CN103739672B - 一种聚乙二醇修饰的抑制vegfr2酪氨酸激酶多肽及其应用 - Google Patents
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Abstract
本发明涉及药物领域，具体涉及具有抑制VEGFR2酪氨酸激酶活性，治疗实体肿瘤的多肽。此多肽经过了聚乙二醇修饰，其序列为mPEG-SC10k-MVIVEFCK是全新的序列，它们可以在体外抑制VEGFR2酪氨酸激酶活性，并在体内试验中提高荷瘤小鼠生存率，具有潜在的新药开发价值。
Description
技术领域
本发明涉及聚乙二醇修饰的VEGFR2酪氨酸激酶抑制剂及其应用，具体涉及具有抑制VEGFR2酪氨酸激酶活性、可治疗实体肿瘤的的多肽。
背景技术
研究表明，实体瘤的生长依赖于新生血管生成，新生血管不仅可以提供肿瘤所需要的营养和氧气，***代谢产物，而且是远处转移的途径。因此，阻断新生血管形成可能成为阻止肿瘤生长和转移的手段，从而激发了对促血管生成分子和抗血管生成分子的广泛研究。
相比传统肿瘤治药物疗，肿瘤血管生成抑制剂最大优点在于：①选择性作用于血管内皮细胞，全身毒副作用小；②靶细胞为血管内皮细胞，药物易从血液中到达与之接触发生作用； 血管内皮细胞无或少突变，不易产生耐药性，可长期用药；可与放化疗方法联合应用并减轻后者的毒副反应。
血管内皮生长因子受体2（VEGFR2）亦称含激酶***域的受体(KDR)， 属于受体酪氨酸激酶超家族。血管内皮生长因子受体2在新生血管生成过程中起着主要的作用。其配体VEGF通过刺激细胞表面VEGFR2活化内皮细胞，发生生化信号的复杂级联与细胞外基质组分和可溶性因子相互作用，导致腔管形成并且分化成成熟的血管。另外，这些被活化的细胞经过细胞增殖过程，来提高细胞粘附分子的表达，增加蛋白水解酶的分泌，增加细胞迁移和侵袭。目前， 靶向KDR的抑制剂已成为开发新兴抗血管新生药物的研究热点。尽管如此，并没有成熟开发的血管内皮生长因子受体2酪氨酸激酶多肽抑制剂问世，用于治疗实体瘤。
MVIVEFCK是一个全新的序列，前期的研究表明，该多肽经反复体内外活性评价证实具有较好的抑瘤效果，能够显著抑制VEGFR2酪氨酸激酶活性。然而上述多肽的半衰期短，拟用临床人的给药是每天静脉滴注，这给患者带来了一定的痛苦。
文献报道中，对分子结构进行修饰或改造是解决半衰期较短、需连续给药问题的常用方法，其中以化学修饰应用最为广泛，常用的化学修饰剂有聚乙二醇(polye thylene glycol，PEG)、葡聚糖、聚氨基酸、聚酸酐等。PEG具有无毒、无免疫原性、水溶性好的特点，被美国食品与药物管理局(FDA)认可作为药品的辅助原料和修饰剂。蛋白质类药物经PEG修饰后，分子量增加，肾小球的滤过率减少，PEG的屏障作用保护了蛋白质不易被蛋白水解酶水解，同时减少了中和抗体的产生，这些均有助于蛋白质类药物生物半衰期的延长。目前已有多种PEG修饰的蛋白质类药物上市销售。但PEG修饰同时也可能影响蛋白质的生物学活性，其影响大小与修饰剂、修饰条件及蛋白质本身的性质有关。对于具体的蛋白质，其最佳修饰需通过制备PEG修饰的蛋白质及生物活性研究来决定。合成小分子多肽的PEG修饰研究起步较晚，但已引起不少研究者的关注。
发明内容
发明目的
本发明针对mPEG-SC-MVIVEFCK做了进一步研究，发现其在降低给药频率的情况下对多种肿瘤有治疗作用。
技术方案
一种聚乙二醇修饰的抑制VEGFR2酪氨酸激酶多肽，其特征在于其序列为mPEG-SC10k-MVIVEFCK。mPEG-SC的分子量为5000-20000。一种聚乙二醇修饰的抑制VEGFR2酪氨酸激酶多肽在制备***药物中的应用，其特征在于所述的肿瘤为起源于人的胃部、皮肤、头颈部、甲状腺、胰腺、肺脏、食管、乳腺、肾脏、胆囊、结肠/直肠、卵巢、子宫、子宫颈、***、膀胱、睾丸的原发/继发的癌或肉瘤。
有益效果
为了延长多肽MVIVEFCK的半衰期，我们采用不同分子量的聚乙二醇（PEG）对此多肽进行了修饰，发现mPEG-SC10k-MVIVEFCK具有延长半衰期，但又不影响其体内外活性的特点。一个多肽的修饰产物属于一个新型分子，往往与修饰前的分子在活性上产生不同的效果。本发明针对上述聚乙二醇修饰的VEGFR2酪氨酸激酶抑制剂mPEG-SC10k-MVIVEFCK对多种肿瘤有治疗作用进行了大量的体内外活性研究，发现给药频率降低的情况下，mPEG-SC10k-MVIVEFCK对抑制多种肿瘤生长保持了很好的活性，拓展了其社会价值和经济价值。
具体实施方式
本发明涉及多肽由吉尔生化(上海)有限公司合成。
实施例1
聚乙二醇修饰的VEGFR2酪氨酸激酶抑制剂对体外培养肿瘤细胞的生长和存活IC50。
采用 MTT 比色法。将对数生长的U937细胞，以 1.0×105加入 96 孔培养板中，培养 24h，实验孔、阳性药物对照孔分别加入不同浓度的实验药物聚乙二醇修饰的VEGFR2酪氨酸激酶抑制剂和阳性对照药物紫杉醇；空白组加入相同体积的溶剂。每孔设五个复孔，培养 48h，分别在0h、2h、8h、14h、20h、24h、36h、，48h 每孔加入 MTT，作用 4h 后，加入 DMSO，孵育 30min，在酶标仪 620nm 处测定吸光度 A 值，按公式肿瘤细胞生长抑制率＝（1-实验组吸光值/对照组吸光值）×100％。计算出实验药物的 IC50 为2.23μM。
实施例2
用肿瘤模型检测聚乙二醇修饰的VEGFR2酪氨酸激酶抑制剂的体内活力。
建立U937肿瘤模型，阳性对照药物紫杉醇；空白组加入相同体积的溶剂， 实验组设3个剂量：0.75、1.5μM、3μM mg/Kg。21天后，观察小鼠存活数量，计算存活率。结果显示，聚乙二醇修饰的VEGFR2酪氨酸激酶抑制剂可有效地保护小白鼠，提高荷瘤小鼠的生存率，生存率达到89.1%。
SEQUENCE LISTING
<110> 瑞雪, 罗
<120> 一种聚乙二醇修饰的抑制VEGFR2酪氨酸激酶多肽及其应用
<130>
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 8
<212> PRT
<213> 人工序列
<400> 1
mPEG-SC1000-Met Val Ile Val Glu Phe Cys Lys
1 5
Claims (2)
1.一种聚乙二醇修饰的抑制VEGFR2酪氨酸激酶多肽，其特征在于其序列为mPEG-SC-MVIVEFCK。
2.根据权利要求1所述的一种聚乙二醇修饰的抑制VEGFR2酪氨酸激酶多肽，其特征在于所述的mPEG-SC的分子量为10000。
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| WO2007069272A2 (en) * | 2005-10-21 | 2007-06-21 | Panacea Biotec Limited | Pharmaceutical composition comprising at least one anticancer drug and at least one polymer |
| CN101238149A (zh) * | 2005-07-22 | 2008-08-06 | 皮埃尔法布尔制药公司 | 新抗igf-ir抗体及其用途 |
| WO2011151412A1 (en) * | 2010-06-01 | 2011-12-08 | Pierre Fabre Medicament | Novel anti-cmet antibody |
| CN102292106A (zh) * | 2008-11-25 | 2011-12-21 | 奥尔德生物制药公司 | Il-6抗体及其用途 |
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| CN101238149A (zh) * | 2005-07-22 | 2008-08-06 | 皮埃尔法布尔制药公司 | 新抗igf-ir抗体及其用途 |
| WO2007069272A2 (en) * | 2005-10-21 | 2007-06-21 | Panacea Biotec Limited | Pharmaceutical composition comprising at least one anticancer drug and at least one polymer |
| CN102292106A (zh) * | 2008-11-25 | 2011-12-21 | 奥尔德生物制药公司 | Il-6抗体及其用途 |
| WO2011151412A1 (en) * | 2010-06-01 | 2011-12-08 | Pierre Fabre Medicament | Novel anti-cmet antibody |
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