n-succinyl-chitosan and Sarcoma-180

N-Succinyl-chitosan has favourable properties as a drug carrier, such as biocompatibility, low toxicity and long-term retention in the body. It is a good candidate for cancer chemotherapy as a polymeric drug carrier. This study describes the preparation and characterization of 5-fluorouracil-loaded N-succinyl-chitosan nanoparticles (5-FU-Suc-Chi/NP) by an emulsification solvent diffusion method. The influence of the initial 5-FU concentration on the nanoparticle characteristics and release behaviour in phosphate-buffered saline solution (PBS) was evaluated. The Suc-Chi nanoparticles had a particle diameter (Z-average) in the range 202 approximately 273 nm and a negative zeta-potential (approx. -27 to -18 mV). The formulation with an initial 5-FU concentration of 1000 microg mL-1 provided the highest loading capacity (19%) and the highest extent of release (61% at 24 h). The 5-FU-Suc-Chi/NP showed good anti-tumour activity against Sarcoma 180 solid tumour and mild toxicity. According to the data obtained, this Suc-Chi-based nanotechnology opens new and interesting perspectives for cancer chemotherapy.

Topics: Animals; Antimetabolites, Antineoplastic; Chitosan; Colloids; Delayed-Action Preparations; Diffusion; Drug Carriers; Drug Compounding; Fluorouracil; Mice; Mice, Inbred BALB C; Nanoparticles; Neoplasm Transplantation; Particle Size; Sarcoma 180; Solubility; Time Factors

The water-soluble, low toxic and less biodegradable chitosan derivative N-succinyl-chitosan (Suc-chitosan) was investigated for body distribution and urinary excretion on a long-time scale (24-72 h after i.v. injection) using a fluorescein-labeling technique. Fluorescein isothiocyanate (FITC)-labeled Suc-chitosan (Suc-chitosan-FTC) was characterized for molecular weight, succinylation degree and FTC content. Systemic retention and tissue distribution of Suc-chitosan-FTC were examined after i.v. administration to normal and Sarcoma 180 tumor-bearing mice. Suc-chitosan-FTC was sustained at a high level in the circulation over 72 h; that is, the plasma half-life in normal mice was 100.3 h and that in tumor-bearing mice was 43.0 h, which was longer than those of other long-circulating macromolecules reported to date. As to the tissues except blood circulation, Suc-chitosan-FTC was distributed very little in tissues other than the tumor. Although the total amount of Suc-chitosan-FTC residing in tested tissues decreased gradually, urinary excretion did not increase from 24 h after injection. These observations suggested that Suc-chitosan-FTC may be eliminated by mechanisms other than in the urine or moved to tissues other than those tested. The ratio of tumor accumulation reached a plateau at 48 h after injection, and the accumulation level, approximately 10%, was similar to those observed for other reported long-circulating macromolecules.

Topics: Animals; Biocompatible Materials; Biotransformation; Chitin; Chitosan; Half-Life; Injections, Intravenous; Male; Mice; Mice, Inbred Strains; Sarcoma 180; Tissue Distribution

Highly-succinylated N-succinyl-chitosan (Suc) was fluorescein-labeled, and the labeled product (Suc-FTC) was examined for biodisposition in Sarcoma 180-bearing mice after i.v. and i.p. administration. Suc-FTC injected intravenously was sustained at a high level in the blood circulation and showed little distribution to tissues other than tumor. On the other hand, it took a few hours for Suc-FTC to be transferred to the blood circulation after i.p. administration. There were no marked differences in the distribution of Suc-FTC between i.v. and i.p. administration routes except in the early stage. The urinary excretion of Suc-FTC following both i.v. and i.p. administration was small, but the excretion tended to be suppressed after i.p. administration. Water-soluble Sucmitomycin C conjugate (Suc-MMC) prepared using water-soluble carbodiimide exhibited marked effect at a high dose and suppressed the acute toxic side effect of MMC. Suc-MMC tended to be more toxic at i.p. administration than at i.v. administration. The difference in biodisposition between the two administrations was thought to affect the toxic side effect. The plasma levels of conjugated and free MMCs at 8 h after i.v. administration were higher than those at 8 h after i.p. administration. These suggested more localization of the conjugate in peripheral tissues and less excretion at i.p. administration, which might result in greater toxicity.

Topics: Animals; Antineoplastic Agents; Cell Division; Chitin; Chitosan; Drug Carriers; Injections, Intraperitoneal; Injections, Intravenous; Male; Mice; Mitomycin; Molecular Weight; Sarcoma 180; Solubility; Tissue Distribution