Therapy of Angiogenic Eye Diseases by Novel Drug Targeting Based on Metal Coordination

根据近两年的研究，我们发现葡聚糖是最好的水溶性聚合物，可以用于血管生成部位的药物靶向。将二乙三胺五乙酸(DTPA)引入葡聚糖的羟基，制备了DTPA引入的具有螯合残基的葡聚糖衍生物(DTPA-Dex)。通过改变反应条件，可以控制DTPA的引入比例。在有锌离子存在的情况下，将所制备的DTPA-Dex与干扰素β在水溶液中混合，得到具有锌离子配位的DTPA-Dex-干扰素结合物。在兔视网膜下血管生成模型中静脉注射结合物后，用常规的ELISA法评估干扰素在血管生成部位的蓄积。结合物注射剂在兔视网膜血管新生部位的干扰素含量明显高于游离干扰素注射剂。这一发现表明，基于锌-lt；2+-gt；配位的葡聚糖结合使干扰素能够靶向动物的视网膜下血管生成部位。治疗实验表明，静脉注射含锌离子配位的DTPA-地塞米松-干扰素结合物对视网膜下血管生成的抑制作用明显强于游离干扰素或不含锌离子的DTPA-地塞米松混合物。高效的干扰素通过与葡聚糖的金属配位结合靶向血管生成部位，可能导致干扰素在视网膜下发挥更好的抗血管生成作用。在不同的兔视网膜下血管生成模型中，观察到金属配位的DTPA-Dex-干扰素结合物具有相似的抗血管生成作用

Based on the research of last two years, we have found that dextran is the best watersoluble polymer which can be used for drug targeting to the angiogenic site. Diethylenetriamine pentaacetic acid (DTPA) was introduced to the hydroxyl groups of dextran to prepare DTPA-introduced dextran derivatives with chelating residues (DTPA-dex). The ratio of DTPA introduced was controllable by changing the reaction conditions. The DTPA-dex prepared was mixed in an aqueous solution with interferon (IFN) β in the presence of Zn ions to obtain the DTPA-dex-IFN conjugate with Zn^<2+> coordination. Following the intravenous injection of conjugate into a rabbit model of subretinal angiogenesis, the accumulation of IFN in the angiogenic site was evaluated by the conventional ELISA method. Significantly higher IFN amount was detected in the angiogenic site of rabbit retina for the conjugate injection than the free IFN injection. This finding indicates that the dextran conjugation based on Zn^<2+> coordination enables IFN to target to the subretinal angiogenic site of animals. Therapeutic experiments revealed that the intravenous injection of DTPA-dex-IFN conjugate with Zn^<2+> coordination suppressed the progression of subretinal angiogenesis to a significantly greater extent than that of free IFN or the mixture of DTPA-dex without Zn^<2+> ions. It is possible that efficient IFN targeting to the angiogenic site by metal coordinated conjugation with dextran results in superior anti-angiogenic effect of IFN in the subretina. The similar anti-angiogenic effect of DTPA-dex-IFN conjugate with metal coordination was observed for different rabbit models of subretinal angiogenesis