Antisense DNA delivery in vivo: Liver targeting by receptor-mediated uptake

X. M. Lu, A. J. Fischman, S. L. Jyawook, K. Hendricks, R. G. Tompkins, Martin Yarmush

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Antisense oligodeoxynucleotides coupled to asialoglycoprotein carrier molecules were evaluated in terms of their ability to accumulate preferentially in the liver and thus potentially serve as an important method to regulate liver gene expression. Methods: Native and asialo-human alpha-1 acid glycoproteins were derivatized with low molecular weight poly(L)lysine and complexed with an antisense DNA (67 mer) complementary to the 5' end of rat serum albumin mRNA. The asialoglycoprotein antisense complex (conjugate) was characterized with respect to size, stability, and anti-sense loading, and the biodistribution of the conjugate was determined for normal rats at 5 min and 1, 6, and 24 hr after intravenous injection. In vivo stability of the anti-sense asialoglycoprotein complex was also evaluated using double- labeled ( 32 P-antisense and 3 H-glycoprotein) preparations. Results: The results of the conjugate characterization studies demonstrated that at least 30% of the anti-sense DNA dissociated from the carrier after 7 min under chromatographic conditions. When the conjugate was incubated with PBS, MEM or MEM plus 10% FBS for 1 hr at 37°C, about 85% of the antisense DNA was dissociated from the carrier. The results of the biodistribution studies showed that the accumulation of the asialo-glycoprotein anti-sense complex in the liver was rapid and greatly exceeded the accumulation of the sialo- glycoprotein antisense analog or antisense alone. Conclusion: These findings have significant implications for the targeted delivery of therapeutic antisense molecules to the liver.

Original languageEnglish (US)
Pages (from-to)269-275
Number of pages7
JournalJournal of Nuclear Medicine
Volume35
Issue number2
StatePublished - Jan 1 1994
Externally publishedYes

Fingerprint

Antisense DNA
Asialoglycoproteins
Glycoproteins
Liver
Oligodeoxyribonucleotides
Serum Albumin
Intravenous Injections
Lysine
Molecular Weight
Gene Expression
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

Cite this

Lu, X. M., Fischman, A. J., Jyawook, S. L., Hendricks, K., Tompkins, R. G., & Yarmush, M. (1994). Antisense DNA delivery in vivo: Liver targeting by receptor-mediated uptake. Journal of Nuclear Medicine, 35(2), 269-275.
Lu, X. M. ; Fischman, A. J. ; Jyawook, S. L. ; Hendricks, K. ; Tompkins, R. G. ; Yarmush, Martin. / Antisense DNA delivery in vivo : Liver targeting by receptor-mediated uptake. In: Journal of Nuclear Medicine. 1994 ; Vol. 35, No. 2. pp. 269-275.
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Lu, XM, Fischman, AJ, Jyawook, SL, Hendricks, K, Tompkins, RG & Yarmush, M 1994, 'Antisense DNA delivery in vivo: Liver targeting by receptor-mediated uptake', Journal of Nuclear Medicine, vol. 35, no. 2, pp. 269-275.

Antisense DNA delivery in vivo : Liver targeting by receptor-mediated uptake. / Lu, X. M.; Fischman, A. J.; Jyawook, S. L.; Hendricks, K.; Tompkins, R. G.; Yarmush, Martin.

In: Journal of Nuclear Medicine, Vol. 35, No. 2, 01.01.1994, p. 269-275.

Research output: Contribution to journalArticle

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T2 - Liver targeting by receptor-mediated uptake

AU - Lu, X. M.

AU - Fischman, A. J.

AU - Jyawook, S. L.

AU - Hendricks, K.

AU - Tompkins, R. G.

AU - Yarmush, Martin

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N2 - Antisense oligodeoxynucleotides coupled to asialoglycoprotein carrier molecules were evaluated in terms of their ability to accumulate preferentially in the liver and thus potentially serve as an important method to regulate liver gene expression. Methods: Native and asialo-human alpha-1 acid glycoproteins were derivatized with low molecular weight poly(L)lysine and complexed with an antisense DNA (67 mer) complementary to the 5' end of rat serum albumin mRNA. The asialoglycoprotein antisense complex (conjugate) was characterized with respect to size, stability, and anti-sense loading, and the biodistribution of the conjugate was determined for normal rats at 5 min and 1, 6, and 24 hr after intravenous injection. In vivo stability of the anti-sense asialoglycoprotein complex was also evaluated using double- labeled ( 32 P-antisense and 3 H-glycoprotein) preparations. Results: The results of the conjugate characterization studies demonstrated that at least 30% of the anti-sense DNA dissociated from the carrier after 7 min under chromatographic conditions. When the conjugate was incubated with PBS, MEM or MEM plus 10% FBS for 1 hr at 37°C, about 85% of the antisense DNA was dissociated from the carrier. The results of the biodistribution studies showed that the accumulation of the asialo-glycoprotein anti-sense complex in the liver was rapid and greatly exceeded the accumulation of the sialo- glycoprotein antisense analog or antisense alone. Conclusion: These findings have significant implications for the targeted delivery of therapeutic antisense molecules to the liver.

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Lu XM, Fischman AJ, Jyawook SL, Hendricks K, Tompkins RG, Yarmush M. Antisense DNA delivery in vivo: Liver targeting by receptor-mediated uptake. Journal of Nuclear Medicine. 1994 Jan 1;35(2):269-275.