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

通过近两年的研究，我们发现右旋糖酐是最好的水溶性聚合物，可用于血管生成部位的药物靶向。在葡聚糖的羟基上引入二乙烯三胺五乙酸（DTPA），制备了DTPA引入的葡聚糖螯合衍生物（DTPA-dex）。DTPA的引入比例可以通过改变反应条件来控制。在Zn ~（2+）存在下，将DTPA-dex与干扰素β（IFN β）混合，得到具有Zn ~（2+）配位的DTPA-dex-IFN偶联物。在将缀合物静脉内注射到视网膜下血管生成的兔模型中后，通过常规ELISA方法评价IFN在血管生成部位的积累。结合物注射液在兔视网膜血管生成部位的IFN量显著高于游离IFN注射液。这一发现表明，基于Zn^<2+>配位的葡聚糖缀合使IFN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DTPA-dex-IFN偶联物与Zn^<2+>配位抑制视网膜下血管生成的程度明显大于游离IFN或不含Zn^<2+>的DTPA-dex混合物。通过与葡聚糖的金属配位缀合而有效靶向血管生成位点的IFN可能导致IFN在视网膜下的上级抗血管生成作用。DTPA-dex-IFN金属配合物对不同的兔视网膜下血管生成模型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