Development of novel chitosan derivatives as micellar carriers of taxol.
OBJECTIVE
To develop an intravenous injectable carrier composed of chitosan derivatives for taxol.


METHODS
A chitosan with lauryl groups attached to amino groups to provide the hydrophobic moieties and, carboxymethyl groups attached to hydroxy groups to provide the hydrophilic moieties (N-lauryl-carboxymethyl-chitosan = LCC), was newly synthesized. The solubility of taxol in LCC micelles in aqueous solution was examined. The hemolysis test of LCC and the growth inhibition experiment of taxol-loading micelle using KB cells were also performed as in vitro assay.


RESULTS
It was found that LCC solubilized taxol by forming micelles with particle sizes less than 100nm. This particle size was considered effective for passive targeting for tumors. The concentration of taxol in the micellar solution was very high, with a maximum of 2.37mg/mL. This maximum was 1000 times above that in a saturated solution of taxol at pH 7.4. Hemolysis testing as an in vitro assay indicated that LCC was safer than Polysorbate 80 (TO-10M) as intravenous surfactant in terms of induction of membrane damage. As judged by cytostatic activity against KB cells, taxol retained activity even when included in LCC micelles. LCC-entrapped taxol was more effective in cytostatic activity than free taxol in low concentrations.


CONCLUSIONS
The results of solubilization capacity examination, hemolysis testing, and cytostatic activity suggest that LCC may be useful as a carrier of taxol.
Miwa
A
A
Pharmaceutics Laboratory, Pharmaceutical Research Laboratories, Taisho Pharmaceutical Co., LTD, Saitama, Japan. s14831@ccm.taisho.co.jp
Ishibe
A
A
Nakano
M
M
Yamahira
T
T
Itai
S
S
Jinno
S
S
Kawahara
H
H
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001672:Biocompatible Materials / Q000737:chemistry*; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry; D048271:Chitosan; D004285:Dogs; D004337:Drug Carriers; D004912:Erythrocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D007275:Injections, Intravenous; D007850:Lauric Acids / Q000737:chemistry; D008564:Membrane Potentials; D008823:Micelles; D017239:Paclitaxel / Q000493:pharmacokinetics*; D010316:Particle Size; D012995:Solubility
D000972:Antineoplastic Agents, Phytogenic; D001672:Biocompatible Materials; D004337:Drug Carriers; D007850:Lauric Acids; D008823:Micelles; D002686:Chitin; C068302:N-(carboxymethyl)chitosan; D048271:Chitosan; D017239:Paclitaxel