In vivo drug release and antitumor characteristics of water-soluble conjugates of mitomycin C with glycol-chitosan and N-succinyl-chitosan.
The water-soluble conjugates of mitomycin C (MMC) with N-succinyl-chitosan (N-Suc-chitosan) and glycol-chitosan (Gly-chitosan), named N-Suc-chitosan-glu-MMC and Gly-chitosan-glu-MMC, respectively, were characterized mainly by the plasma concentration-time profiles of MMC after intraperitoneal administration and their in vivo antitumor effect against P388 leukemia and Sarcoma 180. Before in vivo evaluation, polymer-drug binding characteristics were checked by gel-chromatography. Gel-chromatographs proposed the covalent binding of 1a-(4-carboxybutyryl)-MMC (glu-MMC) with both the polymer supports. The plasma concentration of MMC showed that each conjugate released MMC in vivo at a similar rate. Kinetic analysis suggested that the in vivo drug release should be considerably faster than the in vitro release in the buffer, pH 7.4, alone. In the treatment against P388 leukemia inoculated intraperitoneally, Gly-chitosan-glu-MMC showed the highest increase in life span (ILS) at 10 mg MMC eq/kg. It was lethally toxic at the dose of 20 mg MMC eq/kg, while N-Suc-chitosan-glu-MMC gave the highest ILS value at this dose. Each conjugate exhibited a little larger ILS value than MMC. For the Sarcoma 180 solid tumor inoculated subcutaneously, the polymer characteristics affected the antitumor effect. Namely, with the intravenous injection, Gly-chitosan-glu-MMC hardly exhibited any tumor growth inhibition, but N-Suc-chitosan-glu-MMC showed significant tumor growth suppression. As to the intratumoral administration, the tendency to suppress tumor growth was observed in MMC and both the conjugates.
Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan.
M
M
Sato
H
H
Onishi
J
J
Takahara
Y
Y
Machida
T
T
Nagai
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D001704:Biopolymers; D001835:Body Weight / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002686:Chitin / Q000031:analogs & derivatives; D048271:Chitosan; D002850:Chromatography, Gel; D003692:Delayed-Action Preparations; D006018:Glycols; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007941:Leukemia P388 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016685:Mitomycin / Q000493:pharmacokinetics / Q000494:pharmacology*; D008937:Mitomycins; D051381:Rats; D017208:Rats, Wistar; D012510:Sarcoma 180 / Q000188:drug therapy; D013386:Succinates; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D001704:Biopolymers; D003692:Delayed-Action Preparations; D006018:Glycols; D008937:Mitomycins; D013386:Succinates; D002686:Chitin; D016685:Mitomycin; D048271:Chitosan