus in mice, 5 making Poly-I inhibition of scavenger receptors a clinically unacceptable approach to improve viral mediated gene delivery.…”

“…The i.v. administration of plasmid DNA and lipoplexes also activates the innate immune response, as does intrabiliary administration of plasmid DNA, chitosan-DNA, and PEI-DNA, which significantly increase the serum concentration of TNF-α 10-fold . The realization that adenovirus is primarily taken up by Kupffer cells via scavenger receptors, and that higher doses of adenovirus (10 12 ) leads to Kupffer cell death and the release of serum lactate dehydrogenase, prompted the use of preadministered Poly-I to inhibit adenovirus accumulation in Kupffer cells and to improve hepatocyte transfection .…”

Targeted Gene Delivery: Importance of Administration Routes

“…For other routes of gene transfer, retrograde intrabiliary injection of naked plasmid DNA, polyethylenimine-plasmid DNA complex and chitosan-plasmid DNA complex resulted in transgene expression in the liver [97]. Intranasal administrations of adenoviral vector [98], lipoplex and polyplex [99] were also tested.…”