Lecithinized ascorbic acid (PC-AS) effectively inhibits murine pulmonary metastasis.
In order to enhance the lipophilicity and develop the efficacy of ascorbic acid (ASA), we synthesized lecithinized ascorbic acid (PC-AS), in which a lecithin was covalently bound to ASA. Its pharmacological activity was also evaluated. The IC50 value of scavenge superoxide anions generated from hypoxanthine in combination with xanthine oxidase, indicated that the antioxidative activity of PC-AS (IC50; 22.19 microM) was about 60% of that shown by ASA (IC50; 13.35 microM). Also, PC-AS suppressed in vitro cell growth of Meth A-T, a highly metastatic cell line established by us. Although its potency (IC50; 110.0 microM) was a little lower than that of ASA, dramatic suppression was observed under serum-free culture conditions (IC50; 13.0 microM). In addition, N-acetylcysteine (NAC), an antioxidant, showed an additive inhibitory effect on cell growth in combination with PC-AS and ASA. Biodistribution studies revealed that PC-AS persisted longer in the blood (AUC0-240 min; 182.8 nmole min ml-1) than ASA (AUC0-240 min; 79.35 nmole min ml-1). It should be noted that intravenous preadministration of PC-AS significantly and dose-dependently reduced the number of colony formation in an experimental murine pulmonary metastasis model. ASA had little effect. [3H]-labeled Meth A-T cells predominantly accumulated in the lung, metastatic target organ, which was reduced by PC-AS. Our in vivo study showed that PC-AS could not totally prevent pulmonary invasion of Meth A-T cells, however, PC-AS effectively inhibited the number of metastatic colony formation. PC-AS's potency was superior to that of unmodified ASA. These findings might be in part ascribed to changes to lecithinization-induced biodistribution, antioxidative activity and cytotoxicity.
Takenaga
M
M
Division of Drug Delivery Systems, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Japan.
Igarashi
R
R
Nakayama
T
T
Mizushima
Y
Y
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000032:analysis; D010713:Phosphatidylcholines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D010713:Phosphatidylcholines; D009569:Nitric Oxide; D001205:Ascorbic Acid