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Surgical Services and Nuclear Medicine Division, Massachusetts General Hospital and Harvard Medical School, and the Shriners Burns Institute, Boston, Massachusetts
Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, New Jersey
Correspondence: For correspondence and reprint requests contact: Dr. Martin L. Yarmush, Massachusetts General Hospital, 32 Fruit St., Bigelow 1302, Boston, MA 02114.
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 anti-sense 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 (32P-antisense and 3H-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 thromatographic 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 anti-sense analog or antisense alone. Conclusion: These findings have significant implications for the targeted delivery of therepeutic antisense molecules to the liver.
Key Words: antisense DNA delivery • receptor-mediated uptake • asialoglycoprotein • oligodeoxynucleotides • sialoglycoprotein
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