Miwa A, Ishibe A, Nakano M, Yamahira T, Itai S, Jinno S, Kawahara H
Pharmaceutics Laboratory, Pharmaceutical Research Laboratories, Taisho Pharmaceutical Co., LTD, Saitama, Japan.
Pharm Res. 1998 Dec;15(12):1844-50. doi: 10.1023/a:1011901921995.
To develop an intravenous injectable carrier composed of chitosan derivatives for taxol.
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.
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.
The results of solubilization capacity examination, hemolysis testing, and cytostatic activity suggest that LCC may be useful as a carrier of taxol.
开发一种由壳聚糖衍生物组成的用于紫杉醇的静脉注射载体。
新合成了一种壳聚糖，其氨基上连接月桂基以提供疏水部分，羟基上连接羧甲基以提供亲水部分（N-月桂基-羧甲基壳聚糖 = LCC）。检测了紫杉醇在LCC胶束水溶液中的溶解度。还进行了LCC的溶血试验以及使用KB细胞的载紫杉醇胶束的生长抑制实验作为体外测定。
发现LCC通过形成粒径小于100nm的胶束使紫杉醇增溶。该粒径被认为对肿瘤的被动靶向有效。胶束溶液中紫杉醇的浓度非常高，最高可达2.37mg/mL。该最大值比pH 7.4时紫杉醇饱和溶液中的浓度高1000倍。作为体外测定的溶血试验表明，就诱导膜损伤而言，LCC作为静脉表面活性剂比聚山梨酯80（TO-10M）更安全。根据对KB细胞的细胞生长抑制活性判断，紫杉醇即使包含在LCC胶束中仍保持活性。在低浓度下，LCC包裹的紫杉醇在细胞生长抑制活性方面比游离紫杉醇更有效。
增溶能力检测、溶血试验和细胞生长抑制活性的结果表明，LCC可能作为紫杉醇的载体有用。
