CN116459270A - 一种药物组合物及其在制备防治眼部新生血管性疾病药物中的应用 - Google Patents
一种药物组合物及其在制备防治眼部新生血管性疾病药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种药物组合物及其在制备防治眼部新生血管性疾病药物中的应用。所述药物组合物包括直接抑制RUNX1/CBFB依赖性反式激活的RUNX1直接抑制剂Ro5‑3335与高效入胞、性质稳定的RUNX1mRNA翻译过程抑制剂DNA核酸四面体‑siRNA复合物;本发明的药物组合物可更加有效减少RUNX1的表达,阻止眼部新生血管的生成,具有显著的协同作用,并且还能够促进生理性血管的生成,从而改善视网膜无灌注区面积,且无明显的药理毒性,可用于预防和/或治疗眼部新生血管性疾病。
Description
技术领域
本发明涉及生物医学技术领域,具体地,涉及一种药物组合物及其在制备防治眼部新生血管性疾病药物中的应用,尤其涉及一种针对Runt相关转录因子(RUNX1)基因位点的药物组合物及其在制备预防和/或治疗眼部新生血管性疾病药物中的应用。
背景技术
眼底新生血管是众多眼底疾病的病理基础,一般发生于缺血缺氧的视网膜脉络膜组织,常见于糖尿病性视网膜病变、湿性老年相关性黄斑变性、早产儿视网膜病变、脉络膜新生血管、视网膜中央/分支静脉阻塞、高度近视视网膜病变、中心性浆液性视网膜病变等。有数据显示眼底新生血管性疾病患者人数在4000万以上,且随着人口老龄化程度加重,患者人数还在不断上升。该病患者视力普遍低下,严重影响患者的生活质量,造成巨大的家庭及社会经济负担。
该病主要的原因在于各种因素引起的视网膜缺血缺氧,刺激血管内皮生长因子(VEGF)等血管生成因子的产生,导致异常的新生血管形成。不同于发育过程中生理性的血管发生,眼底新生血管的血管壁结构薄弱,通透性高,会导致渗漏、出血、组织水肿等一系列改变,最终严重影响视力。目前控制视网膜新生血管形成的方法是通过高频的眼内注射VEGF抑制剂,如VEGF单抗或VEGFR竞争性结合蛋白,抑制VEGF的功能。这一方法虽可抑制新生血管的形成,但需要反复多次的给药,且不能解决视网膜缺血缺氧的问题,属于治标不治本。
近年来,有研究(Identification of RUNX1as a Mediator of AberrantRetinal Angiogenesis[J].Diabetes,2017:1950-1956.)发现了一种视网膜新生血管形成或视网膜异常血管生长的新型治疗靶点—RUNX1。RUNX1是一种转录因子,由1个RUNX1基因编码的α亚基和1个CBFB基因编码的β亚基组成。Runt结构域介导其中一个亚基直接与DNA结合,另一个则是非DNA结合亚基,被称为核心结合因子β(core binding factorβ,CBFβ),RUNX1和CBFβ形成的异二聚体增加了RUNX1的DNA亲和力,可以激活或抑制目标基因的表达。在病理性新生血管组织,如PDR的血管膜、脉络膜新生血管膜等,均可检测到异常的RUNX1高表达,而正常血管中RUNX1无表达。在体外,抑制RUNX1可减少C-PVR细胞的增殖,并且在抑制了新鲜分离的人PVR膜的生长。对于某些特定视网膜病变的眼病来说,通过抑制RUNX1来抑制异常血管形成可能是一种靶向性更强的治疗方法。已有研究在动物实验中证实玻璃体腔注射Ro5-3335(RUNX1-CBFβ相互作用抑制剂)可减少新生血管的面积,然而无法改善视网膜无灌注区面积。且Ro5-3335高剂量应用可能会产生药物毒性作用。探索新的RUX1调控方法具有重要的临床意义。
由于DNA纳米结构具有广泛的生物学功能,DNA纳米技术已被开发并应用于各种领域。DNA四面体(Tetrahedral DNA Nanostructures,TDNs)是一种由4条单链DNA通过变性和复性进而通过链间碱基互补配对形成的一种四面体结构,它易于合成,结构稳定,生物兼容性高,具有稳定结构和优异机械性能,已被广泛应用于各种生物领域。在先的专利对于TDNs在眼科疾病中的用途进行了公开,如专利CN109646450B中披露了TDNs在制备治疗角膜损伤的药物中的用途,专利CN112007044B中公开了TDNs-miR155复合物及其在制备预防或治疗湿性黄斑病变的药物中的用途,专利CN112843085B中公开了TDNs-miR22复合物及其在制备治疗视神经损伤的药物中用途。目前尚未见TDNs与siRNA复合物在眼科疾病中的治疗应用。
发明内容
本发明的目的在于克服现有技术中存在的上述缺陷和不足,提供一种针对Runt相关转录因子(RUNX1)基因位点的药物组合物。
本发明的第二个目的在于提供上述药物组合物在制备预防和/或治疗眼部新生血管性疾病和/或促进生理性血管生成的药物中的应用。
本发明的上述目的是通过以下技术方案给予实现的:
一种靶向RUNX1的药物组合物,包括RUNX1-CBFβ相互作用抑制剂和DNA核酸四面体与靶向RUNX1的小干扰RNA的复合物。
本发明提供的药物组合物的两种组分中,所述Runt相关转录因子(RUNX1)与核心转录因子β(CBFβ)的相互作用抑制剂可抑制RUNX1/CBFB依赖性反式激活,从而直接抑制RUNX1的激活及作用发挥。在一定浓度范围内通过玻璃体腔眼内注药可抑制视网膜新生血管形成。所述DNA核酸四面体与靶向RUNX1的小干扰RNA(siRNA)的复合物,其中小干扰RNA与DNA四面体的至少一条单链连接。所述DNA核酸四面体作为携带靶向RUNX1的siRNA的载体,不易被核酸酶溶解;无需转染,易于穿过细胞膜,药物的细胞摄取效果增强,进而提高siRNA对的降解效力,增加RUNX1的沉默效果,阻止新生血管的生成。在使用浓度下,血管内皮细胞未显示出明显的细胞毒性或不良反应。本发明所述药物组合物相较于两者单独处理可更加有效减少RUNX1的表达,阻止病理性新生血管的生成,具有显著的协同作用,并且还能够促进生理性血管的生成,从而改善视网膜无灌注区面积,可用于预防和/或治疗眼部新生血管性疾病。
优选地,所述RUNX1-CBFβ相互作用抑制剂为Ro5-3335,Ro5-3335是一种苯二氮化合物(CAS编号:30195-30-3)。
优选地,所述靶向RUNX1的小干扰RNA包括正义链和反义链,其核苷酸序列依次如SEQ ID NO.3~4所示。
优选地,所述DNA核酸四面体由四条单链DNA经碱基互补配对形成,所述四条单链DNA的核苷酸序列分别如SEQ ID NO.5~8所示。
优选地,所述UNX1-CBFβ相互作用抑制剂和DNA核酸四面体与靶向RUNX1的小干扰RNA(siRNA)的复合物所述摩尔比为75:1。
所述DNA核酸四面体-siRNA复合物的制备方法为先将siRNA的正义链或反义链与DNA核酸四面体其中一条单链连接,再将连接siRNA的单链与其他三条单链加热变性再迅速降温复性,制备得到核酸四面体-siRNA复合物。
本发明的药物组合物没有明显的药物毒性;通过在培养液中加入药物组合物的实验组与对照组相比,药物组合物可有效的抑制缺氧状态下视网膜内皮细胞的增殖作用。通过动物实验可知,玻璃体腔注射药物组合物的实验组与对照组相比,药物组合物组更加有效的抑制了视网膜新生血管的生成,具有协同作用,同时明显的减少了视网膜无血管区的面积,促进了生理性血管的形成;并且药物组合物没有明显的视网膜药物毒性,生物安全性高。鉴于病理性新生血管在所有眼部新生血管性疾病中均可见,因此可利用本发明药物组合物来抑制眼部病理性新生血管生成和/或促进眼部生理性血管生成,从而可起到预防和/或治疗眼部新生血管性疾病的作用。
因此,本发明还提供上述任一所述所述药物组合物在制备抑制眼部病理性新生血管生成和/或促进眼部生理性血管生成的药物中的应用。
本发明还提供上述任一所述所述药物组合物在制备预防和/或治疗眼部新生血管性疾病和/或促进眼部生理性血管生成的药物中的应用。
优选地,所述眼部新生血管性疾病包括但不限于视网膜新生血管相关疾病、角膜新生血管相关疾病、虹膜新生血管相关疾病或脉络膜新生血管相关疾病中的一种或多种。
优选地,所述视网膜新生血管性疾病包括但不限于糖尿病性视网膜病变(PDR)、早产儿视网膜病变(ROP)、视网膜静脉阻塞(RVO)、视网膜静脉周围炎、年龄相关性黄斑变性(AMD)、息肉样脉络膜血管病变、高度近视脉络膜新生血管或特发性脉络膜新生血管中的一种或多种。病理性视网膜新生血管在所有年龄段的常见和严重视网膜疾病中均可见。目前,对晚期ROP、PDR或RVO患者进行视网膜光凝治疗,或使用抗血管内皮生长因子(VEGF)治疗以抑制新生血管。由于激光导致视网膜组织丢失,视网膜光凝可导致视力下降、夜间视力下降和持续视野狭窄等并发症。抗VEGF治疗临床上已用于治疗ROP、DR和RVO患者,但存在潜在的缺陷。首先,与阻断血管内皮生长因子信号有关的不良反应,包括对正常视网膜血管生长和视网膜功能的损害。其次,由于持续的缺血/无灌注状态,在玻璃体内注射抗VEGF抗体后,病理性新生血管的复发在早产儿或糖尿病患者中很常见。
优选地,所述药物组合的制剂方式可以是任何适于眼部局部施用的剂型,包括但不限于注射剂、滴眼剂、脂质体或气雾剂中的一种或多种。
作为本发明所述应用的优选实施方式,在细胞给药时,药物组合物中Ro5-3335优选剂量为75μM,DNA核酸四面体-siRNA复合物优选剂量为100nM,药物配比1:1。在动物给药时,Ro5-3335优选剂量为75μM 1μL,DNA核酸四面体-siRNA优选剂量为1μM 1μL。
本发明还提供一种预防和/或治疗眼部新生血管性疾病和/或促进生理性血管生成的药物,所述药物包括上述任一所述药物组合物。所述药物以上述任一所述药物组合物为唯一活性成分搭配药物辅料或作为活性成分之一搭配其它治疗眼部新生血管性疾病的物质共同作为活性成分,再搭配药物辅料。
与现有技术相比,本发明具有以下有益效果:
本发明提供了一种靶向Runt相关转录因子1(RUNX1)基因,将直接抑制RUNX1/CBFB依赖性反式激活的RUNX1直接抑制剂Ro5-3335与高效入胞、性质稳定的RUNX1mRNA翻译过程抑制剂DNA核酸四面体-siRNA复合物结合的药物组合物,可更加有效减少RUNX1的表达,阻止新生血管的生成,具有显著的协同作用,并且还能够促进生理性血管的生成,从而改善视网膜无灌注区面积,且该药物组合物无明显的药理毒性,可用于预防和/或治疗眼部新生血管性疾病。
附图说明
图1为各给药组施用后,不同细胞(HUVEC、HREC)中RUNX1基因的沉默效果,其中包括空白对照组(Control)、siRNA+Lipo转染试剂组、Ro5-3335组、DNA核酸四面体-siRNA复合物组、药物组合物组(Ro5-3335+DNA核酸四面体-siRNA复合物);
图2为各给药组施用后,不同细胞(HUVEC、HREC)中RUNX1蛋白的沉默效果,其中包括空白对照组(Control)、siRNA+Lipo转染试剂组、Ro5-3335组、DNA核酸四面体-siRNA复合物组、药物组合物组(Ro5-3335+DNA核酸四面体-siRNA复合物);
图3为药物组合物各组分及组合物对HUVEC和HREC的存活率实验结果图;
图4为各给药组施用于血管内皮细胞低氧模型后,其细胞增殖水平实验结果图,包括空白对照组(Control)、Aflibercept(AFL,阳性对照)组、Ro5-3335组、DNA核酸四面体-siRNA复合物组、Ro5-3335+AFL组、DNA核酸四面体-siRNA复合物+AFL组、药物组合物组(Ro5-3335+DNA核酸四面体-siRNA复合物);
图5为各给药组施用于小鼠氧诱导视网膜病变(OIR)模型后,各组小鼠视网膜新生血管面积及各组小鼠无血管区面积统计结果,包括空白对照组(Control)、Aflibercept(AFL,阳性对照)组、Ro5-3335组、DNA核酸四面体-siRNA复合物组、Ro5-3335+AFL组、DNA核酸四面体-siRNA复合物+AFL组、药物组合物组(Ro5-3335+DNA核酸四面体-siRNA复合物)。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
实施例1DNA核酸四面体-siRNA复合物的合成
(1)siRNA的合成
根据RUNX1MRNA设计并委托和元生物公司合成siRNA,序列(5’→3’)为siRNA-1:CAGAGUCAGAUGCAGGAUACA(Forward,SEQ ID NO.1),UAUCCUGCAUCUGACUCUGAG(Reverse,SEQID NO.2);siRNA-2:AGUUUCUGCCGAUGUCUUCGA(Forward,SEQ ID NO.3),GAAGACAUCGGCAGAAACUAG(Reverse,SEQ ID NO.4)。
(2)DNA核酸四面体的合成
将四条单链(S1,S2,S3,S4)按照等摩尔比,分别取1μL浓度为100μM的单链母液,加入到含有96μL的TM buffer(10mM Tris-HCl,50mM MgCl2,pH8.0)的200μLEP管中,将反应液加热到95℃维持10min,然后快速降温到4℃维持20min合成了TDNs。
4条单链的序列(5′→3′)如下:
S1:ATTTATCACCCGCCATAGTAGACGTATCACCAGGCAGTTGAGACGA ACATTCCTAAGTCTGAA(SEQ ID NO.5);
S2:ACATGCGAGGGTCCAATACCGACGATTACAGCTTGCTACACGATTC AGACTTAGGAATGTTCG(SEQ ID NO.6);
S3:ACTACTATGGCGGGTGATAAAACGTGTAGCAAGCTGTAATCGACGG GAAGAGCATGCCCATCC(SEQ ID NO.7);
S4:ACGGTATTGGACCCTCGCATGACTCAACTGCCTGGTGATACGAGGA TGGGCATGCTCTTCCCG(SEQ ID NO.8)。
(3)DNA核酸四面体-siRNA复合物的合成
其中S2通过连接序列-TTTCG-与siRNA的正义链以化学键连接,将S2-siRNA、S1、S3、S4按照等摩尔比,分别取1μL浓度为100μM的单链母液,加入到含有96μL的TM buffer(10mM Tris-HCl,50mM MgCl2,pH 8.0)的200μLEP管中,将反应液加热到95℃维持10min,然后快速降温到4℃维持20min合成了TDN-siRNA(TDN-siRNA-1、TDN-siRNA-2)。
注:关于说明书序列表中SEQ ID NO:1~8的说明:根据WIPO·Sequence软件的编辑规则,核苷酸序列必须只包含“WIPO·ST.26附件I第1部分”中列出的符号,碱基“t”在RNA序列中即为“u”,所以本发明上述SEQ ID NO:1~8与序列表中的SEQ ID NO:1~8实质相同。
实施例2细胞实验
(1)RUNX1基因抑制实验
细胞:人视网膜内皮细胞(HREC)、人脐静脉内皮细胞(HUVEC);
实验分组:空白对照组(Control)、siRNA+Lipo转染试剂组、Ro5-3335组、DNA核酸四面体-siRNA复合物组、药物组合物组(Ro5-3335+DNA核酸四面体-siRNA复合物);
实验方法:
1)复苏HREC/HUVEC,稳定培养传代1~2代,转染前一天,6孔板中每个孔内接种细胞,密度约30%,每孔加入2mL完全培养基;
每孔加入2mL新鲜的无血清的生长培养基,用培养基稀释各候选siRNA+Lipofectamine RNAiMAX的复合物加入到各待测细胞组中,使siRNA浓度为20nmol/L。在37℃的二氧化碳培养箱中培养细胞6小时后更换含有血清的培养基并培养细胞48小时后检测沉默效果;
(2)Ro5-3335(75μM)的配制:取1mg Ro5-3335粉剂溶于5.12mL的25mg/mL澄清DMSO中,混合均匀;将上述澄清溶液加入20.48mL的PEG300中,继续加入2.56mL的Tween-80,最后用生理盐水定容至51.2mL;将Ro5-3335和DNA核酸四面体复合物总体积同单独用药组,浓度减半等体积混合成为药物组合物;
(3)检测:上述各组细胞接受处理后按照总RNA提取试剂盒步骤过柱提取,每组取等量RNA参照逆转录试剂盒步骤,进行逆转录合成为cDNA,根据试剂盒指示,以cDNA为模板进行实时荧光PCR扩增,得到Ct值,以β-actin为内参,使用相对定量法计算。结果如图1所示,siRNA-2沉默效果最佳,因此选择siRNA-2进行后续实验;
实验结果:如图1所示,各细胞中基因沉默的作用趋势大致相同,其中siRNA+Lipo组、Ro5-3335组、DNA核酸四面体-siRNA复合物组与空白组相比展现出一定的基因沉默作用。而药物组合物组表现出更佳的抑制效果,具有协同作用。
(2)RUNX1蛋白抑制实验
细胞:人视网膜内皮细胞(HREC)、人脐静脉内皮细胞(HUVEC);
实验分组:空白对照组(Control)、siRNA+Lipo转染试剂组、Ro5-3335组、DNA核酸四面体-siRNA复合物组、药物组合物组(Ro5-3335+DNA核酸四面体-siRNA复合物);
实验方法:细胞培养方法同例2(1),转染/加药后培养24小时收样,提取蛋白,检测浓度后进行Western-Blot实验。
实验结果:如图2所示,药物组合物组的蛋白抑制效果明显优于其他组,具有协同作用。。
(3)细胞存活率实验(CCK8染色)
细胞:人视网膜内皮细胞(HREC)、人脐静脉内皮细胞(HUVEC);
实验分组:空白对照组(Control)、siRNA+Lipo转染试剂组、Ro5-3335组、DNA核酸四面体-siRNA复合物组、药物组合物组(Ro5-3335+DNA核酸四面体-siRNA复合物);
实验方法:
1)将于HREC/HUVEC接种至96孔板中,每孔104个细胞,培养48小时。各给药组施用后孵育24小时,观察细胞并进行后续实验;
2)细胞培养基和CCK8染色原液以1:100比例配置,细胞经药物处理至特定的时间点后弃去上清,每孔加入100μL染液,37℃培养箱中放置1小时;
3)用酶标仪检测450nm的每孔吸光值进行比较,细胞存活率%=[A(加药)-A(空白)]/[A(阴性对照)-A(空白)]。
实验结果:如图3所示,各组细胞CCK8水平相比无较大差异,说明药物复合物对细胞无明显生物学毒性。
实施例3体内外模型实验
(1)血管内皮细胞低氧模型
细胞:人视网膜内皮细胞(HREC)、人脐静脉内皮细胞(HUVEC);
实验分组:①空白对照组(Control):;②Aflibercept(AFL,阳性对照)组:终浓度为1μg/μL;③Ro5-3335组:终浓度为75μM;④DNA核酸四面体-siRNA复合物组:终浓度为100nM;⑤Ro5-3335+AFL组:各自终浓度同上;⑥DNA核酸四面体-siRNA复合物+AFL组:各自终浓度同上;⑦药物组合物组:各自终浓度为上述单独使用时的一半;
实验方法:用添加10%胎牛血清抗生素溶液的改良Eagle‘s培养液培养细胞,在含有95%空气和5%CO2的常氧环境中37℃培养24小时,然后加入各组药物,分别在低氧(37℃,1%O2,5%CO2)下再培养24小时。按厂家说明书进行EDU细胞增殖实验。用共聚焦激光显微镜(Carl Zeiss,Oberkochen,德国)观察6孔板中的内皮细胞的染色图像。采用ImageJ软件进行统计分析。
实验结果:如图4所示,与Control组相比,AFL组、Ro5-3335组、DNA核酸四面体-siRNA复合物组均可抑制内皮细胞增殖,Ro5-3335+AFL组及DNA核酸四面体-siRNA复合物+AFL组展现出优于前3组的抑制效果。值得注意的是,Ro5-3335+DNA核酸四面体-siRNA复合物组展现出明显优于前几组的抑制效果,具有协同作用。
(2)氧诱导视网膜病变(OIR)小鼠模型
1)小鼠出生后P7至P12置于氧气浓度75%的氧箱中,高浓度氧气会导致未成熟视网膜血管的丧失,并减慢正常视网膜血管系统的发育,导致视网膜中央无血管区形成;
2)P12回到正常室内空气中(氧气浓度约21%),低氧环境诱导血管生成因子的表达,导致正常视网膜血管的再生,以及新生血管的病理性形成,模拟ROP的第二阶段;
3)P12玻璃体腔分组给药,给药方式如下:①空白对照组(Control):不进行玻璃体腔给药;②Aflibercept(AFL,阳性对照)组:双眼玻璃体腔给药AFL 1μL40mg/mL;③Ro5-3335组:双眼玻璃体腔给药Ro5-3335 1μL 75μM;④DNA核酸四面体-siRNA复合物组:双眼玻璃体腔给药1μL 1μM;⑤Ro5-3335+AFL组:双眼玻璃体腔给药1μL等体积Ro5-3335和AFL混合物;⑥DNA核酸四面体-siRNA复合物+AFL组:双眼玻璃体腔给药1μL等体积DNA核酸四面体-siRNA复合物和AFL混合物;⑦药物组合物组:双眼玻璃体腔给药1μL等体积Ro5-3335和DNA核酸四面体-siRNA复合物;
4)P17时取材铺片,观察视网膜并进行免疫荧光染色后拍照,ImageJ计算视网膜新生血管及无血管区面积。
实验结果:如图5所示,与Control组相比,AFL组、Ro5-3335组、DNA核酸四面体-siRNA复合物组均可减少视网膜新生血管形成,Ro5-3335+AFL组及DNA核酸四面体-siRNA复合物+AFL组展现出优于前3组的抑制效果。值得注意的是,Ro5-3335+DNA核酸四面体-siRNA复合物组展现出明显优于前几组的新生血管抑制效果,具有协同作用,同时还明显的促进了无血管区生理性血管的生成,从而改善视网膜无灌注区面积。
Claims (10)
1.一种靶向RUNX1的药物组合物,其特征在于,包括RUNX1-CBFβ相互作用抑制剂,DNA核酸四面体与靶向RUNX1的小干扰RNA的复合物。
2.根据权利要求1所述组合物,其特征在于,所述RUNX1-CBFβ相互作用抑制剂为Ro5-3335。
3.根据权利要求1所述药物组合物,其特征在于,所述靶向RUNX1的小干扰RNA包括正义链和反义链,其核苷酸序列依次如SEQ ID NO.3~4所示。
4.根据权利要求1所述药物组合物,其特征在于,所述DNA核酸四面体由四条单链DNA经碱基互补配对形成,所述四条单链DNA的核苷酸序列分别如SEQ ID NO.5~8所示。
5.根据权利要求1所述药物组合物,其特征在于,所述RUNX1-CBFβ相互作用抑制剂、DNA核酸四面体与靶向RUNX1的小干扰RNA的复合物的摩尔比为75:1。
6.权利要求1~5任一所述药物组合物在制备预防和/或治疗眼部新生血管性疾病和/或促进生理性血管生成的药物中的应用。
7.根据权利要求6所述应用,其特征在于,所述眼部新生血管性疾病包括视网膜新生血管相关疾病、角膜新生血管相关疾病、虹膜新生血管相关疾病或脉络膜新生血管相关疾病中的一种或多种。
8.根据权利要求7所述应用,其特征在于,所述视网膜新生血管性疾病包括糖尿病性视网膜病变、早产儿视网膜病变、视网膜静脉阻塞、视网膜静脉周围炎、年龄相关性黄斑变性、息肉样脉络膜血管病变、高度近视脉络膜新生血管或特发性脉络膜新生血管中的一种或多种。
9.根据权利要求6所述应用,其特征在于,所述药物制剂为注射剂、滴眼剂、脂质体或气雾剂中的一种或多种。
10.一种预防和/或治疗眼部新生血管性疾病和/或促进生理性血管生成的药物,其特征在于,所述药物包括权利要求1~5任一所述药物组合物。
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