CN108570094A - Ae多肽及其在制备肿瘤靶向诊治递药***中的用途 - Google Patents
Ae多肽及其在制备肿瘤靶向诊治递药***中的用途 Download PDFInfo
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Abstract
AE多肽及其在制备肿瘤靶向诊治递药***中的用途。本发明属药学领域,涉及高度稳定且可靶向表皮生长因子受体和表皮生长因子受体突变体III高表达细胞的D构型多肽DAE及L构型多肽,及在制备肿瘤诊断和靶向治疗的诊断和治疗药物复合物、修饰的高分子载体材料及其所构建的脂质体、聚合物胶束、聚合物圆盘、纳米粒等递药***中的应用。经试验结果显示:DAE的EGFR蛋白和EGFRvIII蛋白结合活性在血清中更稳定;所修饰的药物被表达EGFR或EGFRvIII的阳性细胞和肿瘤组织特异性摄取,具有良好的肿瘤靶向和影像功能;构建的纳米递药***能有效将药物递送至靶组织,体内主动靶向效果更优,在肿瘤诊断和靶向治疗中具备良好的应用前景。
Description
技术领域
本发明属药学领域,涉及AE多肽及其在制备肿瘤靶向诊治递药***中的用途,具体涉及高度稳定且可靶向表皮生长因子受体和表皮生长因子受体突变体 III高表达细胞的D构型多肽,及D构型多肽和L构型多肽的药物复合物和修饰的纳米递药***,尤其涉及D构型多肽DAE(D构型氨基酸序列DFDADLDGDEDA),及L构型多肽LAE(L构型氨基酸序列FALGEA)和D构型多肽DAE在制备肿瘤诊断和靶向治疗的诊断和治疗药物复合物、修饰的高分子载体材料及其所构建的脂质体、聚合物胶束、聚合物圆盘、纳米粒等递药***中的应用。
背景技术
资料显示肿瘤是严重威胁人类生命和健康的疾病,其死亡率高居所有疾病死亡率首位。传统的化疗作为肿瘤药物治疗的主要手段,存在对肿瘤组织选择性差、毒性大、治疗窗窄、易产生多药耐药等缺陷,因此,为克服化疗的局限性,近年来,主动靶向成为提高肿瘤组织靶向效率的重要策略。主动靶向策略主要针对肿瘤组织中高表达的受体或转运体,利用与特异性受体或转运体具有识别、结合能力的对应配体,将药物或纳米递药***递送至肿瘤组织或细胞中。常用的对应配体包括单克隆抗体、多肽、核酸适体、小分子化合物等,研究显示,配体修饰后的药物或纳米递药***可通过细胞表面受体或转运体与配体的特异性识别、结合、内化,将药物递送至肿瘤组织和细胞内,从而实现对肿瘤的主动靶向。
表皮生长因子受体(EGFR)是表皮生长因子的特异性受体,EGFR信号转导途径在肿瘤细胞的增殖、损伤修复、侵袭及新生血管形成等方面起重要作用。在大多数肿瘤中(如乳腺癌、胶质瘤、***癌、非小细胞肺癌等),EGFR存在过表达且伴随突变、重排。研究报导,40-50%的胶质瘤细胞存在EGFR异常增高并伴随多种基因突变,最常见的突变形式是表皮生长因子受体突变体III (EGFRvIII),EGFR胞外部分2-7外显子的缺失形成的EGFRvIII,可通过非配体依赖的自身磷酸化,产生持续的转导信号,促进胶质瘤细胞的增殖、侵袭和迁移;LAE(L构型氨基酸序列FALGEA)是通过混合物位置扫描库筛选出的与 EGFR和EGFRvIII有高度结合活性的六肽,能靶向EGFR和EGFRvIII高表达的肿瘤新生血管、拟态血管和肿瘤细胞,但迄今,尚未见有用于介导药物进行肿瘤靶向诊疗方面的报道。
发明内容
本发明的目的是提供AE多肽在肿瘤靶向诊疗中的应用并进一步优化已有多肽的稳定性,达到更好的体内肿瘤靶向效果。具体涉及制备具有高稳定性的D 构型多肽DAE(D构型氨基酸序列DFDADLDGDEDA),并以LAE(L构型氨基酸序列FALGEA)和DAE修饰药物分子和高分子载体材料,构建AE药物复合物、 AE修饰的纳米递药***,以实现药物对肿瘤的靶向诊疗。
具体的,本发明利用固相多肽合成技术,设计并制备了D构型多肽DAE,该多肽对血清具有高稳定性、与表皮生长因子受体(EGFR)和表皮生长因子受体突变体III(EGFRvIII)具有高亲和力。
本发明中,LAE与所设计的DAE连接半胱氨酸后,利用其分子中巯基与马来酰亚胺功能化荧光物质(如Fluorescein、近红外染料Cy5.5、IR820、DiR、磁共振影像剂Gd-DTPA、放射影像剂99mTc-DTPA等)反应形成复合物;
本发明中,LAE和所设计的DAE修饰药物,包括通过马来酰亚胺己肼衍生物反应形成pH敏感腙键(涉及阿霉素、表阿霉素等含酮或醛基的药物)、或通过3-(2-吡啶二巯基)丙酸衍生物反应形成二硫键(涉及紫杉醇、多烯紫杉醇、喜树碱、羟基喜树碱、9-硝基喜树碱、长春新碱等含羟基或氨基的药物)、或通过多巴胺与药物中硼酸基团反应形成pH敏感硼酸脂(涉及硼替佐米等含硼酸基团的药物)、或通过固相合成直接形成酰胺键(涉及p53激活肽、抗菌肽、多肽毒素等多肽药物)的多肽-药物复合物;
本发明中,LAE和所设计的DAE连接半胱氨酸后,修饰在含马来酰亚胺功能基的聚乙二醇-二硬脂酰基磷脂酰乙醇胺(PEG-DSPE)、聚乙二醇-聚乳酸 (PEG-PLA)、聚乙二醇-乳酸羟基乙酸共聚物(PEG-PLGA)、聚乙二醇-聚己内酯(PEG-PCL)等高分子载体材料上,可用于构建LAE和DAE修饰的脂质体、聚合物胶束、聚合物圆盘、纳米粒等递药***。
本发明所设计的LAE和DAE修饰的纳米递药***包载紫杉醇、多烯紫杉醇、阿霉素、表阿霉素、喜树碱、羟基喜树碱、9-硝基喜树碱、长春新碱、硼替唑米、卡非佐米、小白菊内酯、p53激活肽、蜂毒肽、蝎毒肽等抗肿瘤药物;也可包载荧光物质香豆素6、FAM,近红外染料Cy5.5、IR820、DiR、DiD、磁共振影像剂Gd-DTPA等影像物质。
本发明所设计的DAE可介导药物或纳米递药***靶向EGFR和EGFRvIII 高表达的细胞及其组织,用于肿瘤的靶向诊断和治疗。
本发明提供了DAE制备和性质考察以及上述LAE和DAE所修饰的药物复合物和纳米递药***用于肿瘤诊疗的物质基础;本发明的试验结果表明:LAE和DAE均可介导的体内主动靶向;与LAE相比,DAE在血清中稳定性更好,因而其介导的体内主动靶向效果更优。本发明的实施例中,公开了下述技术方案:
1.AE、AE-Cys及其荧光标记物(AE-Fluorescein、AE-Cy7)的合成
采用固相多肽合成方法制备LAE、LAE-Cys、DAE、DAE-Cys。通过马来酰亚胺基团与巯基的Michael加成反应合成LAE-Fluorescein、DAE-Fluorescein、LAE-Cy7、DAE-Cy7;HPLC、MS表征结构;
2.AE-DTPA-Gd与AE-DTPA-99mTc的合成
通过马来酰亚胺基团与巯基的Michael加成反应合成DAE-DTPA或LAE-DTPA,螯合Gd或99mTc得AE-DTPA-Gd或AE-DTPA-99mTc;
3.AE稳定性和受体亲和性评价
从血清稳定性、与高表达EGFR和EGFRvIII的细胞摄取能力两方面进行DAE 性质的考察,将DAE和LAE分别与小鼠血清在37℃进行孵育,在不同时间点检测多肽的浓度进行稳定性的比较,比较DAE-Fluorescein、LAE-Fluorescein对EGFR 和EGFRvIII高表达的细胞(如:脐静脉内皮细胞HUVEC)和模型肿瘤细胞(如:脑胶质瘤细胞U87)的体外靶向性,比较体外3D肿瘤球模型对DAE-Fluorescein、LAE-Fluorescein的摄取能力;
4.AE药物复合物的制备
连接半胱氨酸后的LAE和DAE与药物的马来酰亚胺己肼衍生物反应,形成含pH敏感腙键的多肽-药物复合物,其中所涉及药物包括阿霉素、表阿霉素等含酮或醛基的药物;
连接半胱氨酸后的LAE和DAE与药物的3-(2-吡啶二巯基)丙酸衍生物反应,形成含二硫键的多肽-药物复合物,其中所涉及药物包括紫杉醇、多烯紫杉醇、喜树碱、羟基喜树碱、9-硝基喜树碱、长春新碱等含羟基或氨基的药物;
LAE和DAE通过修饰上多巴胺进而与药物的硼酸基团反应,形成含pH敏感硼酸脂的多肽-药物复合物,其中所涉及药物包括硼替佐米等含硼酸基团的药物;
LAE和DAE通过固相合成直接与多肽药物缩合制成融合多肽,其中所涉及药物包括p53激活肽、抗菌肽、多肽毒素等多肽药物;
5.AE脂质体递药***的构建与表征
首先合成DAE、LAE修饰的高分子材料DAE-PEG-DSPE和LAE-PEG-DSPE。通过连接DAE-Cys和LAE-Cys上的游离巯基与Mal-PEG-DSPE反应得到DAE-PEG-DSPE和LAE-PEG-DSPE;
然后分别制备DAE和LAE修饰的脂质体(DAE-Liposome和LA7R-Liposome),以一定比例的HSPC/Chol/mPEG2000-DSPE/AE-PEG-DSPE为膜材料和药物 (FAM、DiR或者阿霉素),采用成膜水化法制备脂质体(AE-Liposome/FAM、 AE-Liposome/DiR或AE-Liposme/DOX),用挤压过膜的方法减小脂质体粒径,构建平均粒径在100nm左右的脂质体。激光散射粒度仪表征胶束粒径和粒径分布;
6.AE胶束递药***的构建与表征
首先合成LAE和DAE修饰的高分子材料LAE-PEG-PLA和DAE-PEG-PLA,通过连接半胱氨酸后多肽上的游离巯基与Mal-PEG-PLA所含马来酰亚胺的反应实现材料的合成,1H-NMR表征;
然后制备LAE和DAE胶束(LAE-Micelle、DAE-Micelle)。一定量的 AE-PEG-PLA,mPEG-PLA和药物(香豆素-6、DiR或者紫杉醇)采用成膜法制备胶束(AE-Micelle/C6、AE-Micelle/DiR或AE-Micelle/PTX),激光散射粒度仪表征胶束粒径和粒径分布;
7.AE-Micelle的体内外肿瘤靶向性评价
考察U87细胞体外肿瘤球模型对LAE-Micelle/C6、DAE-Micelle/C6和 mPEG-Micelle/C6的摄取情况;
通过荷U87皮下移植瘤模型裸鼠尾静脉分别注射LAE-Micelle/DiR、DAE-Micelle/DiR和mPEG-Micelle/DiR,比较不同组在各时间点的肿瘤内分布;
8.AE-Micelle/PTX的体内抗肿瘤效果评价
通过荷U87皮下移植瘤模型裸鼠尾静脉分别注射LAE-Micelle/PTX、DAE-Micelle/PTX、mPEG-Micelle/PTX、临床用制剂泰素、生理盐水,以瘤体积、瘤重和肿瘤组织细胞凋亡、新生血管和拟态血管数量为指标评价不同载紫杉醇胶束的体内抗肿瘤效果。
本发明提供了LAE多肽修饰的药物复合物和修饰的纳米递药***,能实现肿瘤的靶向诊断和治疗;同时针对L构型多肽在血液中易降解,可能导致肿瘤靶向能力降低的问题,提供了高度稳定且与EGFR和EGFRvIII有高度结合活性的D构型多肽靶向分子DAE(D构型氨基酸序列DFDADLDGDEDA),并构建其修饰的药物复合物和修饰的纳米递药***,获得了更好的体内肿瘤靶向和诊疗效果。
附图说明
图1、DAE的HPLC和ESI-MS图谱
色谱方法:色谱柱(YMC,C18):150×4.6mm;流动相A:水(含0.1%三氟乙酸),流动相B:乙腈(含0.1%三氟乙酸);洗脱程序:0-30min 5%B-65%B;流速:0.7mL/min;柱温:40℃;检测:UV 214nm,保留时间:13.95min,ESI-MS: 606,与理论分子量相符合。
图2、DAE-Cys的HPLC和ESI-MS图谱
色谱方法同上,保留时间:14.33min。ESI-MS:709.2,与理论分子量相符合。
图3、LAE的HPLC和ESI-MS图谱
色谱方法同上,保留时间:13.95min。ESI-MS:606,与理论分子量相符合。
图4、LAE-Cys的HPLC和ESI-MS图谱
色谱方法同上,保留时间:14.33min。ESI-MS:709.2,与理论分子量相符合。
图5、DAE-Fluorescein的HPLC和ESI-MS图谱
色谱方法同上,保留时间:18.63min。ESI-MS:1137.18,与理论分子量相符合。
图6、LAE-Fluorescein的HPLC和ESI-MS图谱
色谱方法同上,保留时间:18.63min。ESI-MS:1137.18,与理论分子量相符合。
图7、DAE-Cy7的HPLC和ESI-MS图谱
色谱方法同上,保留时间:31.21min。ESI-MS:1416.66,与理论分子量相符合。
图8、LAE-Cy7的HPLC和ESI-MS图谱
色谱方法同上,保留时间:31.21min。ESI-MS:1416.66,与理论分子量相符合。
图9、DAE-PEG-DSPE和LAE-PEG-DSPE的1H-NMR图谱
Mal-PEG-DSPE的核磁图谱于6.7ppm显示出马来酰亚胺峰,而LAE-PEG-DSPE、DAE-PEG-DSPE核磁图谱中该峰消失,显示Mal-PEG-DSPE中的马来酰亚胺基团已连接上AE。
图10、DAE-PEG-PLA和LAE-PEG-PLA的1H-NMR图谱
Mal-PEG-PLA的核磁图谱于6.7ppm显示出马来酰亚胺峰,而LAE-PEG-PLA、DAE-PEG-PLA核磁图谱中该峰消失,显示Mal-PEG-PLA中的马来酰亚胺基团已连接上AE。
图11、载阿霉素脂质体的粒径
图为各载阿霉素脂质体的粒径,由图可知,各处方脂质体大小和形态均无显著差异。
图12、DAE和LAE的血清稳定性
图纵坐标为完整多肽的残留百分比,可见DAE在50%小鼠血清中的稳定性显著高于LAE,孵育2h,LAE完全降解、DAE几乎不降解。
图13、脑胶质瘤细胞U87对Fluorescein标记多肽的摄取
其中,左图和右图分别为Fluorescein标记的DAE和LAE与U87细胞作用 4h后的激光共聚焦照片和流式细胞荧光检测结果,可见U87细胞对DAE和LAE 的摄取明显高于游离荧光素,但对两种多肽的摄取没有明显差异。
图14、脐静脉内皮细胞HUVEC对Fluorescein标记多肽的摄取
其中,左图和右图分别为Fluorescein标记的DAE和LAE与HUVEC细胞作用4h后的激光共聚焦照片和流式细胞荧光检测结果。可见HUVEC细胞对DAE 和LAE的摄取明显高于游离荧光素,但对两种多肽的摄取没有明显差异。
附图15、U87体外肿瘤球模型对Fluorescein标记多肽的摄取
图为Fluorescein标记的DAE和LAE分别与U87体外肿瘤球模型作用4h后的荧光断层扫描图像,可见U87体外肿瘤球模型对DAE和LAE的摄取明显高于游离荧光素,但对两种多肽的摄取没有明显差异。
图16、Cy7标记多肽的荷皮下移植瘤裸鼠体内分布
其中,图A为荷U87皮下移植瘤裸鼠尾静脉注射Cy7标记多肽2h后的离体肿瘤影像分布结果;图B为离体肿瘤的荧光半定量结果;图C为离体肿瘤和脏器的荧光分布图像;图D为离体肿瘤和脏器的荧光半定量结果,结果表明, Cy7标记的DAE和LAE在肿瘤内的蓄积均显著高于游离Cy7(***p<0.001),DAE 肿瘤靶向效果优于LAE。
图17、U87体外肿瘤球模型对载C6胶束的摄取
图为DAE-Micelle/C6、LAE-Micelle/C6、mPEG-Micelle/C6与U87体外肿瘤球模型细胞作用30min后的荧光断层扫描图像可见U87肿瘤球对DAE-Micelle、LAE-Micelle的摄取量显著高于未修饰胶束。
图18、载近红外荧光染料胶束的皮下瘤裸鼠体内分布
其中,图A为尾静脉注射载近红外荧光染料DiR胶束各个时间点在体荧光分布图像;图B为给予制剂24h后离体肿瘤和脏器的荧光分布图像;图C为图 B的荧光半定量统计结果,结果表明,相比mPEG-Micelle,DAE-Micelle和LAE-Micelle能更好地靶向至肿瘤部位,且DAE-Micelle的靶向效果优于LAE-Micelle。
图19、载紫杉醇胶束的粒径
图为各载紫杉醇胶束的粒径,由图可知,各处方胶束大小和形态均无显著差异。
图20、载紫杉醇胶束体外抗U87细胞和HUVEC细胞活性曲线
其中,图A和图B分别为mPEG-Micelle/PTX、DAE-Micelle/PTX、LAE-Micelle/PTX和泰素抗U87细胞和HUVEC细胞的活性曲线。图A表明U87 细胞给药4h培养72h后,其IC50分别为0.21、0.02、0.05和0.31nM。三种胶束均能抑制U87细胞的体外生长,其中DAE-Micelle/PTX体外活性为LAE-Micelle/PTX的2.5倍。图B表明HUVEC细胞给药4h后培养72h,其IC50分别为0.70、0.06、0.21和0.85nM。三种胶束均能抑制HUVEC细胞的体外生长,其中DAE-Micelle/PTX体外活性为LAE-Micelle/PTX的3.5倍。
图21、载紫杉醇胶束对新生血管体外模型的抑制
其中,图A为mPEG-Micelle/PTX、LAE-Micelle/PTX、DAE-Micelle/PTX和对体外新生血管模型的抑制照片,图B为新生血管形成率定量结果,相比于mPEG-Micelle/PTX,DAE-Micelle/PTX和LAE-Micelle/PTX抑制新生血管的形成更显著,且DAE-Micelle的抑制效果优于LAE-Micelle(*p<0.05,**p<0.01)。
图22、载紫杉醇胶束对拟态血管体外模型的抑制
其中,图A为mPEG-Micelle/PTX、LAE-Micelle/PTX、DAE-Micelle/PTX和对体外拟态血管模型的抑制照片,图B为各组拟态血管结构的形成率定量结果,相比于mPEG-Micelle/PTX,DAE-Micelle/PTX和LAE-Micelle/PTX抑制拟态血管的形成更显著,且DAE-Micelle的抑制效果优于LAE-Micelle(*p<0.05, ***p<0.001)。
图23、载紫杉醇胶束抑制皮下移植瘤效果
其中图A为各组裸鼠肿瘤体积随时间变化的曲线,与生理盐水组相比,各给药组对肿瘤生长均有抑制作用。相比于mPEG-Micelle/PTX,DAE-Micelle/PTX 和LAE-Micelle/PTX均能显著抑制肿瘤生长,且DAE-Micelle/PTX抗肿瘤药效显著优于LAE-Micelle/PTX(n=8,***p<0.001),图B为将裸鼠处死取出肿瘤组织后称重并进行统计分析,结果表明各组瘤重大小为:DAE-Micelle /PTX<LAE-Micelle/PTX<mPEG-Micelle/PTX,DAE-Micelle/PTX的抑瘤效果最显著(n=8,***p<0.001)。
图24、TUNEL染色结果
图为mPEG-Micelle/PTX、LAE-Micelle/PTX、DAE-Micelle/PTX和皮下瘤的TUNEL染色照片(bar=100μm),其中细胞核呈棕黄色或棕褐色为阳性凋亡细胞,与mPEG-Micelle/PTX相比,DAE-Micelle/PTX和LAE-Micelle/PTX促进肿瘤组织凋亡更显著,且DAE-Micelle的促凋亡作用优于LAE-Micelle。
图25、CD31/PAS双染色结果
图为mPEG-Micelle/PTX、LAE-Micelle/PTX、DAE-Micelle/PTX和的 CD31/PAS双染色照片(bar=100μm),细胞核呈棕黄色或棕褐色为新生血管,与 mPEG-Micelle/PTX相比,DAE-Micelle/PTX和LAE-Micelle/PTX抑制新生血管的形成更显著,且DAE-Micelle的新生血管抑制作用优于LAE-Micelle。
具体实施方式
通过下述实施例将有助于进一步理解本发明,但本发明不局限于如下描述范围。
实施例1
AE、AE-Fluorescein、AE-Cy7、AE-DTPA-Gd、AE-DTPA-99mTc、AE-药物、 AE-PEG-PLA的合成与表征
1)LAE和DAE、LAE-Cys和DAE-Cys的合成与表征
采用固相多肽合成法,设计并合成由D构型氨基酸所构成的DAE(序列为DFDADLDGDEDA)和DAE-Cys(序列为DFDADLDGDEDADC)以及L构型氨基酸所构成的LAE(序列为FALGEA)和LAE-Cys(序列为FALGEAC)。
具体方法:以Boc固相多肽合成法,在PAM树脂上按序列依次接入氨基酸,以HBTU/DIEA为缩合剂、TFA为脱保护剂进行反应。反应完成后,将树脂用含 P-cresol的氟化氢进行切割,冰浴搅拌反应1h,反应结束后减压抽去氟化氢,冰***沉淀并洗涤沉淀3次,沉淀以20%乙腈重新溶解,收集滤液后旋蒸,得到多肽粗品溶液,多肽粗品用乙腈/水(含0.1%TFA)体系分离纯化。HPLC和ESI-MS 表征DAE、DAE-Cys、LAE和LAE-Cys的纯度和分子量(Mw),HPLC图谱、质谱图如图1、图2、图3和图4所示;
2)AE-Fluorescein与AE-Cy7的合成与表征
将上述制得的DAE-Cys或LAE-Cys溶于0.1M的PBS溶液中(pH7.2), Fluorescein-5-maleimide溶于DMF,两者混合后磁力搅拌反应,HPLC监测,待反应完全后制备液相纯化,用乙腈/水(含0.1%TFA)体系分离纯化,冷冻干燥得DAE-Fluorescein或LAE-Fluorescein纯品,HPLC图谱、质谱图如图5、6所示;
AE-Cy7的制备方法同上,HPLC图谱、质谱图如图7、8所示;
3)AE-DTPA-Gd与AE-DTPA-99mTc的制备
maleimide-DTPA溶于DMF,同上与DAE-Cys或LAE-Cys的PBS溶液混合搅拌反应,制备液相纯化,冷冻干燥得DAE-DTPA或LAE-DTPA纯品,螯合Gd 或99mTc即得AE-DTPA-Gd或AE-DTPA-99mTc;
4)AE-药物复合物的制备,包括,
以AE-阿霉素复合物制备作为AE连接含酮或醛基药物的实例;9.4mg AE-Cys(DAE-Cys或LAE-Cys)溶于3mL磷酸盐缓冲液(0.1mM,pH 7.0),加入10倍摩尔量的三(2-羧乙基)膦(TCEP),于4℃搅拌20min。然后加入4倍摩尔量的阿霉素6-马来酰亚胺己肼衍生物,于室温避光反应1h。反应液用制备液相纯化,冷冻干燥得DAE或LAE-阿霉素复合物。
以AE-紫杉醇复合物作为AE以二硫键连接含羟基或氨基药物的实例;200mg 紫杉醇溶于10mL氯仿中,冷却至0-5℃,先后加入39.99mg DCC及60.4mg 3-(2- 吡啶二巯基)丙酸,加料完毕后,升至室温反应过夜,反应液过滤,经柱层析纯化(CHCl3/MeOH=50:1-15:1,V/V洗脱)得紫杉醇3-(2-吡啶二巯基)丙酸衍生物,紫杉醇3-(2-吡啶二巯基)丙酸衍生物溶解在5mL DMF中,1.5倍摩尔量的AE-Cys 溶解在PBS/DMF中,溶液pH值保持4~5,将紫杉醇3-(2-吡啶二巯基)丙酸衍生物滴加至巯基多肽溶液中,于室温反应6h,经制备液相纯化冻干得AE-紫杉醇复合物;
以AE-硼替佐咪复合物作为AE连接含硼酸基团药物的实例,依照AE的合成在树脂上依次接入氨基酸,待多肽的所有氨基酸残基接入完毕,三氟乙酸脱去氮端的Boc保护。加入含3倍摩尔量的丁二酸酐与DIEA的DMF溶液,于室温反应30min。洗涤树脂后,加入5倍摩尔量的三甲基氯硅烷保护多巴胺,并以 HBTU/DIEA为缩合剂,于室温反应1h。树脂用HF切割,并经制备型HPLC纯化得AE-多巴胺衍生物,在pH7.4的缓冲液中,AE-多巴胺衍生物与硼替佐咪以摩尔比1:1混合即得AE-硼替佐咪复合物;
以AE-PMI融合多肽作为AE连接多肽药物的实例,直接通过固相多肽合成法制得,具体方法为:确定AE-PMI多肽序列后,按与制备AE相同的方法依次接入氨基酸,经HF切割并纯化后得AE-PMI融合多肽;
5)AE-PEG-DSPE的合成与表征
将DAE-Cys或LAE-Cys溶于0.1M的PBS溶液中(pH7.2),取Mal-PEG-PLA 溶于DMF,两者混合后磁力搅拌反应,HPLC监测,待Mal-PEG-DSPE反应完全后停止反应,过量的DAE-Cys、LAE-Cys和DMF透析(截留分子量3.5kDa) 除去,冷冻干燥得DAE-PEG-DSPE或LAE-PEG-DSPE,NMR表征其结构(如图 9所示);
6)AE-PEG-PLA的合成与表征
将DAE-Cys或LAE-Cys溶于0.1M的PBS溶液中(pH7.2),取Mal-PEG-PLA 溶于DMF,两者混合后磁力搅拌反应,HPLC监测,待Mal-PEG-PLA反应完全后停止反应,过量的DAE-Cys、LAE-Cys和DMF透析(截留分子量3.5kDa)除去,冷冻干燥得DAE-PEG-PLA或LAE-PEG-PLA,NMR表征其结构(如图10 所示)。
实施例2 AE脂质体/Dox的制备
PEG-脂质体膜材料处方组成为HSPC/Chol/mPEG2000-DSPE(52:43:5, mol/mol),多肽修饰的PEG脂质体膜材料处方为HSPC/Chol/mPEG2000-DSPE/多肽-PEG-DSPE(52:43:3:2,mol/mol),称取上述膜材料溶于氯仿,减压旋转蒸发除去有机溶媒,得均匀脂质膜,真空干燥24h,采用硫酸铵梯度法制备包载阿霉素(DOX)的各脂质体,动态光散射法测定粒径分布(如图11所示)。
实施例3 AE的血清稳定性考察
将DAE及LAE配成1mg/mL水溶液,取0.1mL加入0.9mL的50%小鼠血清中,37℃孵育,分别于0、5和15min,0.5、1、2、4、6和8h取出100μL,加入20μL三氯乙酸(TCA)沉淀血清中蛋白,4℃静置20min,12000转/分钟离心 10min,取上清液20μL进行HPLC分析,血清稳定性结果(如图12所示)表明,DAE具有比LAE更好的血清稳定性。
实施例4 AE的体外细胞靶向性验证
1)AE对脑胶质瘤细胞U87的体外靶向性
取对数生长期的单层培养的脑胶质瘤细胞(U87细胞),用0.25%胰蛋白酶消化单层培养细胞,用含10%胎牛血清的DMEM培养液配成单细胞悬液,以每孔1×105个细胞接种于12孔培养板中,每孔体积1mL,将培养板移入二氧化碳培养箱中,37℃、5%CO2及饱和湿度条件下培养24h,用含10%胎牛血清的DMEM培养液配制浓度为5μM的FAM、DAE-Fluorescein及LAE-Fluorescein溶液,将培养板中的培养液吸出,分别加入上述溶液,37℃孵育4h,吸弃上清液,用PBS溶液洗三次,4%多聚甲醛固定液固定细胞,DAPI细胞核染色后,激光共聚焦观察,细胞内化照片如图13左图所示,另用PBS洗三次后,进行流式细胞仪分析,结果如图13右图所示;
2)AE对人脐静脉内皮细胞HUVEC的体外靶向性
取对数生长期的单层培养的人脐静脉内皮细胞(HUVEC细胞),同上试验,细胞内化照片如图14左图所示,流式细胞仪分析结果如图14右图所示;
3)AE对U87体外肿瘤球模型的靶向性
取48孔培养板每孔加入Agrose胶溶液150μL,UV light下照射30min待其凝固后,每孔接种400μL U87细胞悬液,细胞密度为2×103个/孔,置于二氧化碳培养箱中,37℃、5%CO2及饱和湿度条件下培养7天即形成肿瘤球,用含10%胎牛血清的DMEM培养液配制浓度为5μM的FITC、DAE-Fluorescein及LAE-Fluorescein溶液,将培养板中的培养液吸出,分别加入上述溶液,37℃孵育 4h,吸弃上清液,用PBS溶液洗三次,多聚甲醛固定后,荧光显微镜观察,照片如图15所示。
实施例5 AE体内肿瘤靶向性验证
首先构建皮下瘤动物模型,将处于对数生长期的U87细胞胰酶消化,调整细胞浓度为3×107个/mL,接种100μL至裸小鼠右背侧近腋部皮下,接种后饲养于SPF级,定期观察肿瘤大小,待肿瘤大小为200mm3时,筛选出无坏死、肿瘤形状规则的荷瘤裸鼠,分组进行试验,200μL相同荧光强度的Cy7、DAE-Cy7及LAE-Cy7溶液通过尾静脉注入荷瘤裸鼠动物模型体内,2h后处死裸鼠,取出肿瘤,用活体成像仪检测荧光在荷瘤裸鼠体内的分布并进行荧光半定量计算,结果如图16所示。
实施例6 AE-Micelle体外靶向性验证
1)AE-Micelle/C6胶束的制备
AE-Micelle的处方为9mg mPEG-PLA,1mg AE-PEG-PLA,称取上述胶束材料和5ug香豆素-6溶解在2ml乙腈中,37℃水浴,减压(~0.085MPa)旋转蒸发除去有机溶媒,成均匀膜,室温真空干燥过夜,加入2ml生理盐水水化,CL-4B 柱层析除去未包封的C6,制得AE-Micelle/C6;
2)AE-Micelle对U87体外肿瘤球模型的靶向性
用含10%胎牛血清的DMEM培养液配制C6浓度为5μM的 mPEG-Micelle/C6、DAE-Micelle/C6和LAE-Micelle/C6溶液,将构建有肿瘤球的培养板中的培养液吸出,分别加入上述溶液,37℃孵育30min,吸弃上清液,用 PBS溶液洗三次,多聚甲醛固定后,荧光显微镜观察,结果如图17所示。
实施例7 AE-Micelle体内靶向性验证
1)AE-Micelle/DiR的制备
以制备AE-Micelle/C6相同的方法制备AE-Micelle/DiR;
2)AE-Micelle体内靶向性验证
分别尾静脉注射100μL的mPEG-Micelle/DiR、DAE-Micelle/DiR和LAE-Micelle/DiR溶液,分别在注射后4、6、8、12及24h时麻醉小鼠,用活体成像仪记录荧光在荷瘤裸鼠体内的分布并进行荧光半定量计算,结果如图18所示。
实施例8 AE-Micelle/PTX体外药效学试验
1)AE-Micelle/PTX的制备及表征
以制备AE-Micelle/C6相同的方法制备AE-Micelle/PTX。激光散射粒度仪表征胶束粒径和粒径分布(如图19所示);
2)AE-Micelle/PTX体外药效试验
以4.0×103个/孔将U87细胞或HUVEC细胞接种于96孔板,24h后,将培养液吸出,加入200μL一系列浓度的mPEG-Micelle/PTX、DAE-Micelle/PTX、LAE-Micelle/PTX及泰素,给药4h培养72h后,加入MTT溶液继续培养4h,弃去培养液,加入150μL DMSO,振荡至紫色颗粒溶解,用酶标仪在590nm处测定吸光度值,采用MTT法测定细胞存活率,计算半数致死剂量,结果如图20 所述;
3)AE-Micelle/PTX对新生血管形成的抑制试验
取24孔培养板每孔加入50μL基质胶,平铺于24孔板内,37℃培养箱内孵育30min待其凝固,0.25%胰酶消化HUVEC细胞,用含1μM紫杉醇的胶束或游离紫杉醇药液的DMEM培养液配成单细胞悬液,以每孔1×105个细胞接种于24 孔培养板中,37℃、5%CO2及饱和湿度条件下培养12h后观察血管样结构形成 (如图21A所示)并计算血管样结构的形成率(如图21B所示);
4)AE-Micelle/PTX对拟态血管形成的抑制试验
取24孔培养板每孔加入50μL基质胶,平铺于24孔板内,37℃培养箱内孵育30min待其凝固,0.25%胰酶消化U87细胞,用含1μM紫杉醇的胶束或游离紫杉醇药液的DMEM培养液配成单细胞悬液,以每孔1×105个细胞接种于24孔培养板中,37℃、5%CO2及饱和湿度条件下培养12h后观察血管样结构形成(如图22A所示)并计算拟态血管结构的形成率(如图22B所示)。
实施例9 AE-Micelle/PTX体内药效试验
1)AE-Micelle/PTX对皮下移植瘤抑制试验
构建U87皮下瘤动物模型,定期观察肿瘤大小,待肿瘤大小为100mm3时,分组进行试验,分别尾静脉注射mPEG-Micelle/PTX、DAE-Micelle/PTX、LAE-Micelle/PTX、市售泰素以及生理盐水各100μl,给药组的PTX总给药剂量为25mg/kg,分为五次,每次给药间隔为两天,隔天以游标卡尺测量肿瘤的长径 (a)及短径(b),根据公式计算各组裸鼠肿瘤体积,绘制肿瘤体积随时间的变化曲线,计算各组统计学差异,
肿瘤体积计算公式:V瘤体积=0.5(a×b2)
给药15天后(接种后21天),断颈处死所有裸鼠,取皮下肿瘤并称重,并计算各组统计学差异(如图23所示);
2)AE-Micelle/PTX促凋亡试验
荷瘤裸鼠完成五次给药后,处死取出瘤组织进行固定,石蜡包埋切片。采用末端脱氧核苷酸转移酶(TDT)介导的dUTP缺口末端标记法(Terminal deoxynucleotidylTransferase-mediated dUTP nick end labeling,TUNEL)检测肿瘤细胞的凋亡程度,细胞核呈棕黄色或棕褐色即判定为凋亡细胞,在光学显微镜下连续观察3个高倍视野计数阳性细胞,结果如图24所示;
3)AE-Micelle/PTX对肿瘤血管抑制试验
荷瘤裸鼠完成五次给药后,处死取出皮下瘤固定,石蜡包埋切片,进行CD31 免疫组化染色与PAS双染,在光学显微镜下观察血管生成情况,结果如图25所示。
Claims (17)
1.AE多肽,其特征在于,其包括D构型多肽DAE,其中,D构型氨基酸序列为DFDADLDGDEDA,及L构型多肽LAE,其中,L构型氨基酸序列为FALGEA。
2.权利要求1所述的AE多肽,其特征在于,其中的D构型多肽DAE在制备肿瘤靶向诊治递药***中的用途。
3.按权利要求2所述的用途,其特征在于,所述的D构型多肽DAE同时靶向表皮生长因子受体和表皮生长因子受体突变体III,用于药物或纳米递药***的靶向递送。
4.按权利要求2所述的用途,其特征在于,所述的D构型多肽DAE介导表皮生长因子受体和表皮生长因子受体突变体III,实现药物分子或纳米载药***的肿瘤靶向递送。
5.一种DAE-X复合物,其特征在于,采用权利要求1所述的D构型多肽DAE巯基化后与含有马来酰亚胺基团的影像物质反应获得。
6.一种LAE-X复合物,其特征在于,采用权利要求1所述的LAE巯基化后与含有马来酰亚胺基团的影像物质反应获得;所述的LAE-X复合物同时靶向表皮生长因子受体和表皮生长因子受体突变体III。
7.按权利要求5或6所述的DAE-X复合物或LAE-X复合物,其特征在于,所述复合物中X选自荧光物质Fluorescein,近红外染料Cy7、IR820、DiR,磁共振影像剂Gd-DTPA或放射影像剂99mTc-DTPA,用于高表达表皮生长因子受体或表皮生长因子受体突变体III肿瘤的影像诊断和示踪。
8.按权利要求1所述的AE多肽,其特征在于,其中的D构型多肽DAE通过pH敏感的腙键、pH敏感的硼酸脂键、二硫键与治疗药物连接,或直接与多肽药物缩合制成融合多肽,获得DAE-Y复合物;
其中的L构型多肽LAE通过pH敏感的腙键、pH敏感的硼酸脂键、二硫键与治疗药物连接,或直接与多肽药物缩合制成融合多肽,获得LAE-Y复合物。
9.按权利要求9所述的AE多肽,其特征在于,所述的DAE-Y复合物或LAE-Y复合物中Y是抗肿瘤药物阿霉素、表阿霉素、紫杉醇、多烯紫杉醇、喜树碱、羟基喜树碱、9-硝基喜树碱、长春新碱、硼替佐米、小白菊内酯、p53激活肽、蜂毒肽或蝎毒肽。
10.按权利要求1所述的AE多肽,其特征在于,其中的D构型多肽DAE巯基化后与含有马来酰亚胺基团的聚乙二醇-Z复合物连接,得到DAE-聚乙二醇-Z复合物;
其中的LAE巯基化后与马来酰亚胺化的聚乙二醇-Z复合物连接,得到LAE-聚乙二醇-Z复合物。
11.按权利要求10所述的AE多肽,其特征在于,所述的DAE-聚乙二醇-Z复合物或和LAE-聚乙二醇-Z复合物中Z选自磷脂、聚乳酸(PLA)、乳酸羟基乙酸共聚物(PLGA)或聚己内酯(PCL)。
12.按权利要求11所述的AE多肽,其特征在于,其中制得的DAE-聚乙二醇-磷脂复合物或LAE-聚乙二醇-磷脂复合物在用于制备脂质体递药***、聚合物胶束递药***或聚合物圆盘递药***中的用途。
13.按权利要求11所述的AE多肽,其特征在于,其中制得的的DAE-聚乙二醇-聚乳酸复合物、DAE-聚乙二醇-乳酸羟基乙酸共聚物复合物、DAE-聚乙二醇-聚己内酯复合物、LAE-聚乙二醇-聚乳酸复合物、LAE-聚乙二醇-乳酸羟基乙酸共聚物复合物或LAE-聚乙二醇-聚己内酯复合物在用于制备聚合物胶束递药***或纳米粒递药***中的用途。
14.按权利要求12或13所述的AE多肽,其特征在于,所述制得的脂质体递药***、聚合物胶束递药***、聚合物圆盘递药***或纳米粒递药***用于包载诊断药物。
15.按权利要求14所述的AE多肽,其特征在于,所述的诊断药物,选自荧光物质香豆素6、FAM,近红外染料Cy7、IR820、DiR、DiD或磁共振影像剂Gd-DTPA,用于高表达表皮生长因子受体或表皮生长因子受体突变体III肿瘤的影像诊断和示踪。
16.按权利要求12或13所述的AE多肽,其特征在于,所述制得的脂质体递药***、聚合物胶束递药***、聚合物圆盘递药***或纳米粒递药***包载抗肿瘤药物。
17.按权利要求16所述的AE多肽,其特征在于,所述的抗肿瘤药物选自阿霉素、表阿霉素、紫杉醇、多烯紫杉醇、喜树碱、羟基喜树碱、9-硝基喜树碱、长春新碱、硼替佐米、卡非佐米、小白菊内酯、p53激活肽、蜂毒肽或蝎毒肽,用于高表达表皮生长因子受体或表皮生长因子受体突变体III肿瘤的靶向治疗。
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