Perrone Mara, Lopedota Angela, Liberati Elisa, Russo Vincenzo, Cutrignelli Annalisa, Laquintana Valentino, de Sousa Irene Pereira, Franco Massimo, Tongiani Serena, Denora Nunzio, Bernkop-Schnürch Andreas
Department of Pharmacy - Drug Sciences, University of Bari "Aldo Moro", Bari, Italy; Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innsbruck, Austria.
Department of Pharmacy - Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.
Eur J Pharm Biopharm. 2017 Jun;115:168-176. doi: 10.1016/j.ejpb.2017.02.018. Epub 2017 Mar 6.
The aim of this study was to synthesize, characterize and evaluate the mucoadhesive properties of the first thiolated hyperbranched natural polysaccharide with biodegradability and biocompatibility features. In detail, glycogen-cysteamine conjugates were synthesized through a first step of oxidative ring opening applying increasing concentrations of sodium periodate, to obtain polymers with different degrees of oxidation, and a second step of reductive amination with a constant amount of cysteamine. The obtained glycogen-cysteamine conjugates were characterized regarding their content of free and total thiol groups by Ellman's assay, biocompatibility, swelling/erosion behavior, rheological synergism and mucoadhesive properties in comparison to the unmodified glycogen. The higher the concentration of periodate was, the higher was the content of total thiol groups being in the range of 255.7±12-1194.5±82μmol/g, biocompatibility remained unaffected by these structural changes. On the contrary, the mucoadhesive properties, evaluated by tensile, rheological synergism and rotating cylinder studies, appear to be influenced by the thiol groups concentration on the glycogen. In particular the glycogen-cysteamine conjugate exhibiting the highest degree of thiolation showed a 79-fold increase in viscosity over a time period of 8h, as well as, remained attached on freshly excised porcine mucosa 32-fold longer than the unmodified polymer. The higher was the amount of conjugated thiol groups, the higher was the water absorption capacity of glycogen-cysteamine tablets in Simulated Intestinal Fluid pH 6.8 (SIF). The introduction of thiol moieties on polymer changed the characteristics of the polysaccharide by improving mucoadhesion properties. Therefore, this work represents the first study describing thiolated natural dendrimers as potential platform useful to realize appropriate mucoadhesive nanocarrier systems suitable to prolong mucosal residence time.
本研究的目的是合成、表征并评估首个具有生物可降解性和生物相容性特征的硫醇化超支化天然多糖的粘膜粘附特性。具体而言，糖原-半胱胺共轭物的合成过程如下：第一步通过应用浓度递增的高碘酸钠进行氧化开环，以获得具有不同氧化程度的聚合物；第二步用恒定数量的半胱胺进行还原胺化。通过埃尔曼法测定游离和总硫醇基团含量，对所得糖原-半胱胺共轭物的生物相容性、溶胀/侵蚀行为、流变协同作用和粘膜粘附特性进行表征，并与未修饰的糖原进行比较。高碘酸盐浓度越高，总硫醇基团含量越高，范围为255.7±12 - 1194.5±82μmol/g，这些结构变化未影响生物相容性。相反，通过拉伸、流变协同作用和旋转圆筒研究评估的粘膜粘附特性似乎受糖原上硫醇基团浓度的影响。特别是，硫醇化程度最高的糖原-半胱胺共轭物在8小时内粘度增加了79倍，并且在新鲜切除的猪粘膜上的附着时间比未修饰的聚合物长32倍。共轭硫醇基团的数量越多，糖原-半胱胺片剂在pH 6.8模拟肠液（SIF）中的吸水能力越高。在聚合物上引入硫醇部分通过改善粘膜粘附特性改变了多糖的特性。因此，这项工作代表了第一项将硫醇化天然树枝状大分子描述为潜在平台的研究，该平台可用于实现适合延长粘膜滞留时间的合适粘膜粘附纳米载体系统。
