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The invention of the intellectualization cytokine using a synthetic biological response modifier.

使用合成生物反应调节剂的智能化细胞因子的发明。

基本信息

批准号：
11672259
负责人：
KUBO Kazuyoshi
金额：
$ 2.5万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11672259/
关键词：
Antineoplastic-Agents Drug-Carriers Maleic-Anhydrides Tumor-Necrosis-Factor 抗腫瘍作用 DMMAn

项目摘要

The purpose of this study is to further explore the usefulness of conjugation with functional polymeric modifiers for clinical application of bioactive proteins and to increase the therapeutic efficacy of tumor necrosis factor alpha (TNF-alpha) by conjugation in vivo. We synthesized TNF-alpha conjugated with the copolymer of divinyl ether and maleic anhydride (DIVEMA), which has intrinsic antitumor activity as a synthetic biological response modifier. The synthesis of DIVEMA-TNF-alpha could be controlled by the addition of 2,3-dimethylmaleic anhydride (DMMAn), which binds to or separates from amino groups when the pH is changed. The specific activity of DIVEMA-TNF-alpha (+) synthesized with DMMAn was hardly decreased in vitro. However, DIVEMA-TNF-alpha (-), which is conjugated without blocking by DMMAn, had a markedly diminished specific activity. DIVEMA-TNF-alpha (+) caused a dramatic hemorrhagic necrotic effect on the tumor when compared to native TNF-alpha 24 h after i.v. injection into mice bearing Sarcoma-180 solid tumors. In addition, DIVEMA-INF-alpha (+) at a dose of only 100 Japan reference units per mouse revealed a dramatic antitumor effect that is approximately 100 times greater than native TNF-alpha and that could induce complete regression in all five mice bearing Meth-A solid tumors without any apparent side effects. Because neither DIVEMA alone nor a mixture of TNF-alpha and DIVEMA caused antitumor activity with i.v. administration, the increase in antitumor potency of TNF-alpha may be caused by the covalent conjugation with DIVEMA.DIVEMA-TNF-alpha at low dose revealed dramatic antitumor potency. Because TNF-alpha injected in vivo is extremely low-dose, concentration of intrinsic TNF-alpha in vivo is not influenced. Therefore, the cytokine network in vivo is not destroyed. These results suggest that DIVEMA is a useful polymeric modifier for conjugation of TNF-alpha to increase its antitumor activity.

本研究的目的是进一步探索与功能性聚合物修饰剂缀合用于生物活性蛋白的临床应用的有用性，并通过缀合在体内增加肿瘤坏死因子α（TNF-α）的治疗功效。我们合成了与二乙烯基醚和马来酸酐的共聚物（DIVEMA）缀合的TNF-α，其作为合成的生物反应调节剂具有固有的抗肿瘤活性。DIVEMA-TNF-α的合成可以通过加入2，3-二甲基马来酸酐（DMMAn）来控制，当pH值改变时，DMMAn与氨基结合或分离。用DMMAn合成的DIVEMA-TNF-α（+）的比活性在体外几乎没有降低。然而，DIVEMA-TNF-α（-）结合后未被DMMAn阻断，其比活性明显降低。静脉注射给携带肉瘤-180实体瘤的小鼠后24小时，与天然TNF-α相比，DIVEMA-TNF-α（+）对肿瘤产生显著的出血性坏死作用。此外，每只小鼠仅100日本参考单位剂量的DIVEMA-INF-α（+）显示出显著的抗肿瘤作用，约为天然TNF-α的100倍，并且可以诱导所有五只携带Meth-A实体瘤的小鼠完全消退，而没有任何明显的副作用。由于静脉注射DIVEMA单独或TNF-α和DIVEMA的混合物均不产生抗肿瘤活性，TNF-α的抗肿瘤效力的增加可能是由与DIVEMA的共价缀合引起的。低剂量的DIVEMA-TNF-α显示出显著的抗肿瘤效力。由于体内注射的TNF-α是极低剂量的，因此体内内源性TNF-α的浓度不受影响。因此，体内的细胞因子网络不会被破坏。这些结果表明，DIVEMA是一种有用的聚合物修饰剂，用于缀合TNF-α以增加其抗肿瘤活性。