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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-α 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.

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References

Alemany

, Suzuki

, Curiel

D.T.

2000. Blood clearance rates of adenovirus type 5 in mice. J. Gen. Virol., 81:2605–2609.

Bircher

1999. Oxford Textbook of Clinical Hepatology. Oxford University Press: NY, 13–21.

Chen

C.Y.

, Liu

H.S.

, Lin

X.Z.

2005. Hydrodynamics-based gene delivery to the liver by bile duct injection of plasmid DNA—the impact of lasting biliary obstruction and injection volume. Hepatogastroenterology, 52:25–28.

Dai

, Jiang

, Tan

G.C.

et al. 2006. Chitosan-DNA nanoparticles delivered by intrabiliary infusion enhance liver-targeted gene delivery. Int. J. Nanomedicine, 1:507–522.

De Godoy

J.L.

, Malafosse

, Fabre

et al. 1999. In vivo hepatocyte retrovirus-mediated gene transfer through the rat biliary tract. Hum. Gene Ther., 10:249–257.

Dow

S.W.

, Fradkin

L.G.

, Liggitt

D.H.

et al. 1999. Lipid-DNA complexes induce potent activation of innate immune responses and antitumor activity when administered intravenously. J. Immunol., 163:1552–1561.

, Zhang

, Dong

et al. 2005. A remarkable permeability of canalicular tight junctions might facilitate retrograde, non-viral gene delivery to the liver via the bile duct. Gut, 54:1473–1479.

Kako

, Nishikawa

, Yoshida

, Takakura

2008. Effects of inflammatory response on in vivo transgene expression by plasmid DNA in mice. J. Pharm. Sci., 97:3074–3083.

Krieg

A.M.

1999. Direct immunologic activities of CpG DNA and implications for gene therapy. J. Gene Med., 1:56–63.

10.

Krieg

A.M.

2000. The role of CpG motifs in innate immunity. Curr. Opin. Immunol., 12:35–43.

11.

Lieber

, He

C.Y.

, Meuse

et al. 1997. The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. J. Virol., 71:8798–8807.

12.

Otsuka

, Baru

, Delriviere

et al. 2000. In vivo liver-directed gene transfer in rats and pigs with large anionic multilamellar liposomes: routes of administration and effects of surgical manipulations on transfection efficiency. J. Drug Target., 8:267–279.

13.

Peeters

M.J.

, Patijn

G.A.

, Lieber

et al. 1996. Adenovirus-mediated hepatic gene transfer in mice: comparison of intravascular and biliary administration. Hum. Gene Ther., 7:1693–1699.

14.

Sakurai

, Terada

, Yasuda

et al. 2002. The role of tissue macrophages in the induction of proinflammatory cytokine production following intravenous injection of lipoplexes. Gene Ther., 9:1120–1126.

15.

Schiedner

, Hertel

, Johnston

et al. 2003. Selective depletion or blockade of Kupffer cells leads to enhanced and prolonged hepatic transgene expression using high-capacity adenoviral vectors. Mol. Ther., 7:35–43.

16.

Sullivan

D.E.

, Dash

, Du

et al. 1997. Liver-directed gene transfer in non-human primates. Hum. Gene Ther., 8:1195–1206.

17.

Tao

N.J.

, Gao

G.P.

, Parr

et al. 2001. Sequestration of adenoviral vector by Kupffer cells leads to a nonlinear dose response of transduction in liver. Mol. Ther., 3:28–35.

18.

Tominaga

, Kuriyama

, Yoshiji

et al. 2004. Repeated adenoviral administration into the biliary tract can induce repeated expression of the original gene construct in rat livers without immunosuppressive strategies. Gut, 53:1167–1173.

19.

Uehara

, Honda

, Hatano

et al. 1999. Gene transfer to the rat biliary tract with the HVJ-cationic liposome method. J. Hepatol., 30:836–842.

20.

Van Rooijen

, Sanders

1994. Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J. Immunol. Methods, 174:83–93.

21.

Van Rooijen

, Van Kesteren-Hendrikx

2002. Clodronate liposomes: perspectives in research and therapeutics. J. Liposome Res, 12:81–94.

22.

Van Rooijen

, Van Kesteren-Hendrikx

2003. “In vivo” depletion of macrophages by liposome-mediated “suicide” Methods Enzymol., 373:3–16.

23.

Van Til

N.P.

, Markusic

D.M.

, Van Der Rijt

et al. 2005. Kupffer cells and not liver sinusoidal endothelial cells prevent lentiviral transduction of hepatocytes. Mol. Ther., 11:26–34.

24.

Wolff

, Worgall

, Van Rooijen

et al. 1997. Enhancement of in vivo adenovirus-mediated gene transfer and expression by prior depletion of tissue macrophages in the target organ. J. Virol., 71:624–629.

25.

Yang

Y.P.

, Raper

S.E.

, Cohn

J.A.

et al. 1993. An approach for treating the hepatobiliary disease of cystic-fibrosis by somatic gene-transfer. Proc. Natl. Acad. Sci. U.S.A., 90:4601–4605.

26.

Yew

N.S.

, Wang

K.X.

, Przybylska

et al. 1999. Contribution of plasmid DNA to inflammation in the lung after administration of cationic lipid:pDNA complexes. Hum. Gene Ther., 10:223–234.

27.

Zhang

J.S.

, Liu

, Huang

2005. Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity. Adv. Drug Deliver. Rev., 57:689–698.

28.

Zhang

X.H.

, Collins

, Sawyer

G.J.

et al. 2001. In vivo gene delivery via portal vein and bile duct to individual lobes of the rat liver using a polylysine-based nonviral DNA vector in combination with chloroquine. Hum. Gene Ther., 12:2179–2190.

29.

Zhang

X.H.

, Sawyer

G.J.

, Dong

X.B.

et al. 2003. The in vivo use of chloroquine to promote non-viral gene delivery to the liver via the portal vein and bite duct. J. Gene Med., 5:209–218.

30.

Zhang

, Chirmule

, Gao

G.P.

et al. 2001. Acute cytokine response to systemic adenoviral vectors in mice is mediated by dendritic cells and macrophages. Mol. Ther., 3:697–707.

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

Abstract

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