Wang Ying, Xin Dingcheng, Hu Jiawen, Liu Kaijian, Pan Jiangao, Xiang Jiannan
Biomedical Engineering Center, Hunan University, Changsha, China.
Bioorg Med Chem Lett. 2009 Jan 1;19(1):149-52. doi: 10.1016/j.bmcl.2008.10.132. Epub 2008 Nov 5.
A model ternary heparin conjugate by direct covalent bond strategy has been developed, in which modified heparin using active mix anhydride as intermediate conjugates with model drug molecule and model specific ligand, respectively. Designed ester bonds between model drug and heparin facilitate hydrolysis kinetics research. The strategy can be extended to design and synthesize a targeted drug delivery system. The key point is to use mixed anhydride groups as activating intermediates to mediate the synthesis of the ternary heparin conjugate. Formation of mixed anhydride is detected by the conductimetry experiment. The ternary heparin conjugate is characterized by (13)C NMR, FT-IR and GPC, respectively. The decreased trend on degree of substitution (DS) is consistent with that of introduced anticancer drug and specific ligand in drug delivery system. Moreover, their anticoagulant activity is evaluated by measuring activated partial thromboplastin time (APTT) and anti-factor Xa activity. The results show that model ternary heparin conjugate with reduced anticoagulant activity may avoid the risk of severe hemorrhagic complication during the administration and is potential to develop a safe and effective drug delivery system on anticancer research.
通过直接共价键策略开发了一种模型三元肝素缀合物，其中以活性混合酸酐为中间体修饰的肝素分别与模型药物分子和模型特异性配体缀合。模型药物与肝素之间设计的酯键有助于水解动力学研究。该策略可扩展用于设计和合成靶向给药系统。关键是使用混合酸酐基团作为活化中间体来介导三元肝素缀合物的合成。通过电导实验检测混合酸酐的形成。分别通过(13)C NMR、FT-IR和GPC对三元肝素缀合物进行表征。取代度(DS)的下降趋势与给药系统中引入的抗癌药物和特异性配体的下降趋势一致。此外，通过测量活化部分凝血活酶时间(APTT)和抗Xa因子活性来评估它们的抗凝活性。结果表明，具有降低抗凝活性的模型三元肝素缀合物可避免给药期间严重出血并发症的风险，并且在抗癌研究中具有开发安全有效给药系统的潜力。
