CN113425859B - 一种GnRH多肽修饰的探针、包含它的制剂、药物组合物及其制备方法与应用 - Google Patents
一种GnRH多肽修饰的探针、包含它的制剂、药物组合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于生物医药成像领域,公开了一种GnRHa‑PEG‑Rh760探针、制剂、药物组合物及其制备方法和应用,所述探针具体为GnRH多肽修饰的聚乙二醇化Rh760成像探针,所述探针由GnRH多肽、FMOC‑PEG2000‑COOH、近红外荧光染料Rh760偶联而成。本发明利用聚乙二醇的修饰,制备得到具有优良化学特性与组织生物学分布的成像探针,并在GnRH受配体介导的组织特异性结合,以及Rh760近红外荧光特性的基础上,通过静脉给药,实现表达GnRH受体的肿瘤病灶和转移灶的特异性显像,进一步提高了探针在荧光成像和荧光指导手术中的应用价值。
Description
技术领域
本发明属于生物医药成像领域,涉及一种一种GnRH多肽修饰的探针、包含它的制剂、药物组合物及其制备方法与应用,具体涉及GnRH多肽修饰的聚乙二醇化Rh760成像探针、包含它的制剂、药物组合物及其制备方法与应用。
背景技术
手术切除是实体瘤的主要治疗手段,术中对肿瘤病灶的准确识别是提高手术疗效的关键。现有的影像学检查均为肿瘤非特异性成像,且难以便捷地在术中实时显示肿瘤病灶,进而无法为术者提供指导。
肿瘤靶向的荧光成像探针,可相对特异地识别肿瘤细胞,通过术中荧光成像的方式实时显示肿瘤病灶。促性腺激素释放激素(Gonadotropin-releasing hormone,GnRH)受体在激素相关性肿瘤(卵巢癌、子宫内膜癌、乳腺癌、前列腺癌)、以及其他肿瘤(胰腺癌、肺癌、黑色素瘤、脑胶质瘤)中呈现出较高的表达率;而其在正常生理条件下的表达相对局限于垂体和生殖系统。因此,GnRH受体有望作为肿瘤特异性成像的靶位点。而能够与其特异性结合的GnRH类似物,即GnRH受体激动剂或拮抗剂,则可用作成像探针的靶向定位基团。
本课题组在前期利用临床药物GnRH受体拮抗剂西曲瑞克Cetrorelix的氨基酸序列,修饰近红外荧光染料吲哚菁绿(Indocyanine green,ICG),开发了GnRHa-ICG靶向探针。该探针可在腹腔给药的条件下,特异性显像卵巢癌腹腔种植灶。然而尽管卵巢癌的转移倾向为腹腔种植播散,但更多的实体瘤为血行和淋巴转移为主,所述探针无法实现肿瘤病灶和转移灶的全面显像,因此,成像探针的生物相容性、体内循环时间等化学特性亟待改善。
因此,本发明在前期基础上,结合聚乙二醇(Polyethylene glycol,PEG)的修饰,研制了新型且适用于静脉给药的靶向GnRH受体的PEG化的近红外荧光成像探针,能够特异性识别并显像表达GnRH受体的肿瘤病灶及其转移灶。该探针有望在实体瘤的荧光成像和荧光指导手术中发挥良好的应用潜力。
发明内容
本发明提供一种GnRH多肽修饰的聚乙二醇化Rh760成像探针及其制备方法与应用。所述GnRH多肽修饰的聚乙二醇化Rh760成像探针(GnRHa-PEG-Rh760)由GnRH多肽(GnRHa)、FMOC-PEG2000-COOH、近红外荧光染料Rh760偶联而成。
其中,GnRH多肽序列为
D-2-Nal-D-4-Cl-Phe-D-3-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2。
GnRH多肽的结构、FMOC-PEG2000-COOH的结构、近红外荧光染料Rh760的结构、以及偶联后的靶向成像探针GnRHa-PEG-Rh760的结构见附图1。
本发明还提供了一种成像探针GnRHa-PEG-Rh760的制备方法,所述方法包括:由GnRH多肽、FMOC-PEG2000-COOH、近红外荧光染料Rh760偶联制备得到所述GnRH多肽修饰的聚乙二醇化Rh760成像探针。
具体地,所述成像探针的制备方法包括:
(1)Rink树脂、氨基酸Fmoc-D-Ala-OH、DCM、DIPEA,进行反应;结束后,封闭反应;
(2)加入哌啶,脱除Fmoc;直至树脂检测显色;
(3)称取下一氨基酸Fmoc-Pro-OH、HOBT,加入DMF、DIC反应;直至树脂检测呈无色;
(4)重复第2、3步骤直到肽链偶联结束,脱除Fmoc,称取下一物料FMOC-PEG2000-COOH、HOBT,加入DMF、DIC反应;直至树脂检测呈无色;
(5)脱除Fmoc,称取下一物料Rh760-GA、HOBT,加入DMF、DIC反应,直至树脂检测呈无色;
(6)将树脂用甲醇抽干,加入切割液切割,冰乙醚沉降,得到蓝绿色固体产物所述GnRH多肽修饰的聚乙二醇化Rh760成像探针GnRHa-PEG-Rh760。
本发明所述GnRH多肽修饰的聚乙二醇化Rh760成像探针(GnRHa-PEG-Rh760)能够靶向识别表达GnRH受体的肿瘤病灶,可通过静脉给药,实现肿瘤病灶及其转移灶的近红外荧光成像。
基于此,本发明提供了所述成像探针GnRHa-PEG-Rh760在制备肿瘤成像药剂中的应用。
其中,所述成像探针GnRHa-PEG-Rh760用于肿瘤诊断成像、肿瘤术中成像或肿瘤治疗成像。
本发明还提供了所述成像探针GnRHa-PEG-Rh760在制备治疗肿瘤的药物中的应用。
其中,所述肿瘤包括激素相关性肿瘤(卵巢癌、子宫内膜癌、乳腺癌、前列腺癌)、以及其他表达GnRH受体的肿瘤(胰腺癌、肺癌、黑色素瘤、脑胶质瘤)。优选地,所述肿瘤为卵巢癌。
本发明所述肿瘤包括肿瘤病灶及其转移灶。所述转移灶包括但不限于腹腔转移、淋巴结转移和/或远处转移。
本发明的有益效果包括:
1.本发明利用PEG的修饰,优化成像探针的化学特性与体内或组织的生物学分布,制备一种靶向成像探针GnRHa-PEG-Rh760;并在GnRH受配体介导的组织特异性结合,以及Rh760近红外荧光特性的基础上,通过静脉给药,实现肿瘤病灶、腹腔转移灶、淋巴和/或远处转移灶的特异性显像,进一步提高探针在肿瘤诊治中的应用价值。
2.本发明所述成像探针GnRHa-PEG-Rh760与未经PEG修饰的探针GnRHa-ICG相比,具有优良化学特性与组织生物学分布特性,通过静脉给药,能够实现静脉给药后肿瘤病灶和淋巴等远处转移灶的特异性显像。
3.本发明所述成像探针GnRHa-PEG-Rh760与未经GnRH多肽靶向修饰的PEG-Rh760相比,能够减少探针与其他正常组织的非特异性结合,更加有效地识别并显像肿瘤病灶,进一步提高了探针在荧光成像和荧光指导手术中的应用价值。
附图说明
图1GnRHa-PEG-Rh760的合成路线。
图2GnRHa-PEG-Rh760的质谱表征。
图3GnRHa-PEG-Rh760的紫外吸收光谱和荧光光谱。
图4GnRHa-PEG-Rh760对肿瘤细胞的特异性结合。
图5GnRHa-PEG-Rh760在裸鼠卵巢癌皮下瘤模型的成像。
图6GnRHa-PEG-Rh760在裸鼠卵巢癌腹腔转移模型的成像及组织分布。
图7GnRHa-PEG-Rh760在裸鼠卵巢癌淋巴转移模型的成像。
图8GnRHa-PEG-Rh760的体内安全性评价。
图9不同PEG制备的成像探针在裸鼠卵巢癌皮下瘤模型的成像。
图10未经PEG修饰的成像探针在裸鼠卵巢癌皮下瘤和腹腔转移模型的成像。
具体实施方式
下面结合实施例进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。实施本发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
本发明提供一种GnRH多肽修饰的聚乙二醇化Rh760成像探针GnRHa-PEG-Rh760,所述探针由GnRH多肽(GnRHa)、FMOC-PEG2000-COOH、近红外荧光染料Rh760偶联而成。GnRH多肽序列为
D-2-Nal-D-4-Cl-Phe-D-3-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala-NH2。
GnRHa-PEG-Rh760的合成路线见图1。
GnRHa-PEG-Rh760的结构为:
在一具体实施方式中,本发明所述成像探针GnRHa-PEG-Rh760用于卵巢癌腹腔转移治疗。
在一具体实施方式中,本发明所述成像探针GnRHa-PEG-Rh760用于卵巢癌淋巴转移治疗。
本发明还提供了一种静脉给药用于靶向GnRHa近红外成像的方法,所述方法包括,向个体中注射如上所述的成像探针GnRHa-PEG-Rh760。
本发明还提供了一种静脉给药靶向GnRHa治疗肿瘤的方法,所述方法包括,向个体中注射如上所述的成像探针GnRHa-PEG-Rh760。所述肿瘤如上文所述。
本发明还提供了一种静脉给药的制剂或药物组合物,所述制剂或药物组合物包括如上所述的成像探针GnRHa-PEG-Rh760。本发明中,所述静脉给药的制剂或药物组合物还包括药学上可接受的载体。
实施例1制备成像探针GnRHa-PEG-Rh760
制备成像探针GnRHa-PEG-Rh760的步骤如下所示:
1.称取Rink树脂0.5g,加入4mL二氯甲烷(DCM)浸泡5min,用N,N-二甲基甲酰胺(DMF)洗涤2次,加入0.2mmol Fmoc-D-Ala-OH、6mL DCM、0.5mL N,N-二异丙基乙胺(DIPEA),反应90min。结束后补加0.5mL分析甲醇,1mL DCM,封闭反应20min。
2.用DMF洗涤4次,加入哌啶(体积分数20%哌啶+80%DMF)反应20min脱除Fmoc。用DMF洗涤5次,取少量树脂,加入茚三酮(5g茚三酮/100mL分析乙醇)2滴、吡啶2滴,100℃2min,显色即可。
3.称取下一氨基酸Fmoc-Pro-OH(0.45mmol)+1-羟基苯并三氮唑(HOBT)(0.45mmol),加入5mL DMF、0.5mL N,N'-二异丙基碳二亚胺(DIC)反应1h,用DMF洗涤4次,取少量树脂检测,检测方法同步骤2,无色即可。
4.重复第2、3步骤直到肽链偶联结束,脱除Fmoc,称取下一物料FMOC-PEG2000-COOH(0.45mmol)+HOBT(0.45mmol),加入5mL DMF、0.5mL DIC反应1h,用DMF洗涤4次,取少量树脂检测,检测方法同步骤2,无色即可。
5.脱除Fmoc,称取下一物料Rh760-GA(0.15mmol)+HOBT(0.45mmol),加入5mL DMF、0.5mL DIC反应1h,用DMF洗涤4次,取少量树脂检测,检测方法同步骤2,无色即可。
6.将树脂用甲醇抽干,加入10mL切割液(体积分数95%TFa+1%H2O+2%EDT+2%TIS)摇晃切割2h。所得反应液用40mL冰乙醚沉降,得到蓝绿色固体产物GnRH多肽修饰的聚乙二醇化Rh760成像探针(GnRHa-PEG-Rh760)。
所得产物靶向探针GnRHa-PEG-Rh760的表征检测结果见图2和图3,平均分子量为4000Da,在DMSO中的吸收峰位于780nm,发射峰位于805nm。
实施例2GnRHa-PEG-Rh760对肿瘤细胞的特异性结合
分别将卵巢癌细胞A2780和肺癌细胞H1299按1x103/200μL密度接种于8孔腔室载玻片。待细胞汇合度达50-60%时,弃培液,加入50μM实施例1的GnRHa-PEG-Rh760,37℃孵育2h。然后弃上清,多聚甲醛室温固定。用WGA Alexa488染细胞膜、DAPI染细胞核。Confocal荧光显微镜观察并拍照。
由图4可见,GnRH受体阳性的A2780细胞内蓄积了较强的探针荧光信号,而GnRH受体阴性的H1299细胞中未见明显探针信号。结果表明,本发明实施例1制备的靶向探针GnRHa-PEG-Rh760能够特异性结合GnRH受体阳性的肿瘤细胞。
实施例3GnRHa-PEG-Rh760用于肿瘤靶向成像
所述GnRH多肽修饰的聚乙二醇化Rh760成像探针(GnRHa-PEG-Rh760)用于肿瘤靶向成像的具体实施方式如下:
3.1GnRHa-PEG-Rh760在裸鼠卵巢癌皮下瘤模型的成像
将人卵巢癌细胞A2780按5x106/100μL接种于5-6周龄雌性Balb/c裸鼠右侧胁肋部,待成瘤后开始成像实验。
将裸鼠模型分为2组,分别尾静脉注射实施例1的靶向探针GnRHa-PEG-Rh760(2.0mg/kg体重)(实验组)、未经GnRH多肽靶向修饰的对照探针PEG-Rh760(对照组)。
在注射后不同时间点(24h、48h、72h、96h)利用小动物活体光学成像系统进行近红外荧光成像检测(激发/发射:740/790nm)。
结果显示,实施例1的靶向探针GnRHa-PEG-Rh760能够特异性蓄积于卵巢癌皮下瘤病灶,在给药后24-48h时间点时瘤体的荧光信号较强;而在裸鼠其他部位未见明显的荧光信号。非靶向对照探针PEG-Rh760给药后经肾脏、膀胱快速代谢出体内,在肿瘤病灶未见明显蓄积(图5)。
3.2GnRHa-PEG-Rh760在裸鼠卵巢癌腹腔转移模型的成像
利用慢病毒载体建立稳定表达荧光素酶Luciferase和绿色荧光蛋白的人卵巢癌细胞系A2780(简称A2780-Luc)。将A2780-Luc细胞按1x107/200μL接种于5周龄雌性Balb/c裸鼠腹腔,约2周后开始成像实验。
将裸鼠模型分为2组,分别尾静脉注射实施例1的靶向探针GnRHa-PEG-Rh760(2.0mg/kg)、未经GnRH多肽靶向修饰的对照探针PEG-Rh760。在注射探针24h后,利用小动物活体光学成像系统进行在体的近红外荧光成像(激发/发射:740/790nm)。同时,在成像前10-20min向裸鼠注射成像底物D-荧光素钾盐(150mg/kg体重),利用小动物活体光学成像系统进行生物发光成像,将A2780-Luc细胞的生物发光信号与探针的荧光信号进行比较。随后收集离体组织,包括肿瘤转移灶、对照组织(骨骼肌)、主要脏器(心脏、肺脏、肝脏、脾脏、肾脏、肠道、子宫、卵巢),检测其生物发光信号与近红外荧光信号。
由图6所示,实施例1的靶向探针GnRHa-PEG-Rh760在卵巢癌腹腔转移多发灶中均呈现出较高的近红外荧光信号强度,而在对照组织骨骼肌、以及其他正常脏器(心脏、肺脏、脾脏、肾脏、肠道等)中未检测到明显信号。在体与离体的肿瘤近红外荧光成像信号与A2780-Luc细胞的生物发光信号可以互相验证。未经GnRH多肽靶向修饰的对照探针PEG-Rh760在肿瘤转移灶未呈现出明显的近红外荧光信号。结果表明,靶向探针GnRHa-PEG-Rh760能够特异性识别卵巢癌腹腔转移灶。
3.3GnRHa-PEG-Rh760在裸鼠卵巢癌淋巴转移模型的成像
利用慢病毒载体建立稳定表达荧光素酶Luciferase和绿色荧光蛋白的人卵巢癌细胞系ES-2(简称ES-2-Luc)。将ES-2-Luc细胞按2x106/50μL接种于5周龄雌性Balb/c裸鼠足垫,约3-4周后可在腘窝、腹股沟和髂淋巴结观察到肿瘤转移。
将裸鼠模型分为2组,分别尾静脉注射本发明实施例1的成像探针GnRHa-PEG-Rh760(2.0mg/kg)、未经GnRH多肽靶向修饰的对照探针PEG-Rh760。在注射后24h时间点,利用小动物活体光学成像系统进行在体和离体组织(足垫肿瘤病灶和淋巴结)的近红外荧光成像检测(激发/发射:740/790nm)。同时,在成像前10-20min用D-荧光素钾盐处理裸鼠(150mg/kg体重),利用小动物活体光学成像系统行荧光素生物发光成像,并将其与探针的近红外荧光进行共定位分析。随后收集离体组织,包括足垫肿瘤病灶、肿瘤引流侧淋巴结和对侧淋巴结,进行生物发光与近红外荧光成像与分析。
结果显示,尾静脉注射成像探针后24h,本发明实施例1的成像探针GnRHa-PEG-Rh760能够特异性识别并显像足垫肿瘤病灶、肿瘤引流侧有转移的淋巴结,如腘窝、腹股沟等淋巴结,而对侧无转移的正常淋巴结未见靶向探针的荧光信号蓄积。在体和立体组织检测都显示,GnRHa-PEG-Rh760的近红外荧光信号与肿瘤自带的荧光素生物发光信号可以互相验证(图7)。同时,结果也提示,未经GnRH多肽靶向修饰的对照探针PEG-Rh760并不能有效识别足垫肿瘤病灶和有转移的淋巴结。
实施例4GnRHa-PEG-Rh760的体内安全性评价
所述GnRH多肽修饰的聚乙二醇化Rh760成像探针(GnRHa-PEG-Rh760)体内安全性评价的具体实施方式如下:
将裸鼠随机分为2组,向实验组裸鼠尾静脉注射实施例1的靶向探针GnRHa-PEG-Rh760(2.0mg/kg体重),向对照组裸鼠尾静脉注射等体积的PBS溶液。观察1周。牺牲裸鼠,收集心脏、肝脏、脾脏、肺脏、肾脏、骨骼肌组织,固定包埋,制备石蜡切片。经HE染色后,利用显微镜观察病理变化。在观察期间,裸鼠未出现明显的毒副反应,上述脏器组织未出现明显的病理改变(图8)。提示靶向探针GnRHa-PEG-Rh760没有明显的生物毒性,相容性较好。
对比例1不同PEG制备的成像探针在裸鼠卵巢癌皮下瘤模型的成像
按照实施例1的方法,分别使用不同分子量的PEG(包括PEG4(单体)、PEG1000(聚合物)、PEG2000(聚合物))制备成像探针,制备得到的成像探针分别为GnRHa-PEG4-Rh760、GnRHa-PEG1000-Rh760、GnRHa-PEG2000-Rh760探针(即本发明所述GnRHa-PEG-Rh760)。
按照实施例3第3.1所述的方法建立裸鼠卵巢癌皮下瘤模型,按照该实施例的方法,通过尾静脉给药,在裸鼠卵巢癌皮下瘤模型中检测3种探针的体内成像效果。
如图9所示,在注射探针后24小时,GnRHa-PEG2000-Rh760探针(即本发明所述GnRHa-PEG-Rh760)可靶向显示肿瘤,而GnRHa-PEG4-Rh760和GnRHa-PEG1000-Rh760富集于肝脏组织,在皮下瘤中未见明显信号。
对比例2未经PEG修饰的成像探针GnRHa-ICG在裸鼠卵巢癌皮下瘤和腹腔转移模型中的成像
本课题组在前期研究中发明了成像探针GnRHa-ICG(靶向探针GnRHa-ICG),其可以通过腹腔注射高效显像腹腔的肿瘤种植病灶,适用于具有腹腔种植播散倾向特征的疾病病灶的显像,但是对于血行或淋巴转移途径为主的肿瘤并不适用。
如实施例3第3.1建立裸鼠卵巢癌皮下瘤模型,按照该实施例的方法注射成像探针GnRHa-ICG;如实施例3第3.2建立裸鼠卵巢癌腹腔转移模型,按照该实施例的方法注射成像探针GnRHa-ICG。
结果如图10所示,由图可知,GnRHa-ICG成像探针经腹腔给药后可特异性结合裸鼠腹腔转移灶,但是,经尾静脉给药的探针信号集中于肝脏,难以显示皮下瘤。
综上,体内成像结果显示,本发明实施例1的靶向成像探针GnRHa-PEG-Rh760具有很好的生物相容性与体内循环时间,通过静脉注射的全身给药途径,可特异性显像卵巢癌皮下瘤、腹腔转移和淋巴转移灶。与未经PEG修饰的靶向探针(GnRHa-ICG)相比,实现了静脉给药后淋巴等远处转移灶的显像。与未经GnRH多肽靶向修饰的单纯PEG-Rh760相比,减少了探针与其他正常组织的非特异性结合,能够更加有效地识别并显像肿瘤病灶及其转移灶。本发明进一步提高了所述靶向成像探针GnRHa-PEG-Rh760在荧光成像和荧光指导手术中的应用价值。
以上实施例仅用以说明本发明的技术方案而非对其限制;尽管参照较佳实施例对本发明进行了详细的说明,所属领域的普通技术人员应当理解:依然可以对本发明的具体实施方式进行修改或者对部分技术特征进行等同替换;在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点均应涵盖在本发明请求保护的技术方案范围当中。
Claims (9)
2.根据权利要求1所述GnRH多肽修饰的聚乙二醇化Rh760成像探针的制备方法,其特征在于,由GnRH多肽、FMOC-PEG2000-COOH、近红外荧光染料Rh760偶联制备得到所述GnRH多肽修饰的聚乙二醇化Rh760成像探针。
3.根据权利要求1所述GnRH多肽修饰的聚乙二醇化Rh760成像探针在制备适于静脉给药或全身给药的肿瘤成像药剂和/或在制备适于静脉给药或全身给药的治疗肿瘤的药物中的应用。
4.根据权利要求3所述的应用,其特征在于,所述肿瘤为激素相关性肿瘤或表达GnRH受体的肿瘤。
5.根据权利要求4所述的应用,其特征在于,所述激素相关性肿瘤选自卵巢癌、子宫内膜癌、乳腺癌、前列腺癌;所述表达GnRH受体的肿瘤选自胰腺癌、肺癌、黑色素瘤、脑胶质瘤;所述肿瘤包括肿瘤病灶和/或转移灶。
6.根据权利要求5所述的应用,其特征在于,所述转移灶是指腹腔转移、淋巴结转移和/或远处转移。
7.一种制剂或药物组合物,其特征在于,所述制剂或药物组合物包括根据权利要求1所述的GnRH多肽修饰的聚乙二醇化Rh760成像探针。
8.根据权利要求7所述的制剂或药物组合物,其特征在于,所述制剂作为成像探针,用于肿瘤诊断成像、肿瘤术中成像或肿瘤治疗成像;所述药物组合物用于肿瘤治疗。
9.根据权利要求7所述的制剂或药物组合物,其特征在于,所述制剂或药物组合物适于静脉给药或全身给药。
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