Hepatotropic conjugate of adenine arabinoside monophosphate with lactosaminated poly-L-lysine. Synthesis of the carrier and pharmacological properties of the conjugate.
OBJECTIVE
The hepatotropic conjugate of adenine arabinoside monophosphate with lactosaminated poly-L-lysine (L-Poly(Lys)) must have a high solubility in order to be injected in a small volume compatible with the intramuscular route. In this paper the molecular weights of Poly(Lys) which allowed the synthesis of conjugates with the properties of high solubility and limited loss by the kidney were determined and a procedure for obtaining Poly(Lys) preparations with the required range of polymerization has been described.


METHODS
Conjugates were prepared using Poly(Lys) of different molecular weights obtained by the procedure described here or purchased from a commercial source. Their solubility and renal loss in mice was determined.


RESULTS
Poly(Lys) with molecular weights ranging from 45,000 and 65,000 Da guarantees high solubility and low renal elimination of the conjugates. Conjugate preparations with these properties, intramuscularly administered to woodchuck hepatitis virus-infected woodchucks for 37 days at a daily dose of 5.8 mg/kg exerted a strong antiviral activity. These preparations were devoid of acute toxicity in rat and caused no toxic effects when injected intramuscularly daily for 28 days at a dose ten times higher than that active in woodchucks.


CONCLUSIONS
The results support the possibility of a clinical use of L-Poly(Lys) to obtain liver targeting of adenine arabinoside monophosphate for the treatment of chronic hepatitis B virus infection.
Fiume
L
L
Dipartimento di Patologia sperimentale, Università di Bologna, Italy.
Di Stefano
G
G
Busi
C
C
Mattioli
A
A
Battista Gervasi
G
G
Bertini
M
M
Bartoli
C
C
Catalani
R
R
Caccia
G
G
Farina
C
C
Fissi
A
A
Pieroni
O
O
Giuseppetti
R
R
D'Ugo
E
E
Bruni
R
R
Rapicetta
M
M
D000606:Amino Sugars / Q000008:administration & dosage; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000633:toxicity; D004337:Drug Carriers; D005260:Female; D006509:Hepatitis B / Q000188:drug therapy*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008392:Marmota; D051379:Mice; D011107:Polylysine / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D001084:Vidarabine Phosphate / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity
D000606:Amino Sugars; D000998:Antiviral Agents; D004337:Drug Carriers; D001084:Vidarabine Phosphate; C032233:lactosamine; D011107:Polylysine