Mucoadhesive polymers as platforms for peroral peptide delivery and absorption: synthesis and evaluation of different chitosan-EDTA conjugates
Mucoadhesive polymers as platforms for peroral peptide delivery and absorption: synthesis and evaluation of different chitosan-EDTA conjugates
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DOI：
10.1016/s0168-3659(97)00136-3
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发表时间：
1998-01-02
影响因子：
10.8
通讯作者：
Krajicek, ME
中科院分区：
文献类型：
--
作者：
Bernkop-Schnurch, A;Krajicek, ME
本研究的目的是合成和评价粘附性聚合物，显示出高结合二价阳离子的能力，而二价阳离子是肠道蛋白水解酶的重要辅助因子。在酰胺键的作用下，络合剂EDTA与壳聚糖伯氨基发生共价键合作用。以游离壳聚糖为1.0，1克剩余游离氨基含量最低(0.1+/-0.03%；平均+/-SD，n=3)的结合物，在肠道pH-条件下分别能结合1.4+/-0.1 mM钙、2.0+/-0.1 mM锌和1.9+/-0.03 mM钴(平均+/-SD，n=3)。壳聚糖-EDTA偶联物对丝氨酸蛋白酶胰蛋白酶(EC 3.4.21.4)、α-糜蛋白酶(EC 3.4.21.1)和弹性蛋白酶(EC 3.4.21.36)的蛋白降解活性无抑制作用，而对锌蛋白酶羧肽酶A(EC 3.4.17.1)和氨基肽酶N(EC 3.4.11.2)的蛋白分解活性有明显的抑制作用。此外，它在水和碱性水溶液中表现出快速溶胀特性。结合物的粘附力甚至高于壳聚糖盐酸盐。然而，降低聚合物上共价连接的EDTA的百分比，会导致粘附力显著降低。根据这些结果，壳聚糖-EDTA偶联物显示出最低数量的剩余游离氨基，似乎是一种有效的工具来克服口服治疗多肽的酶屏障。(C)1998年爱思唯尔科学公司。
The purpose of the present study was to synthesize and evaluate mucoadhesive polymers, exhibiting a high capacity to bind bivalent cations which are essential co-factors for intestinal proteolytic enzymes. Under the formation of amide bonds, the complexing agent EDTA was covalently bound to the primary amino groups of chitosan. One gram of the resulting conjugate with the lowest amount of remaining free amino groups (0.1+/-0.03%; mean+/-SD, n=3) based on free chitosan as 1.0 was capable of binding 1.4+/-0.1 mM calcium, 2.0+/-0.1 mM zinc and 1.9+/-0.03 mM cobalt (mean+/-SD, n=3) under intestinal pH-conditions, respectively. Whereas proteolytic activity of the serine proteases trypsin (EC 3.4.21.4), alpha-chymotrypsin (EC 3.4.21.1) and elastase (EC 3.4.21.36) could nor be inhibited, proteolytic activity of the zinc proteases carboxypeptidase A (EC 3.4.17.1) and aminopeptidase N (EC 3.4.11.2) was strongly inhibited by the chitosan-EDTA conjugate. Moreover, it displays quick swelling properties in water and basic aqueous solutions. The adhesive force of the conjugate was even higher than of chitosan HCl. However, lowering the percentage of covalently attached EDTA on the polymer, leads to a significantly reduced adhesive force. According to these results, chitosan-EDTA conjugates exhibiting the lowest amount of remaining free amino groups, seem to be a useful tool in overcoming the enzymatic barrier for perorally administered therapeutic peptides. (C) 1998 Elsevier Science B.V.