N-succinyl-chitosan as a drug carrier: water-insoluble and water-soluble conjugates.
N-succinyl-chitosan (Suc-Chi) has favourable properties as a drug carrier such as biocompatibility, low toxicity and long-term retention in the body. It was long retained in the systemic circulation after intravenous administration, and the plasma half-lives of Suc-Chi (MW: 3.4 x 10(5); succinylation degree: 0.81 mol/sugar unit; deacetylation degree: 1.0 mol/sugar unit) were ca. 100.3h in normal mice and 43 h in Sarcoma 180-bearing mice. The biodistribution of Suc-Chi into other tissues was trace apart from the prostate and lymph nodes. The maximum tolerable dose for the intraperitoneal injection of Suc-Chi to mice was greater than 2 g/kg. The water-insoluble and water-soluble conjugates could be prepared using a water-soluble carbodiimide and mitomycin C (MMC) or using an activated ester of glutaric MMC. In vitro release characteristics of these conjugates showed similar patterns, i.e. a pH-dependent manner, except that water-insoluble conjugates showed a slightly slower release of MMC than water-soluble ones. The conjugates of MMC with Suc-Chi showed good antitumour activities against various tumours such as murine leukaemias (L1210 and P388), B16 melanoma, Sarcoma 180 solid tumour, a murine liver metastatic tumour (M5076) and a murine hepatic cell carcinoma (MH134). This review summarizes the utilization of Suc-Chi as a drug carrier for macromolecular conjugates of MMC and the therapeutic efficacy of the conjugates against various tumours.
Kato
Yoshinori
Y
Department of Drug Delivery Research, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, 142-8501 Tokyo, Japan. ykato@mri.jhu.edu
Onishi
Hiraku
H
Machida
Yoshiharu
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002686:Chitin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics*; D048271:Chitosan; D004337:Drug Carriers / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D012995:Solubility; D014018:Tissue Distribution; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004337:Drug Carriers; C118639:N-succinyl-chitosan; D002686:Chitin; D048271:Chitosan