CN116462750A - 一种基于蛋白fgf19的仿生多肽及其应用 - Google Patents
一种基于蛋白fgf19的仿生多肽及其应用 Download PDFInfo
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Abstract
本发明公开了一种基于蛋白FGF19的仿生多肽FGF19‑1及其应用。本发明利用能够与成纤维细胞生长因子受体FGFR4特异性结合的内源性蛋白FGF19,设计相关仿生多肽,同时结合光学成像技术以及偶联荧光染料技术,使其能够应用于肝细胞肝癌的早期准确筛查和术中精确导航。本发明公开的FGF19‑1氨基酸序列为:Ile‑Met‑Pro‑Asn‑Glu‑Tyr‑Asn‑Val‑Lys‑Val‑Asn‑Tyr‑Glu‑Asn‑Pro‑Met‑Ile,其可与FGFR4高表达的肿瘤细胞特异性结合,偶联荧光染料后经活体光学成像和结果证实对肝细胞肝癌具有优异的显像成果。
Description
技术领域
本发明属于生物医学工程领域,涉及一种基于蛋白FGF19的仿生多肽及其应用。
背景技术
肝细胞肝癌(HCC)是常见的原发性恶性肝肿瘤之一,约占肝肿瘤的80%。在我国HCC引起的肿瘤相关病死率位居第三,仅次于肺癌和胃癌,其5年生存率低于18%,但复发率却高达70%。尽管目前国外学术界已经对肝细胞肝癌进行了很长时间的研究,了解到了HCC的大多数病因,也已经发现多种分子途径参与HCC的发生与发展。但以目前的医药水平难以攻克晚期恶性肿瘤,及早发现与治疗依然是目前治疗恶性肿瘤最有效的手段。因此肿瘤的早期诊断对于提高患者的生存率具有重大意义。分子成像的意义也不仅在于早期筛查。手术治疗是肿瘤治疗的手段之一,除了患有慢性肝病或肝硬化等患者不能接受手术外,肝切除术是治疗肝细胞肝癌的重要手段,然而对肿瘤边界的精确定位一直是需要攻克的科研难题,为外科手术医生提供手术边界,使肿瘤完整切除,可降低病人术后复发可能。
分子探针是实现分子成像的先决条件和核心技术。分子影像技术的发展除了需要先进的成像设备外,还需要发展新型而高效的分子探针。分子探针作为分析传感和光学成像的强大工具,可以直接在分子水平上对生物分析物进行可视化分析,并为复杂的生物结构和过程提供有用的信息。分子探针的基本成像原理是将制备好的荧光探针以注射等方式进入到活体组织中,使靶点与分子探针相互作用,再以合适的成像系统检测出分子探针发出的信息。借助靶向肿瘤的分子探针可以实现早期筛查和肿瘤的早期诊断。另外,分子影像技术不仅可显示肿瘤形态,还能反映肿瘤生物学信息。目前已有各种各样的肿瘤分子探针,可通过分子成像对肿瘤多种恶性表型特征进行检测,为肿瘤精准治疗提供依据。
对于国外学术界对肝细胞肝癌的研究,他们已经发现证据表明成纤维细胞生长因子(FGFs)通路基因在预后中的作用。而FGFR酪氨酸激酶家族包括FGFR1、FGFR2、FGFR3和FGFR4,由胞外变异区保守区、FGF结合区、单次跨膜区及胞内酪氨酸激酶区组成。FGF信号对肿瘤的发展起着重要的作用,在目前已知的信息中:对结直肠癌,乳腺癌而言,FGFR1变异最多,其次是FGFR3,而FGFR2,FGFR4则变异较少;对胃癌而言,FGFR2变异最多,FGFR1,FGFR3比例相近。且近一半的癌症中未检测出FGFR4变异,这也导致我们能够针对FGFR4的研究较少,对FGFR4的了解甚少。现有的对FGFR4的研究大多在探讨该靶点的信号通路及其对各种肿瘤细胞增殖/迁移的影响,或是研究其抑制剂的合成及体外抗肿瘤活性,国内外未有研究FGFR4靶点近红外探针的报导出现,而该靶点在多种肿瘤均有表达,因此开发基于FGFR4靶点的探针具有重要意义。
FGF成员中仅有FGF19与FGFR4特异性结合,FGF19是一个内分泌型生长因子,与特异性受体FGFR4结合激活下游的多种信号,介导癌症细胞增殖、抗凋亡、血管生成、耐药及上皮-间充质转换而转移。FGF19与FGFR4的结合导致受体二聚化和酪氨酸激酶结构域的转磷酸化,通过细胞内受体底物和磷脂酶Cγ激活下游信号通路。FGFR4在正常人体各组织器官中表达有限,在阳性肿瘤中表达水平较高,FGFR4可以成为肿瘤特异性成像的靶点。
发明内容
发明目的:本发明目的是提供一种基于蛋白FGF19的仿生多肽及其应用。本发明利用能够与FGFR4特异性结合的内源性蛋白FGF19,设计相关仿生多肽,同时结合光学成像技术以及偶联荧光染料技术,使其能够应用于肝细胞肝癌的早期准确筛查和术中精确导航。
成纤维细胞生长因子FGF19与FGFR4特异性结合,且FGFR4与癌症的转移、存活及增殖有着密切联系,而抑制这一信号通路则能降低肿瘤的侵袭力。基于这两点,本发明开发了一种基于蛋白FGF19的仿生多肽。
本发明还要解决的技术问题是如何特异性的构建识别FGFR4的探针并且提高探针对靶点FGFR4的特异性和靶向性。
本发明首先使用MOE软件进行分析,根据计算结果在FGF19蛋白上截取三段与FGFR4相互作用力最大的肽段,命名为FGF19-1、FGF19-2和FGF19-3,参见图1。使用模拟软件GROMACS,目的是为了通过分子模拟手段预先评估多肽的稳定性,对数据图中分析三个肽段与FGFR4结合的RMSD图进行分析,选择与FGFR4结合后整体构象最稳定的多肽,参见图2。
本发明还要解决的技术问题是如何表征探针特异性,即通过什么方法或技术能够证实该探针特异性识别FGFR4受体。
本发明通过流式细胞术检测荧光靶向化合物对细胞的亲和力,流式分析表明FGF19-1探针与FGFR4亲和力最强,证明了该探针能特异性识别FGFR4受体。
本发明最后要解决的技术问题是如何表征分子探针识别受体的表达量。
本发明通过动物模型分析可以看出FGF19-1探针在肿瘤停留时间较长,表明探针识别受体的相对表达量较多。
技术方案:本发明的目的通过下述技术方案实现:
本发明提供了一种基于蛋白FGF19的仿生多肽,所述多肽的序列如下:
Ile-Met-Pro-Asn-Glu-Tyr-Asn-Val-Lys-Val-Asn-Tyr-Glu-Asn-Pro-Met-Ile。
本发明还提供了上述基于蛋白FGF19的仿生多肽在制备肝细胞肝癌肿瘤诊断试剂中的应用。
所述肝细胞肝癌肿瘤诊断试剂为肿瘤诊断显像剂。
所述肿瘤诊断显像剂为肿瘤边界的精准定位和手术导航的显像试剂或放射性核素显像试剂。
本发明还提供了一种荧光靶向化合物,在上述基于蛋白FGF19的仿生多肽的氨基酸序列N端连接M标记,所述M表示光标记或放射性核素标记。
所述光标记选自有机发色团、有机荧光团、光吸收化合物、光反射化合物、光散射化合物或生物发光分子中的一种。
所述有机发色团为近红外荧光染料标记;所述近红外荧光染料选自MPA、IRDye800、Cy7.5或Cy5.5。
所述放射性核素标记选自Tc99m,Ga68,F18,I125,I131,Lu177或Cu64。
本发明使用固相合成方法合成相关多肽,再通过缩合反应偶联近红外染料MPA。使用质谱对纯化后的样品验证,确认样品的结构和组成。
本发明利用流式细胞术测定三条先导肽与FGFR4高表达细胞HepG2的亲和力,筛选出亲和力较高的多肽分子探针,使其与分子模拟评估的结果一致。使用小白鼠做成像实验,尾静脉给药,在近红外荧光成像系统下观察,得出结论:给药后1h肿瘤有明显摄取,且在肿瘤滞留时间均超过12h。
本发明还提供了上述荧光靶向化合物在制备肿瘤靶向药物载体中的应用。
本发明还提供了上述荧光靶向化合物作为特异性识别FGFR4受体的分子探针的应用。
有益效果:
1、本发明开发了一种基于蛋白FGF19的仿生多肽FGF19-1,可用于靶向成纤维细胞生长因子受体4(FGFR4)。利用FGFR4受体在肝细胞肝癌中的高表达,基于FGF19-1与FGFR4特异性结合的原理,从而实现肝细胞肝癌的早期诊断以及术中导航。
2、FGF19-1组成均为氨基酸,原料易得,合成成本廉价,且合成方法简单。同时能够通过延长多肽的半衰期来提高多肽在体内的循环时间,促进影像探针在肿瘤部位的聚集和滞留,进而获得更佳的肿瘤显像效果,有利于推广临床应用。
3、本发明利用的近红外荧光染料MPA穿透深度更深、背景组织自发荧光更弱的优点,在荧光成像和荧光指导手术中有良好的应用前景。
4、该蛋白质序列制备成放射性药物可用于某些肿瘤的筛查和早期诊断,还可以实时无创在位监测早期恶性肿瘤以及治疗。
附图说明
图1为FGFR4-FGF19对接构象图;
图2为FGF19肽段与FGFR4结合的均方根偏差RMSD(Root Mean SquareDeviation);
图3为荧光靶向化合物MPA-FGF19-1的质谱图;
图4为荧光靶向化合物MPA-FGF19-1的HPLC图;
图5为流式细胞术检测不同荧光靶向化合物对HepG2细胞的亲和力结果;
图6为由MPA-FGF19-1制备成的探针对于肿瘤模型的靶向性。
具体实施方式
下面通过具体实施例对本发明技术方案进行详细说明,但是本发明的保护范围不局限于所述实施例。
以下实施例中所使用的化学物质均为现有物质或市售商品。
以下实施例中使用的氨基酸均购自吉尔生化(上海)有限公司。
以下实施例中所涉及的多肽均由中国药科大学顾月清课题组独立合成。
实施例1FGF19-1的制备
FGF19-1氨基酸序列:
Ile-Met-Pro-Asn-Glu-Tyr-Asn-Val-Lys-Val-Asn-Tyr-Glu-Asn-Pro-Met-Ile。
(1)树脂溶胀
在反应柱中加入200mg Rink Amide MBHA树脂,然后加入二氯甲烷(DCM)使其溶胀,微微鼓吹氮气20分钟,使树脂充分溶胀开来。抽干二氯甲烷溶液,再用二甲基甲酰(DMF)洗涤3遍并抽干。
(2)脱除Fmoc
在反应柱中加入20%哌啶的DMF溶液,去保护5分钟一次,共两次,第一次哌啶脱Fmoc后不用DMF洗涤。反应结束后,用DMF、DCM、DMF依次分别洗涤树脂3次。
(3)连接所有氨基酸
重复上述步骤至所有氨基酸(吉尔生化(上海)有限公司)接上,最后一个氨基酸脱Fmoc。DMF洗涤两遍,DCM洗涤两遍,甲醇洗涤两遍,抽干10分钟至成粉末状。
(4)偶联
准确称取投料树脂摩尔数3倍的Fmoc-Val-OH(吉尔生化(上海)有限公司)与O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU),完全溶于DMF中,加N,N-二异丙基乙胺(DIPEA))使羧基活化后,将溶液加入反应柱中进行反应,反应30分钟后,用DMF、DCM、DMF依次分别洗涤3次,然后抽干溶剂,取5mg树脂加入6%茚三酮/乙醇溶液和80%苯酚/乙醇溶液各一滴进行检测。若缩合已经完全,无游离氨基存在,则溶液呈无色或淡黄色;否则树脂或溶液将变为蓝色或者红褐色,说明反应不完全。反应结束后,用DCM、DCM、DMF一次分别洗涤3次。重复上述操作,依次偶联其他氨基酸,直至偶联完最后一次氨基酸Fmoc-Ile-OH,用甲醇洗涤所得到的peptidyl resin,真空干燥箱里充分干燥。
(5)裂解
取120mL的裂解液(87.5%三氟乙酸+5%苯甲硫醚+2.5%乙二硫醇+2.5%苯酚+2.5%水)加入树脂中,在低温条件下震荡2h,然后用砂芯漏斗将裂解液与树脂分离,保留滤液。将滤液缓慢滴加到冰无水乙醚中,滴加完毕后,自然沉降30min。然后离心得固体,用乙醚洗涤固体三遍,将所得沉淀烘干后,得到干粉粗品。
(6)纯化
采用高效液相色谱法进行纯化,纯化用色谱填料为10μm的C18制备柱,流动相系统为0.1%TFA/水溶液-0.1%TFA/乙腈溶液,采用梯度洗脱,循环进样纯化,取粗品溶液上样于色谱柱中,启动流动相洗脱,收集主峰蒸去乙腈后,得到目标多肽浓缩液,然后冻干得到目标多肽,最后测定质荷比,确定分子量[M-H]-=905。
参照实施例1的制备方法,制备FGF19-2、FGF19-3:
FGF19-2氨基酸序列:Ac-Ile-Asn-Pro-Asn-Gly-Tyr-Gln-Val-NH2
FGF19-3氨基酸序列:
Ac-Ile-Met-Pro-Asn-Glu-Gly-Gly-Gly-Pro-Asp-Val-Gly-Ser-Ser-Asn-NH2
实施例2荧光靶向化合物MPA-FGF19-1的制备
(1)MPA来自我们课题组前期申请的一篇发明专利,授权专利号:CN101440282。
取0.02mmol MPA溶于200μL超干DMSO中,加入3.7mg 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐和2.2mg N-羟基琥珀酰亚胺(EDCI/NHS)(摩尔比MPA:EDCI:NHS=1:1.5:1.5),避光反应4h,进行羧基活化反应。
(2)取固相合成的FGF19-1 0.02mmol与0.1mmol三乙胺和200μL超干DMSO加入到5mL反应瓶中,氮气保护下反应10min;将上述反应(1)中溶液加入(2)的反应液中,室温搅拌反应12h。
(3)反应结束后,通过冻干浓缩反应液,然后加入蒸馏水稀释,用制备液相进行分离纯化,制备液相条件如下所示:使用了Agilent 1220InfinityⅡ系列HPLC系统配备Agilent ZORBAX SB-C18半制备柱(9.4×250mm,5μm),梯度淋洗60分钟,流速2mL/min,其中流动相A为超纯水(0.01%TFA),B为乙腈(0.01%TFA)。淋洗梯度设定为0-5分钟时,95%A和5%B;15分钟时,85%A和15%B;30分钟时,70%A和30%B;45分钟时,50%A和50%B。最后制得的产物经分析型HPLC和ESI-MS质谱分析确认为预期产物MPA-FGF19-1,其质谱图见图3,HPLC图谱见图4。
参照实施例2的制备方法,制备MPA-FGF19-2、MPA-FGF19-3。
实施例3 MPA-FGF19-1对HepG2细胞的亲和力
将培养好的人肝癌HepG2细胞从12孔板上洗脱后重悬于PBS溶液,分别与实施例2制备的MPA-FGF19-1共孵育2小时,并通过流式细胞术检测其平均荧光强度,荧光强度越强则证明对细胞的亲和力越强。当探针与细胞上的受体亲和力强时,流式细胞仪检测出的细胞平均荧光强度值高,参见图5。流式分析表明MPA-FGF19-1与FGFR4亲和力最强,证明了该探针能特异性识别FGFR4受体。
实施例4 MPA-FGF19-1在肝癌HepG2荷瘤鼠体内的光学成像试验
将实施例2制备的化合物MPA-FGF19-1溶于生理盐水溶液,配制成浓度为1mg/1mL的溶液,通过尾静脉分别给3只肝癌HepG2荷瘤裸鼠(体重约20克)注射MPA-FGF19-1药物溶液15μL,并于给药后0h、0.5h、1h、2h、4h、6h和12h进行光学信号采集(南京诺源医疗器械有限公司的近红外荧光成像系统)。观察探针在小鼠体内的分布以及在肿瘤区域的富集。
从1h的成像图中可以看出探针已经在肿瘤中有明显聚集,肿瘤边缘轮廓较清晰,直至12h探针依然在肿瘤中有滞留。显像结果如图6所示。
实施例5 MPA-FGF19-1在肝癌SMMC-7721荷瘤鼠体内的光学成像试验
将实施例2制备的化合物MPA-FGF19-1溶于生理盐水溶液,配制成浓度为1mg/1mL的溶液,通过尾静脉分别给3只肝癌SMMC-7721荷瘤裸鼠(体重约20克)注射MPA-FGF19-1药物溶液15μL,并于给药后0h、0.5h、1h、2h、4h、6h和12h进行光学信号采集(南京诺源医疗器械有限公司的近红外荧光成像系统)。观察探针在小鼠体内的分布以及在肿瘤区域的富集。
从1h的成像图中可以看出探针已经在肿瘤中有明显聚集,肿瘤边缘轮廓较清晰,直至12h探针依然在肿瘤中有滞留。显像结果如图6所示。
因此,荧光靶向化合物MPA-FGF19-1能够作为特异性识别FGFR4受体的分子探针,从而实现肝细胞肝癌的早期诊断以及术中导航。
对比例1根据专利CN114933633B所述制备方法制备得到多肽YQGF-7,其氨基酸序列如下:
Ac-Ile-Met-Pro-Asn-Glu-Tyr-Asn-Val-NH2。
对比例2根据专利CN113817023 B所述制备方法制备得到多肽YQGF-2、YQGF-4、YQGF-5,其氨基酸序列如下:
YQGF-2:Ac-ILe-Arg-Pro-Asp-Gly-Tyr-Asn-Val-NH2
YQGF-4:Ac-ILe-homoArg-Pro-Asp-Gly-Tyr-Asn-Val-NH2
YQGF-5:Ac-ILe-Arg-Pro-Asp-Gly-Tyr-Asn-Nva-NH2。
将本发明制备的多肽FGF19-1与对比例1、对比例2制备的多肽,运用SPR表面等离子共振技术测定,进行亲和力值比较,结果见表1:
表1亲和力值比较
多肽名称 | 亲和力:Kd值 |
YQGF-7 | 124.17nmol.L-1 |
YQGF-2 | 104.96nmol.L-1 |
YQGF-4 | 121.34nmol.L-1 |
YQGF-5 | 99.69nmol.L-1 |
FGF19-1 | 57.11nmol.L-1 |
由此可见,本发明制备的多肽FGF19-1亲和力更高。高亲和力多肽,有助于提升在肿瘤内的滞留时间,提升滞留探针的数量,提升信号对比度。
如上所述,尽管参照特定的优选实施例已经表示和表述了本发明,但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下,可对其在形式上和细节上作出各种变化。
Claims (10)
1.一种基于蛋白FGF19的仿生多肽,其特征在于,所述多肽的序列如下:
Ile-Met-Pro-Asn-Glu-Tyr-Asn-Val-Lys-Val-Asn-Tyr-Glu-Asn-Pro-Met-Ile。
2.权利要求1所述的基于蛋白FGF19的仿生多肽在制备肝细胞肝癌肿瘤诊断试剂中的应用。
3.根据权利要求2所述的应用,其特征在于,所述肝细胞肝癌肿瘤诊断试剂为肿瘤诊断显像剂。
4.根据权利要求3所述的应用,其特征在于,所述肿瘤诊断显像剂为肿瘤边界的精准定位和手术导航的显像试剂或放射性核素显像试剂。
5.一种荧光靶向化合物,其特征在于,在权利要求1所述的基于蛋白FGF19的仿生多肽的氨基酸序列N端连接M标记,所述M表示光标记或放射性核素标记。
6.根据权利要求5所述的荧光靶向化合物,其特征在于,所述光标记选自有机发色团、有机荧光团、光吸收化合物、光反射化合物、光散射化合物或生物发光分子中的一种。
7.根据权利要求6所述的荧光靶向化合物,其特征在于,所述有机发色团为近红外荧光染料标记;所述近红外荧光染料选自MPA、IRDye800、Cy7.5或Cy5.5。
8.根据权利要求5所述的荧光靶向化合物,其特征在于,所述放射性核素标记选自Tc99m,Ga68,F18,I125,I131,Lu177或Cu64。
9.权利要求5~8任一项所述的荧光靶向化合物在制备肿瘤靶向药物载体中的应用。
10.权利要求5~8任一项所述的荧光靶向化合物作为特异性识别FGFR4受体的分子探针的应用。
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