New cyclodextrin bioconjugates for active tumour targeting
New cyclodextrin bioconjugates for active tumour targeting
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DOI：
10.1080/10611860701349752
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发表时间：
2007-01-01
影响因子：
4.5
通讯作者：
Caliceti, Paolo
中科院分区：
文献类型：
--
作者：
Salmaso, Stefano;Bersani, Sara;Caliceti, Paolo
合成并表征了一种新型环糊精基药物活性靶向载体。首先使β-环糊精与过量的二异氰酸酯反应，并使所得CD-（C-6-NCO）（5）衍生物与700 Da二氨基-PEG反应，得到CD-（C-6-PEG-NH 2）（5）。PEG的五个游离氨基中约有一个被叶酸（FA）功能化，作为肿瘤靶向部分。中间体以及最终产物CD-（C-6-PEG）（5）-FA的化学结构通过H-1和C-13 NMR、反相和凝胶渗透色谱以及LW-Vis光谱进行表征。经修饰后，β-cycloclextrins的溶血活性降低了约70%。在新载体的存在下，β-雌二醇的溶解度增加了300倍以上，苯丁酸氮芥的降解率降低了50- 60%。CD-（C6-PEG）（5）-FA与姜黄素形成包合物，显示缔合常数为954，732 M-1。与天然β-环糊精相比，新载体使姜黄素的溶解度增加了约3200倍，并使其在pH 6.5和7.2下的降解速率分别降低了10倍和45倍。FA受体过表达的人鼻咽肿瘤KB细胞系和非叶酸受体表达的人乳腺癌MCF 7细胞用于评估新药物递送系统的靶向性质。体外研究表明，新载体对叶酸受体过表达的肿瘤细胞具有潜在的选择性，因为用姜黄素负载的CD-（C-6-PEG-NH 2）（5）、胎血清培养基中的姜黄素和CD-（C-6-PEG）（5）-FA分别获得52 μ M、58 μ M和21 μ M的ED 50值。
A new cyclodextrin-based carrier for active targeting of low soluble and degradable drugs has been synthesized and characterized. P-Cyclodextrins were first reacted with excess hexamethylene diisocyanate and the resulting CD-(C-6-NCO)(5) derivative was reacted with 700 Da diamino-PEG to yield CD-(C-6-PEG-NH2)(5). About one out of five free amino groups of PEG were functionalised with folic acid (FA) as a tumour targeting moiety. The chemical structures of the intermediates as well as the final product, CD-(C-6-PEG)(5)-FA, were characterized by H-1 and C-13 NMR, reverse phase and gel permeation chromatography, and LW-Vis spectroscopy. After modification, the haemolytic activity of beta-cycloclextrins decreased by about 70%. In the presence of the new carrier, the P-estradiol solubility increased by more than 300 fold and the chlorambucil degradation rate decreased by 50-60%. CD-(C6-PEG)(5)-FA formed an inclusion complex with curcumin displaying an association constant of 954,732 M-1. The new carrier increased the curcumin solubility by about 3200 fold as compared to native P-cyclodextrins and reduced its degradation rate at pH 6.5 and 7.2 by 10 and 45 fold, respectively. FA receptor-overexpressing human nasopharyngeal tumour KB cell lines and non-folic acid receptor-expressing human breast cancer MCF7 cells were used to evaluate the targeting properties of the new drug delivery system. The in vitro studies demonstrate that the new carrier possesses potential selectivity for the folate receptor-overexpressing tumour cells as ED50 values of 52 mu M, 58 mu M and 21 mu M were obtained with curcumin-loaded CD-(C-6-PEG-NH2)(5), curcumin in foetal serum medium and CD-(C-6-PEG)(5)-FA, respectively.