Synthesis and in vitro evaluation of thiolated hyaluronic acid for mucoadhesive drug delivery
Synthesis and in vitro evaluation of thiolated hyaluronic acid for mucoadhesive drug delivery
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DOI：
10.1016/j.ijpharm.2007.04.019
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发表时间：
2007-10-01
影响因子：
5.8
通讯作者：
Bernkop-Schnuerch, Andreas
中科院分区：
文献类型：
--
作者：
Kafedjiiski, Krum;Jetti, Ram K. R.;Bernkop-Schnuerch, Andreas
本研究的目的是合成并表征一种新型的透明质酸-半胱氨酸乙酯（HA-Cys）偶联物，该偶联物具有更好的粘接性能和显著降低的生物降解率。在碳二亚胺和n -羟基琥珀酰亚胺的介导下，l -半胱氨酸乙酯盐酸盐通过酰胺键与透明质酸（HA，透明质酸）共价结合。采用旋转圆筒法对HA-Cys偶联物在新鲜切除的猪粘膜上的粘附性能进行了体外评价。通过氧化实验对所得共轭物的内聚性能进行了评价。通过粘度测量和分光光度法进行生物降解性研究。以异硫氰酸-右旋糖酐荧光素（FD）为模型化合物进行释放研究。得到的共轭物每克聚合物显示201.3 +/- 18.7 μ mol的固定游离巯基和85.7 +/- 22.3 μ mol的二硫键。旋转圆柱体法的结果表明，HA- cys的粘附时间比未修饰的HA增加了6.5倍以上。在水溶液中，得到的共轭物表现出更好的内聚性能。在粘度实验的框架下，HA- cys的水解程度低于相应的未改性HA。此外，通过二硫键的交联过程也降低了新衍生物的降解率。含有HA-Cys和模型化合物FD的基质片的累积释放研究表明，由于硫聚体基质中分子间和分子内二硫键的原位形成，药物持续释放超过12个小时。根据目前的研究结果，这种新型硫代聚合物似乎代表了一种有前途的多功能赋形剂，用于开发各种药物输送系统。(C) 2007 Elsevier B.V.版权所有
It was the aim of this study to synthesize and characterize a novel hyaluronic acid-cysteine ethyl ester (HA-Cys) conjugate providing improved mucoadhesive properties and a significantly lowered biodegradation rate. Mediated by carbodiimide and N-hydroxysuccinimide, L-Cysteine ethyl ester hydrochloride was covalently attached to hyaluronic acid (HA, hyaluronan) via the formation of an amide bond. The adhesive properties of HA-Cys conjugates were evaluated in vitro on a freshly excised porcine mucosa via the rotating cylinder method. The cohesive properties of the resulting conjugates were evaluated by oxidation experiments. Biodegradability studies were carried out by viscosity measurements and spectrophotometric assays. Release studies were performed with fluorescein isothiocyanate-dextrans (FD) as model compounds. The obtained conjugate displayed 201.3 +/- 18.7 mu mol immobilized free thiol groups and 85.7 +/- 22.3 mu mol disulfide bonds per gram polymer. Results from the rotating cylinder method showed more than 6.5-fold increase in the adhesion time of HA-Cys versus unmodified HA. In aqueous solutions, the obtained conjugate demonstrated improved cohesive properties. The hydrolysis degree of HA-Cys was lower compared with the corresponding unmodified HA in the framework of viscosity experiments. In addition, the cross-linking process via disulfide bonds additionally reduced the rate of degradation of the new derivative. Cumulative release studies out of matrix tablets comprising HA-Cys and the model compound FD demonstrated a sustained drug release for more than 12 It due to in situ formation of inter- and intramolecular disulfide bonds in the thiomer matrix. According to the results of the present study, this novel thiolated polymer seems to represent a promising multifunctional excipient for the development of various drug delivery systems. (C) 2007 Elsevier B.V. All rights reserved.