Liver targeting of interferon through pullulan conjugation.
OBJECTIVE
The purpose of this study was to actively target interferon (IFN) to the liver through its chemical conjugation with pullulan, a water-soluble polysaccharide with a high affinity for the liver.


METHODS
Chemical conjugation of IFN with pullulan was achieved by a cyanuric chloride method. Following intravenous injection of the conjugates to mice, their body distribution and the activity of an IFN-induced enzyme, 2', 5'-oligoadenylate (2-5A) synthetase in the liver and other organs, were evaluated.


RESULTS
The cyanuric chloride method enabled us to prepare an IFN-pullulan conjugate that retained approximately 7-9% of the biological activity of IFN. Pullulan conjugation enhanced the liver accumulation of IFN and the retention period with the results being reproducible. When injected intravenously to mice, the IFN-pullulan conjugate enhanced the activity of 2-5A synthetase in the liver. The activity could be induced at IFN doses much lower than those of free IFN injection. In addition, the liver 2-5A synthetase induced by conjugate injection was retained for 3 days, whereas it was lost within the first day for the free IFN-injected mice.


CONCLUSIONS
IFN-pullulan conjugation was promising for IFN targeting to the liver with efficient exertion of its antiviral activity therein.
Xi
K
K
Research Center for Biomedical Engineering, Kyoto University, Japan.
Tabata
Y
Y
Uno
K
K
Yoshimoto
M
M
Kishida
T
T
Sokawa
Y
Y
Ikada
Y
Y
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005936:Glucans / Q000737:chemistry*; D007275:Injections, Intravenous; D007372:Interferons / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D014018:Tissue Distribution
D000998:Antiviral Agents; D005936:Glucans; C009109:pullulan; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase