CN112442117A - 一种靶向卵泡刺激素受体的肿瘤成像与治疗探针及其制备方法与应用 - Google Patents
一种靶向卵泡刺激素受体的肿瘤成像与治疗探针及其制备方法与应用 Download PDFInfo
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Abstract
为了解决术中准确识别病灶,在近红外荧光染料用于显像优势的基础上,增加其特异性显像。本发明提供一种靶向卵泡刺激素受体的肿瘤成像与治疗探针及其制备方法。本发明由卵泡刺激素多肽(LYTRDLVYKDPARPKIQKTCTF)与近红外荧光染料Rh760偶联而成卵泡刺激素受体靶向的肿瘤成像与治疗探针FSH‑Rh760,优点是,本发明利用FSHR在卵巢癌中高表达,基于FSH多肽与FSHR特异性结合的原理,靶向识别卵巢癌细胞。利用近红外荧光染料Rh760穿透深度更深、背景信号更低的优点,在荧光成像和荧光指导手术中有良好的应用前景。本发明的靶向探针FSH‑Rh760可用于卵巢癌的光热治疗,作为手术治疗的补充,改善卵巢癌预后。
Description
技术领域
本发明涉及一种卵泡刺激素受体靶向的肿瘤成像与治疗探针及其制备方法与应用。
背景技术
卵巢癌死亡率居女性生殖系统恶性肿瘤之首。87%的病例发现时已经是晚期(III期和IV期),10年生存率仅15%。瘤体减灭术联合化疗是晚期卵巢癌的主要治疗方式。手术的彻底性与卵巢癌预后密切相关。为达到彻底切除,术中准确识别病灶是关键。现有的影像学检查如超声、X光、CT、MRI等为肿瘤非特异成像,且难以用于术中实时成像。荧光指导手术使用肿瘤靶向成像探针,与肿瘤细胞特异性结合并标记,通过术中实时荧光成像的方式指导病灶切除。肿瘤靶向探针由靶向基团和荧光探针两部分组成,其中靶向基团决定了成像的特异性,而荧光探针需要具有良好的穿透性和稳定性。
卵巢受下丘脑-垂体-卵巢轴相关激素调节,如卵泡刺激素(Follicle-stimulating hormone, FSH)。生理条件下,卵泡刺激素受体(Follicle-stimulatinghormone receptor, FSHR)主要表达于卵巢,特异性较高。卵巢癌也与下丘脑-垂体-卵巢轴激素关系密切,卵巢癌中FSHR表达率约为50-60%。以FSHR为靶点的卵巢癌靶向治疗已取得系列进展,因此FSHR有望成为卵巢癌特异性成像的靶点。
与FSHR特异性结合的FSH多肽可用作成像探针的靶向基团。以短肽作为靶向基团是一种常用的靶向策略,在肿瘤靶向治疗已有成熟应用,在肿瘤靶向成像的研究也逐渐增多。与单抗相比,短肽具有免疫原性弱、体内快速分布、合成简单、易于修饰等优点。已有基于小分子多肽的肿瘤靶向成像探针进入临床试验阶段。
与传统成像方式相比,近红外荧光(Near infrared, NIR)成像具有实时、快速的特点,近红外荧光染料具有穿透深度更深、背景信号更低的优点,更适合于术中成像。但是,近红外荧光染料不能与肿瘤细胞特异性结合,文献报道吲哚菁绿用于卵巢癌显像的假阳性率达62%。近红外荧光染料Rh760在近红外波段具有较高的发光效率,并且该分子呈电中性,相比于大多数近红外荧光染料带有正电荷或负电荷,其电中性的特点可以更大程度的避免与生物组织中的其他分子发生静电相互作用,从而减弱染料分子的引入对多肽分子靶向性的影响。
发明内容
为了解决术中准确识别病灶,在近红外荧光染料用于显像优势的基础上,增加其特异性显像。本发明提供一种靶向卵泡刺激素受体的肿瘤成像与治疗探针及其制备方法。
本发明由卵泡刺激素多肽(LYTRDLVYKDPARPKIQKTCTF)与近红外荧光染料Rh760偶联而成卵泡刺激素受体靶向的肿瘤成像与治疗探针FSH-Rh760,其结构式是:
所述卵泡刺激素受体靶向的肿瘤成像与治疗探针FSH-Rh760的制备方法步骤如下:
(1)将0.2 mmol化合物Rh760、100 mg (0.25 mmol) 卡特缩合试剂、150 mg (1 mmol)哌嗪和10 mL二氯甲烷溶液加入到50 mL圆底烧瓶中,室温下搅拌反应2 h,反应结束后,减压蒸馏除去溶剂,用二氯甲烷和甲醇作洗脱剂通过柱层析提纯分离得到化合物Rh760-Paz(105 mg),产率:80%;1H NMR (400 MHz, DMSO-d6, δ) 8.99 (bs, 1H), 7.62 (m, 2H),7.53 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 9.2 Hz, J =2.4 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 3.45 (q, J =13.6 Hz, 4H), 3.15-3.45 (m, 6H), 2.2-2.6 (m, 8H), 2.0-2.30 (m, 2H), 1.60 (s,6H), 1.14 (t, J = 7.2 Hz, 6H);
(2)将0.2 mmol化合物Rh760-Paz、86 mg (10 mmol) 戊二酸酐和20 mL二氯甲烷溶液加入到50 mL圆底烧瓶中,室温下搅拌反应2 h,反应结束后,减压蒸馏除去溶剂,用二氯甲烷和甲醇作洗脱剂通过柱层析提纯分离得到化合物Rh760-GA(150 mg),产率:95%;1H NMR(400 MHz, DMSO-d6, δ) 8.99 (bs, 1H), 7.62 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H),7.35 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 6.71 (d, J =9.2 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 3.45 (q, J = 13.6 Hz, 4H), 3.15-3.45(m, 6H), 2.2-2.6 (m, 8H), 2.0-2.30 (m, 2H), 1.60 (s, 6H), 1.14 (t, J = 7.2Hz, 6H);
(3)FSH多肽序列为LYTRDLVYKDPARPKIQKTCTF,①称取2-cl树脂0.5 g,加入4 ml DCM浸泡5 min,用DMF洗涤2次,加入0.2 mmol Fmoc-D-Tyr(tbu)-OH、6 ml DCM、0.5 ml DIEA,反应90 min,结束后补加0.5 ml分析甲醇,1 ml DCM,封闭反应20 min;②用DMF洗涤4次,加入哌啶(20%哌啶+80%DMF)反应20 min脱除Fmoc,用DMF洗涤5次,取少量树脂(10-20粒),加入茚三酮(5g/100ml分析乙醇)2滴、吡啶2滴,100 ℃ 2 min,显色即可;③称取下一个氨基酸Fmoc-D-Thr(tbu)-oh(0.45 mmol)+HOBT(0.45 mmol),加入5 ml DMF、0.5 ml DIC反应1 h,用DMF洗涤4次,取少量树脂(约30粒)检测,无色即可;④重复②、③步骤直到肽链偶联结束,脱除Fmoc,偶联RH760-GA,方法同步骤③;⑤把树脂用甲醇抽干,加入10 ml切割液(95%TFa+1%H2O+2%EDT+2%TIS)摇晃切割2 h,所得反应液用40 ml冰乙醚沉降,得到蓝绿色固体,通过HPLC分离、提纯、冻干,得到蓝绿色固体产物。
本发明可应用于:
(1) 基于Rh760的光热转换特性,能有效用于红外线光照治疗癌病灶;
(2) 基于治疗探针FSH-Rh760在体内识别肿瘤细胞,以及近红外荧光染料Rh760穿透深度更深、背景信号更低的特性,能有效用于荧光成像和荧光指导手术中。
本发明在细胞系检测探针与卵巢癌细胞的结合能力,结果表明,靶向探针FSH-Rh760的结合力强于Rh760。利用裸鼠腹腔种植瘤模型检测探针的活体成像能力,结果表明,靶向探针FSH-Rh760可与腹腔转移灶特异性结合,效果优于Rh760。利用裸鼠腹腔种植瘤模型评价探针的光热治疗效果,靶向探针FSH-Rh760光热治疗组腹腔转移灶数量相较于对照组显著减少。
本发明的优点是:
1. 本发明利用FSHR在卵巢癌中高表达,基于FSH多肽与FSHR特异性结合的原理,靶向识别卵巢癌细胞。
2. 本发明利用近红外荧光染料Rh760穿透深度更深、背景信号更低的优点,在荧光成像和荧光指导手术中有良好的应用前景。
3. 本发明的靶向探针FSH-Rh760可用于卵巢癌的光热治疗,作为手术治疗的补充,改善卵巢癌预后。
本发明能够在体内外靶向识别高表达FSHR的卵巢癌细胞与病灶,较好的区分卵巢癌种植转移灶与肠管等正常组织,术前光热治疗可缩小病灶,有助于提高手术切除率;术后针对难以切除的病灶给予光热治疗,可以降低肿瘤负荷,改善预后。本发明在FSH-Rh760探针特异性识别卵巢癌病灶的基础上,进一步利用其光热转换性质进行光热治疗,杀伤肿瘤细胞。
附图说明
图1 FSH-Rh760探针的合成路线;
图2 FSH-Rh760和Rh760的紫外吸收及荧光图谱;
图3 FSH-Rh760与卵巢癌细胞的结合;
图4 FSH-Rh760用于裸鼠卵巢癌腹腔转移灶的成像;
图5 FSH-Rh760光热治疗的升温曲线;
图6 FSH-Rh760用于裸鼠卵巢癌腹腔转移灶的光热治疗。
具体实施方式
本发明提供一种新型的靶向FSH受体的肿瘤成像与治疗探针FSH-Rh760,由FSH多肽和近红外荧光染料Rh760偶联而成。
制备上述近红外荧光探针的具体实施方式如下:
(1)将0.2 mmol化合物Rh760、100 mg (0.25 mmol) 卡特缩合试剂、150 mg (1 mmol)哌嗪和10 mL二氯甲烷溶液加入到50 mL圆底烧瓶中,室温下搅拌反应2 h,反应结束后,减压蒸馏除去溶剂,用二氯甲烷和甲醇作洗脱剂通过柱层析提纯分离得到化合物Rh760-Paz(105 mg)。产率:80%。1H NMR (400 MHz, DMSO-d6, δ) 8.99 (bs, 1H), 7.62 (m, 2H),7.53 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 9.2 Hz, J =2.4 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 3.45 (q, J =13.6 Hz, 4H), 3.15-3.45 (m, 6H), 2.2-2.6 (m, 8H), 2.0-2.30 (m, 2H), 1.60 (s,6H), 1.14 (t, J = 7.2 Hz, 6H)。
(2)将0.2 mmol化合物Rh760-Paz、86 mg (10 mmol) 戊二酸酐和20 mL二氯甲烷溶液加入到50 mL圆底烧瓶中,室温下搅拌反应2 h,反应结束后,减压蒸馏除去溶剂,用二氯甲烷和甲醇作洗脱剂通过柱层析提纯分离得到化合物Rh760-GA(150 mg)。产率:95%。1HNMR (400 MHz, DMSO-d6, δ) 8.99 (bs, 1H), 7.62 (m, 2H), 7.53 (d, J = 8.4 Hz,1H), 7.35 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 6.71(d, J = 9.2 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 3.45 (q, J = 13.6 Hz, 4H),3.15-3.45 (m, 6H), 2.2-2.6 (m, 8H), 2.0-2.30 (m, 2H), 1.60 (s, 6H), 1.14 (t,J = 7.2 Hz, 6H)。
(3)FSH多肽序列为LYTRDLVYKDPARPKIQKTCTF。①称取2-cl树脂0.5 g,加入4 mlDCM浸泡5 min,用DMF洗涤2次,加入0.2 mmol Fmoc-D-Tyr(tbu)-OH、6 ml DCM、0.5 mlDIEA,反应90 min。结束后补加0.5 ml分析甲醇,1 ml DCM,封闭反应20 min。②用DMF洗涤4次,加入哌啶(20%哌啶+80%DMF)反应20 min脱除Fmoc。用DMF洗涤5次,取少量树脂(10-20粒),加入茚三酮(5g/100ml分析乙醇)2滴、吡啶2滴,100 ℃ 2 min,显色即可。③称取下一个氨基酸Fmoc-D-Thr(tbu)-oh(0.45 mmol)+HOBT(0.45 mmol),加入5 ml DMF、0.5 ml DIC反应1 h,用DMF洗涤4次,取少量树脂(约30粒)检测,无色即可。④重复②、③步骤直到肽链偶联结束,脱除Fmoc,偶联RH760-GA,方法同步骤③。⑤把树脂用甲醇抽干,加入10 ml切割液(95%TFa+1%H2O+2%EDT+2%TIS)摇晃切割2 h。所得反应液用40 ml冰乙醚沉降,得到蓝绿色固体。通过HPLC分离、提纯、冻干,得到蓝绿色固体产物。FSH-Rh760的合成路线见图1。
配置浓度为2 μM的FSH-Rh760和Rh760溶液(溶剂为DMSO),使用分光光度计检测探针的紫外吸收光谱,使用荧光光谱仪检测探针的荧光光谱,结果见附图2。
上述近红外荧光探针用于卵巢癌靶向成像及治疗的具体实施方式如下:
将处于对数生长期的人卵巢癌细胞系A2780、IGROV1(高表达FSHR)和人卵巢癌细胞系SKOV3(低表达FSHR)以2x103个/孔接种于腔室载玻片,待细胞汇合度达50%开始实验。吸去培养液,分别加入10 μM 的FSH-Rh760和Rh760,37 ℃孵育90 min。吸净上清,PBS洗3遍。用4%多聚甲醛于室温固定10 min。吸去固定液,PBS洗1遍。加入细胞膜染料WGA488于室温孵育10 min。吸去细胞膜染料,PBS洗3遍。用含DAPI的荧光封片剂封片,共聚焦显微镜下观察。靶向探针FSH-Rh760的荧光强度高于Rh760,FSHR高表达的A2780、IGROV1细胞的荧光强度高于FSHR低表达的SKOV3细胞(图3)。细胞实验结果表明,靶向探针FSH-Rh760与表达FSHR的卵巢癌细胞的结合力强于Rh760。
将人卵巢癌细胞系A2780-Luc(转染Luciferase基因)消化后制成单细胞悬液,按每只1x107/200 ul接种于雌性裸鼠腹腔。肿瘤细胞在腹腔播散种植生长,2周后种植灶数量可超过10个,大小约0.1-1 cm。实验组荷瘤小鼠腹腔注射60 μg (3 mg/kg)靶向探针FSH-Rh760,对照组荷瘤小鼠腹腔注射10.4 μg(0.52 mg/kg)对照探针Rh760。注射成像探针后2h处死小鼠,打开腹腔同时进行近红外荧光成像和生物发光成像(激发波长为740 nm,发射波长为790 nm),将生物发光信号与荧光信号对比。靶向探针FSH-Rh760在腹腔种植灶有明显信号,且荧光信号与生物发光信号一致;对照探针Rh760信号集中于肝脏,在肿瘤病灶不显像(图4)。裸鼠腹腔种植瘤模型的成像结果提示,靶向探针FSH-Rh760能够特异性识别卵巢癌转移灶。
将人卵巢癌细胞系A2780消化后制成单细胞悬液,按每只1x107/200 ul接种于雌性裸鼠腹腔。将荷瘤小鼠随机分为6组(每组5只):FSH-Rh760+激光组、Rh760+激光组、PBS+激光组、FSH-Rh760组、Rh760组、PBS组。接种细胞7天后,接受光热治疗的3组小鼠每3天照射一次激光,共4次;与之对应的3组小鼠不做激光照射,其他处理不变。接受光热治疗的3组小鼠:实验组小鼠腹腔注射120 μg(6 mg/kg)靶向探针FSH-Rh760,对照组小鼠腹腔注射20.8μg(1.04 mg/kg)对照探针Rh760或者等体积的PBS溶液。注射成像探针后2h用近红外荧光光源对荷瘤小鼠的全腹进行照射,激发光波长为808 nm,功率密度为1.60 W/cm2,照射时间为10 min。用热成像仪监测激光照射下小鼠的腹部体温变化,实验组和对照组小鼠的升温曲线见图5。接种细胞19天后牺牲小鼠,统计腹腔中卵巢癌转移灶的数目。结果显示,FSH-Rh760光热治疗组转移灶数目相较其他5组显著降低(图6),说明靶向探针FSH-Rh760光热治疗可有效减少卵巢癌转移灶数目。
Claims (3)
2.按权利要求1所述卵泡刺激素受体靶向的肿瘤成像与治疗探针FSH-Rh760的制备方法,由卵泡刺激素多肽(LYTRDLVYKDPARPKIQKTCTF)与近红外荧光染料Rh760偶联而成,步骤如下:
(1)将0.2 mmol化合物Rh760、100 mg 的卡特缩合试剂、150 mg 的 哌嗪和10 mL二氯甲烷溶液加入到50 mL圆底烧瓶中,室温下搅拌反应2小时,反应结束后,减压蒸馏除去溶剂,用二氯甲烷和甲醇作洗脱剂通过柱层析提纯分离得到105 mg化合物Rh760-Paz ;
(2)将0.2 mmol化合物Rh760-Paz、86 mg 的 戊二酸酐和20 mL二氯甲烷溶液加入到50mL圆底烧瓶中,室温下搅拌反应2 h,反应结束后,减压蒸馏除去溶剂,用二氯甲烷和甲醇作洗脱剂通过柱层析提纯分离得到150 mg化合物Rh760-GA ;
(3)FSH多肽序列为LYTRDLVYKDPARPKIQKTCTF,①称取2-cl树脂0.5 g,加入4 ml DCM浸泡5 min,用DMF洗涤2次,加入0.2 mmol Fmoc-D-Tyr(tbu)-OH、6 ml DCM、0.5 ml DIEA,反应90 min,结束后补加0.5 ml分析甲醇,1 ml DCM,封闭反应20 min;②用DMF洗涤4次,加入20%哌啶和80%DMF组成的哌啶反应20 min脱除Fmoc,用DMF洗涤5次,取10-20粒树脂,加入茚三酮2滴、吡啶2滴,100 ℃ 2 min,显色即可;③称取下一个0.45 mmol氨基酸Fmoc-D-Thr(tbu)-oh与0.45 mmol的HOBT,加入5 ml DMF、0.5 ml DIC反应1 h,用DMF洗涤4次,取约30粒树脂检测,无色即可;
(4)重复2、3步骤直到肽链偶联结束,脱除Fmoc,偶联RH760-GA,方法同步骤3;
(5)把树脂用甲醇抽干,加入10 ml由95%TFa、1%H2O、2%EDT和2%TIS组成的切割液摇晃切割2 h,所得反应液用40 ml冰乙醚沉降,得到蓝绿色固体,通过HPLC分离、提纯、冻干,得到蓝绿色固体产物。
3.按权利要求1所述探针FSH-Rh760在卵泡刺激素受体靶向成像与治疗的应用。
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