Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 52c, Josef Möller Haus, 6020 Innsbruck, Austria.
J Control Release. 2010 May 21;144(1):32-8. doi: 10.1016/j.jconrel.2010.01.033. Epub 2010 Jan 31.
This study was aimed at improving the mucoadhesive properties of carboxymethyl dextran by the covalent attachment of cysteine. Mediated by a carbodiimide, l-cysteine was covalently attached to the polymer. The resulting CMD-cysteine conjugate (CMD-(273) conjugate) displayed 273+/-20 micromol thiol groups per gram of polymer (mean+/-S.D.; n=3). Within 2h the viscosity of an aqueous mucus/CMD-(273) conjugate mixture pH 7.4 increased at 37 degrees C by more than 85% compared to a mucus/carboxymethyl dextran mixture indicating enlarged interactions between the mucus and the thiolated polymer. Due to the immobilization of cysteine, the swelling velocity of the polymer was significantly accelerated (p<0.05). In aqueous solutions the CMD-(273) conjugate was capable of forming inter- and/or intramolecular disulfide bonds. Because of this crosslinking process within the polymeric network, the cohesive properties of the conjugate were also improved. Tablets comprising the unmodified polymer disintegrated within 15 min, whereas tablets of the CMD-(273) conjugate remained stable for 160 min (means+/-S.D.; n=3). Results from LDH and MTT assays on Caco-2 cells revealed 4.96+/-0.98% cytotoxicity and 94.1+/-0.9% cell viability for the CMD-(273) conjugate, respectively. Controlled release of model compound from CMD-(273) conjugate tablets was observed over 6h. These findings suggest that CMD-(273) conjugate is a promising novel polymer for drug delivery systems providing improved mucoadhesive and cohesive properties, greater stability and biocompatibility.
本研究旨在通过半胱氨酸的共价键合来改善羧甲基葡聚糖的粘弹性。通过碳二亚胺介导，将 L-半胱氨酸共价连接到聚合物上。所得 CMD-半胱氨酸缀合物（CMD-（273）缀合物）每克聚合物显示 273+/-20 微摩尔巯基基团（平均值+/-S.D.；n=3）。在 37°C 下，与羧甲基葡聚糖相比，pH 7.4 的水粘蛋白/CMD-（273）缀合物混合物的粘度在 2 小时内增加了超过 85%，表明粘蛋白和巯基化聚合物之间的相互作用扩大。由于半胱氨酸的固定化，聚合物的溶胀速度显著加快（p<0.05）。在水溶液中，CMD-（273）缀合物能够形成分子内和/或分子间二硫键。由于聚合物网络内的交联过程，缀合物的内聚性能也得到了改善。包含未改性聚合物的片剂在 15 分钟内崩解，而 CMD-（273）缀合物的片剂在 160 分钟内保持稳定（平均值+/-S.D.；n=3）。Caco-2 细胞的 LDH 和 MTT 测定结果分别显示，CMD-（273）缀合物的细胞毒性为 4.96+/-0.98%，细胞活力为 94.1+/-0.9%。从 CMD-（273）缀合物片剂中观察到模型化合物的控释超过 6 小时。这些发现表明，CMD-（273）缀合物是一种很有前途的新型聚合物，可用于药物传递系统，提供改善的粘弹性和内聚性、更大的稳定性和生物相容性。
