CN110075320B - 一种靶向非小细胞肺癌的双模态示踪剂 - Google Patents
一种靶向非小细胞肺癌的双模态示踪剂 Download PDFInfo
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Abstract
本发明提供一种靶向非小细胞肺癌的近红外荧光‑电子计算机断层扫描双模态示踪剂，该双模态示踪剂是一种表面键合表皮生长因子‑1抗体的脂质体，该脂质体是以天然磷脂、棕榈酰三肽‑1、甲氧基聚乙二醇2000磷脂、键合表皮生长因子‑1抗体的甲氧基聚乙二醇2000磷脂作为膜材料，包载吲哚箐绿和碘克沙醇制备而成。该双模态示踪剂具有粒径均一、稳定性高、非小细胞肺癌靶向性好的优势，用于非小细胞肺癌的准确示踪。
Description
技术领域
本发明涉及肿瘤示踪剂领域，特别是一种靶向非小细胞肺癌的近红外荧光-电子计算机断层扫描双模态示踪剂及其制备方法。
背景技术
非小细胞肺癌(NSCLC)是全球范围内发病率、病死率最高的恶性肿瘤，具有恶性程度高、发展速度快、治疗困难、预后差等特点。目前，临床上以“手术+化疗”的综合治疗效果并不理想，主要原因在于化疗制剂缺乏靶向性，全身毒副作用大，且治疗缺乏实时可监控性，无法及时掌握药动学信息，无法及时调整治疗方案。
近红外荧光具有高穿透性与低背景值等优点，其成像可以观察深层组织，同时避免血液或其他体液背景干扰。吲哚箐绿(Indocyanine green，ICG)由两个多环部分和中间相连的碳链组成，是一种能够吸收近红外光(650-900nm)，并产生热效应的荧光染料，其波长范围在740-800nm，在体内不参与任何生物转化，与血浆蛋白与脂蛋白结合，以原型迅速被肝、肾代谢。因其在体内毒性小，安全范围大，已被美国食品与药品监督管理局(FDA)批准，成为一种临床近红外荧光成像对比增强剂，目前已经应用于心输出量检测、肝功能与肝血流量检测，眼底动脉造影等方面。但吲哚箐绿单体在水溶液中容易聚集，在体内易与血浆蛋白结合，经肝迅速代谢，体内半衰期只有约2-4min，无法达到单次给药长时间在肿瘤靶区滞留、实时成像的要求。
碘克沙醇为一种临床用非离子型注射用造影剂，适用于心脑血管造影、静脉内尿路造影。其作用原理是结合碘在血管或组织内吸收X射线造成影像显示。然而作为一种小分子化合物，碘克沙醇在注射体内后，迅速分布与肝肾等区域，并快速经肾代谢，无法为肺等组织提供更清晰的显影效果。此外，多次注射高浓度碘克沙醇易引起肾中聚集，导致肾毒性。
单一的成像技术无法满足临床治疗的实际需要，开发双模态的成像示踪剂对于非小细胞肺癌的治疗具有重大应用意义。但是由于缺乏安全的靶向载体技术，目前尚缺乏一种能够实现非小细胞肺癌准确定位的安全高效的双模态示踪剂。
发明内容
本发明的目的在于克服“目前尚缺乏一种能够实现非小细胞肺癌准确定位的安全高效的双模态示踪剂”的瓶颈，提供一种靶向非小细胞肺癌的双模态示踪剂，实现非小细胞肺癌的安全高效的成像示踪。
申请人研究发现，表皮生长因子-1受体(EGFR)高表达于非小细胞肺癌的细胞膜表面，如果利用单克隆抗体识别癌细胞表面EGFR能够达到靶向递送的作用。此外，利用吲哚箐绿的近红外荧光成像结合碘克沙醇的电子计算机断层扫描(CT)成像，可望为非小细胞肺癌提供安全高效的双模态示踪。但是，吲哚箐绿存在体内易与血浆蛋白结合、半衰期短的缺点，而碘克沙醇存在靶向性差、肾中易聚集导致毒性的不足。如何设计一种同时包载吲哚箐绿和碘克沙醇的双模态示踪剂，并保证其安全性、可重复性、靶向性和体内可监控性，将是一项艰难的挑战。
申请人为此通过大量实验，提供了一种靶向非小细胞肺癌的双模态示踪剂，该双模态示踪剂是一种表面键合表皮生长因子-1抗体的脂质体，该脂质体是以天然磷脂、棕榈酰三肽-1、甲氧基聚乙二醇2000磷脂、键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂作为膜材料，包载吲哚箐绿和碘克沙醇制备而成。
上述的脂质体中各组分浓度如下：
天然磷脂的浓度为100-200mg/ml，棕榈酰三肽-1的浓度为20-40mg/ml，甲氧基聚乙二醇2000磷脂的浓度为5-20mg/ml，键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂的浓度为1-5mg/ml，吲哚箐绿的浓度为0.05-2mg/ml，碘克沙醇的浓度为80-160mg/ml。
上述的脂质体中各组分浓度优选如下：
天然磷脂的浓度为180mg/ml，棕榈酰三肽-1的浓度为30mg/ml，甲氧基聚乙二醇2000磷脂的浓度为10mg/ml，键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂的浓度为3.0mg/ml，吲哚箐绿的浓度为0.1mg/ml，碘克沙醇的浓度为150mg/ml。
上述的双模态示踪剂具有近红外荧光成像和电子计算机断层扫描成像作用。
一种上述的靶向非小细胞肺癌的双模态示踪剂的制备方法，将天然磷脂、棕榈酰三肽-1、甲氧基聚乙二醇2000磷脂、键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂溶于二氯甲烷中，低压旋转蒸发后在瓶底形成一层薄膜，将吲哚箐绿与碘克沙醇溶于蒸馏水中，加入至瓶中搅拌、水化磷脂膜，再利用小型高压均质机800bar均质3次，补加蒸馏水调整溶液总体积，混匀，得到双模态示踪剂溶液。
上述的双模态示踪剂的制备是在避光条件下进行。
上述的双模态示踪剂使用时，应与磷脂微泡混合，形成双模态示踪剂-磷脂微泡复合物，应用于非小细胞肺癌的示踪。
上述的双模态示踪剂粒径均一、稳定性高、安全性高、非小细胞肺癌靶向性好。
本申请保护的技术方案中各组分是协同互补和必要的关系，共同发挥作用。
具体实施方式
下文将详细描述本发明具体实施例。应当注意的是，下述实施例中描述的技术特征或者技术特征的组合不应当被认为是孤立的，它们可以被相互组合从而达到更好的技术效果。
实施例1 靶向非小细胞肺癌的双模态示踪剂的制备
按照表1双模态示踪剂各实验组和对照组的组成，准确量取各组分剂量，按照以下方法制备双模态示踪剂。
制备方法：天然磷脂、棕榈酰三肽-1、甲氧基聚乙二醇2000磷脂、键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂溶于10ml二氯甲烷中，低压旋转蒸发后在瓶底形成一层薄膜，将吲哚箐绿与碘克沙醇溶于8ml蒸馏水中，加入至瓶中搅拌、水化磷脂膜，再利用小型高压均质机800bar均质3次，补加蒸馏水调整溶液总体积达到10ml，混匀，得到双模态示踪剂溶液。
表1双模态示踪剂各实验组和对照组的组成
注：“/”代表该项组分为0；“()”：表示以括号内组分代替该项列名的组分。
实施例2 靶向非小细胞肺癌的双模态示踪剂在体应用效果
非小细胞肺癌(NSCLC)模型动物的建立：将培养的D-荧光素酶标记的小鼠非小细胞肺癌(LLC-Luc)细胞消化并计数，与基质胶1∶1(v/v)混合后放置于冰上备用。细胞最终的浓度为1×107/ml。10％水合氯醛麻醉C56BL/6小鼠，左肋侧剃毛，沿左侧肋弓上1cm处作4-5mm切口，用胰岛素针将0.1ml细胞悬液缓慢注射入小鼠左肺，注射时观察小鼠呼吸，防止进针过深对肺造成严重伤害。注射完成后，用6-0缝线将伤口缝好，碘酒消毒，待小鼠恢复。第0、7、14天腹腔注射D-荧光素，观察小鼠肺部是否有荧光及荧光强弱。第21天处死小鼠，观察肺表面是否有肺癌结节，取部分组织进行切片染色，观察有肺癌病灶区的动物确定非小细胞肺癌模型建立成功。
非小细胞肺癌(NSCLC)模型动物在体应用效果观察：基于实施例1制备的实验组和对照组，各组双模态示踪剂溶液5ml，加入到声诺维(磷脂微泡造影剂)冻干粉中，混合，形成双模态示踪剂-磷脂微泡复合物。在非小细胞肺癌模型动物筋膜成功后第7天或第14天，分别尾静脉注射0.4ml双模态示踪剂-磷脂微泡复合物，随后进行小动物活体成像(近红外荧光成像)与电子计算机断层扫描(CT)，成像后处死小鼠，进行10％多聚甲醛固定，肉眼鉴定肺癌表面结节数量，并与近红外荧光成像和CT成像结果进行对比，计算成像下对肺癌结节的检出率。
表2双模态示踪剂实验组和对照组应用效果
从表2结果可见，各实验组无论在第7天注射还是第14天注射，非小细胞肺癌结节检出率都明显高于对照组的指标。表明本发明的双模态示踪剂具有良好的创造性。实验组中以1组的评分最高，其次是5组和3组。
相比实验组结果，对照组非小细胞肺癌结节检出率明显较差，其中对照组4最差，其次是对照组10。
此外，各实验组和对照组的第7天注射观察的非小细胞肺癌结节检出率高于第14天注射观察的指标，证明双模态示踪剂用于非小细胞肺癌的早期检测效果更好。
由上结果可见，本发明的双模态示踪剂具有良好的非小细胞肺癌靶向示踪效果，各组分之间彼此互补，缺一不可，发挥了协同作用。
上述详细说明是针对发明的可行实施例的具体说明，该实施例并非用以限制本发明的专利范围，凡未脱离本发明的等效实施或变更，均应当包含于本发明的专利范围内。
另外，本领域技术人员还可在本发明权利要求公开的范围和精神内做其它形式和细节上的各种修改、添加和替换。当然，这些依据本发明精神所做的各种修改、添加和替换等变化，都应包含在本发明所要求保护的范围之内。
Claims (7)
1.一种靶向非小细胞肺癌的双模态示踪剂，其特点在于：所述的双模态示踪剂是一种表面键合表皮生长因子-1抗体的脂质体，该脂质体是以天然磷脂、棕榈酰三肽-1、甲氧基聚乙二醇2000磷脂、键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂作为膜材料，包载吲哚箐绿和碘克沙醇制备而成，所述的脂质体中各组分浓度如下：
天然磷脂的浓度为100-200mg/ml，棕榈酰三肽-1的浓度为20-40mg/ml，甲氧基聚乙二醇2000磷脂的浓度为5-20mg/ml，键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂的浓度为1-5mg/ml，吲哚箐绿的浓度为0.05-2mg/ml，碘克沙醇的浓度为80-160mg/ml。
2.根据权利要求1所述的一种靶向非小细胞肺癌的双模态示踪剂，其特征在于：所述的脂质体中各组分浓度如下：
天然磷脂的浓度为180mg/ml，棕榈酰三肽-1的浓度为30mg/ml，甲氧基聚乙二醇2000磷脂的浓度为10mg/ml，键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂的浓度为3.0mg/ml，吲哚箐绿的浓度为0.1mg/ml，碘克沙醇的浓度为150mg/ml。
3.根据权利要求1所述的一种靶向非小细胞肺癌的双模态示踪剂，其特征在于：所述的双模态示踪剂具有近红外荧光成像和电子计算机断层扫描成像作用。
4.一种权利要求1所述的靶向非小细胞肺癌的双模态示踪剂的制备方法，其特征在于：所述的双模态示踪剂采用以下方法制备：
天然磷脂、棕榈酰三肽-1、甲氧基聚乙二醇2000磷脂、键合表皮生长因子-1抗体的甲氧基聚乙二醇2000磷脂溶于二氯甲烷中，低压旋转蒸发后在瓶底形成一层薄膜，将吲哚箐绿与碘克沙醇溶于蒸馏水中，加入至瓶中搅拌、水化磷脂膜，再利用小型高压均质机800bar均质3次，补加蒸馏水调整溶液总体积，混匀，得到双模态示踪剂溶液。
5.根据权利要求4所述的靶向非小细胞肺癌的双模态示踪剂的制备方法，其特征在于：所述的双模态示踪剂的制备是在避光条件下进行。
6.根据权利要求1所述的一种靶向非小细胞肺癌的双模态示踪剂，其特征在于：所述的双模态示踪剂使用时，应与磷脂微泡混合，形成双模态示踪剂-磷脂微泡复合物，应用于非小细胞肺癌的示踪。
7.根据权利要求1所述的一种靶向非小细胞肺癌的双模态示踪剂，其特征在于：所述的双模态示踪剂粒径均一、稳定性高、安全性高、非小细胞肺癌靶向性好。
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