CN108543083A - 一种生物膜包裹的多模态肿瘤造影剂及其制备方法与应用 - Google Patents
一种生物膜包裹的多模态肿瘤造影剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明提供了一种生物膜包裹的多模态肿瘤造影剂及其制备方法与应用。所述的生物膜包裹的多模态肿瘤造影剂,包括生物膜和包裹于生物膜中的超顺磁性四氧化三铁的铁蛋白纳米笼(M‑HFn)和荧光染料,其中的超顺磁性四氧化三铁的铁蛋白纳米笼与荧光染料连接形成荧光染料‑M‑HFn复合物,构建得到用于体内的仿生纳米生物膜载体递送体系,可实现体内长循环,增强对肿瘤靶向性,减少非特异性积累,降低对正常组织的损害,同时增强造影效果。本发明还提供了本发明所述的生物膜包裹的多模态肿瘤造影剂的制备方法,在临床肿瘤学早期诊疗等领域拥有重要的应用前景和研究价值。
Description
技术领域
本发明属于核磁共振造影剂领域,特别涉及一种生物膜包裹的多模态肿瘤造 影剂及其制备方法与应用。
背景技术
癌症是威胁全球人类生命的最大杀手之一,是医学研究领域所面临的一项重 大挑战。核磁共振成像已经成为原发肿瘤和转移瘤诊断中重要的依据。目前肿瘤 检测手段的特异性和灵敏度较低,无法同时实现对肿瘤细胞特异性识别和药物的 可控输运。随着纳米科技的不断发展,纳米荧光探针已经被广泛应用于化学、生 物学、医学等领域,尤其是肿瘤的诊断、成像及治疗。高灵敏度、高选择性地对 多种肿瘤标志物进行检测和成像是当前研究的热点和难点,而将多组分检测的策 略应用于生物模型中,实现动态实时的对活细胞内多种物质的监测对于肿瘤诊断 具有重大意义。
基于纳米材料的新型药物及技术为重大疾病的预防、诊断与治疗提供了新的 思路。研究人员相继提出了一系列可以用于癌症早期诊断和治疗的纳米平台,具 有肿瘤靶向输运标记功能的纳米材料为实现癌症的早期诊断和治疗带来了新的 希望。在这些纳米材料中,铁蛋白纳米粒子具有独特的八面体结构,可用于装载 多种抗癌药物和成像探针分子等方面优点吸引了人们的广泛关注。然而,现有造 影剂(如:Gd-DTPA)主要是经呈高渗透状态的肿瘤血管,被动扩散到肿瘤组织 的细胞间质,这造成铁蛋白体系对肝肾等正常组织的非特异性积累、表面生物功 能化后的稳定性差、难以达到令人满意的对比成像效果等等。因此,迫切需要进 一步系统化的开展具有多重功能的特异性生物分子介导复合纳米粒子,实现体外 对肿瘤细胞的靶向标记和治疗,增强此类纳米载体在微小肿瘤病灶处的标记效果,尽早应用于临床诊断研究。
研究人员在转换发光纳米粒子的合成与制备、表面修饰改性、生物功能化、 生物安全性、细胞标记、活体成像、多模态成像、光动力治疗、以及成像引导下 的癌症治疗等许多领域展开了一系列深入的研究和探索。总体来看,目前尚缺乏 理想的、特异性强的早期诊断方法,尤其对深层肿瘤的早期诊断更为困难。
发明内容
本发明的首要目的在于克服现有技术的缺点与不足,提供一种生物膜包裹的 多模态肿瘤造影剂。本发明通过生物膜包裹近红外荧光探针、M-HFn的超顺磁性 四氧化三铁的铁蛋白纳米笼和抗肿瘤药物,构建一种用于体内的仿生纳米生物膜 载体递送体系,主动靶向至肿瘤组织实现功能化,在临床肿瘤学早期诊疗等领域 拥有重要的应用前景和研究价值。
本发明的另一目的在于提供所述的生物膜包裹的多模态肿瘤造影剂的制备 方法。
本发明的再一目的在于提供所述的生物膜包裹的多模态肿瘤造影剂的应用。
本发明的目的通过下述技术方案实现:
一种生物膜包裹的多模态肿瘤造影剂,包括生物膜和包裹于生物膜中的超顺 磁性四氧化三铁的铁蛋白纳米笼(M-HFn)和荧光染料,其中的超顺磁性四氧化 三铁的铁蛋白纳米笼与荧光染料连接形成荧光染料-M-HFn复合物。
所述的超顺磁性四氧化三铁的铁蛋白纳米笼优选通过如下方法制备得到:
在惰性气氛下,将人FTH1蛋白与脱气NaCl溶液混合在65℃±3℃下反应, 然后同时恒速加入pH 8±1的脱气硫酸亚铁铵、脱气过氧化氢溶液与NaOH溶液, 反应至少持续5min,加入柠檬酸钠;超滤离心或透析,制得所述的载铁铁蛋白纳 米粒子。
所述的生物膜优选为红细胞膜、白细胞膜、血小板膜中的至少一种;进一步 优选为红细胞膜。
所述的荧光染料优选为Cy5.5。
所述的人FTH1蛋白可通过基因工程技术制备或通过市售途径购买得到。
所述的生物膜包裹的多模态肿瘤造影剂的表面还可以连接磷脂-聚乙二醇-靶 向分子,进一步实现靶向。
所述的靶向分子优选为Angiopep-2、RGD多肽、叶酸、整合素、新生血管 靶向肽中的至少一种。
所述的生物膜包裹的多模态肿瘤造影剂的制备方法,包括如下步骤:
(1)将荧光染料与超顺磁性四氧化三铁的铁蛋白纳米笼混合孵育过夜,纯 化后得到所述的荧光染料-M-HFn复合物;
(2)将步骤(1)制得的荧光染料-M-HFn复合物加入到红细胞膜的低渗溶 液中孵育,离心取沉淀,得到负载荧光染料-M-HFn复合物的红细胞血影悬浮液, 将红细胞血影依次通过400nm,200nm,100nm或50nm脂质体制备仪器反复 挤压成型,即得所述的生物膜包裹的多模态肿瘤造影剂。
步骤(1)中所述的纯化优选为柱层析纯化。
当所述的生物膜包裹的多模态肿瘤造影剂表面还连接磷脂-聚乙二醇-靶向分 子时,将所述的生物膜包裹的多模态肿瘤造影剂混合孵育,得到靶向生物膜包裹 的多模态肿瘤造影剂。
所述的生物膜包裹的多模态肿瘤造影剂作为载体材料或制备靶向药物中的 应用。
本发明相对于现有技术具有如下的优点及效果:
(1)本发明通过生物膜包裹Cy5.5-M-HFn,可实现体内长循环,增强对肿 瘤靶向性,减少非特异性积累,降低对正常组织的损害,同时增强造影效果。相 比于传统单一功能的造影剂,本发明通过多模态成像提高组织穿透性以及被靶细 胞摄取的能力,突破多重生理屏障,实现对肿瘤组织的长效靶向递送,可避免单 一检测造成的假阳性结果。
(2)Cy5.5荧光染料与Fe3O4磁性纳米粒子用于癌症诊疗,多模态成像剂提 高组织穿透性以及被靶细胞摄取的能力,突破多重生理屏障,可实现在治疗过程 中通过分子成像实时了解药物分布、吸收情况,监测靶向治疗效果。
(3)用磷脂-聚乙二醇-靶向分子(如RGD)修饰的红细胞膜包裹铁蛋白笼 和抗癌药物复合体系,有效地保护载体内核,有利于靶向肿瘤组织和细胞并降低 对正常组织的影响,在癌症诊疗中具有极大的应用前景。
附图说明
图1是实施例1的靶向造影剂的透射电子显微镜照片图。
图2是不同加载量的超顺磁性四氧化三铁的铁蛋白纳米笼的稳定性结果分析 图。
图3是不同浓度下的超顺磁性四氧化三铁的铁蛋白纳米笼的细胞毒性 (B16F10)结果分析图。
图4是造影剂超顺磁特性检测结果分析图。
图5是实施例1的造影剂作用B16F10细胞的激光共聚焦显微镜照片图。
图6是实施例1制得的造影剂在小鼠皮下肿瘤中的NIR成像图。
图7是实施例1制得的造影剂在小鼠皮下肿瘤中的MRI成像图。
图8是受试小鼠主要器官和肿瘤组织切片照片图,从左到右依次是心脏、肝 脏、脾脏、肺部、肾脏、肿瘤组织的切片。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式 不限于此。
实施例1黑色素瘤靶向造影剂的制备
(1)制备超顺磁性铁蛋白纳米笼(HFn)
表达超顺磁性铁蛋白纳米笼的阳性菌株由湖北百奥斯生物科技有限公司进 行构建,该公司提供质粒构建等服务,细胞亦来源于该公司。
提取人骨骼肌细胞RNA,反转录成cDNA作为模板;扩增人FTH1基因, PCR引物如下(黑色下划线为酶切位点)
F:5’A GTC GCC CAT ATG ACG ACC GCG TCC 3’(Nde I)
R:5’GCC GGA TCC TTA GCT TTC ATT ATCA C 3’(Bam HI)
将PCR产物纯化回收后,经双酶切与pET-30a(+)载体连接,产物转化 XL2-Blue感受态细胞,经Kan+抗性平板筛选,挑菌落鉴定后送至测序。将测序 正确的质粒再转入感受态BL21(DE3)E.Coli中,筛选出阳性菌株。将阳性菌株 加入1L含30mg/L Kan的LB培养基过夜培养,加入1mM的IPTG诱导4h后, 离心收集菌体,用45mL的裂解液(100mM HEPES,50mMNaCl,pH8.0)重悬 沉淀,并分别加入溶菌酶、DNAse和RNAse使其终浓度为50、60和100μg/uL, 室温孵育30min后用弗氏细胞压碎器,处理后在超声破碎仪下进行破碎。离心超 声后的溶液以去掉细胞碎片,取上清在60℃中水浴10min,然后离心去除大部 分细菌杂蛋白,上清通过分子排阻色谱法进行纯化,使用Superose 6亲和层析柱, 将收集到的纯化蛋白在280nm下测吸光值计算蛋白含量,制备得到超顺磁性铁蛋 白纳米笼。
(2)制备超顺磁性四氧化三铁的铁蛋白纳米笼(M-HFn) 将脱气8.0mL,100mM NaCl溶液加到反应瓶中(氩气保护,严格无氧操作), 随后将2.0mg,3.9nmol超顺磁性铁蛋白纳米笼(HFn 1mg/mL)加入瓶中,温度 控制在65℃,pH=8.5,12.5mM,1566μL脱气硫酸亚铁铵,以化学计量比H2O2: Fe2+=1:3配制4.17mM,1566μL脱气过氧化氢溶液,25mM,1566μL NaOH溶 液用于中和反应过程中产生的H+以维持pH=8.5;三者同时以恒速31.3μL/min加 入,理论加载5000Fe(指每个去铁铁蛋白矿化5000个Fe的M-HFn);全部加进 去之后反应持续5min;反应完成后,200μL(300mM)柠檬酸钠被加进去蟄合 游离铁;超滤离心/透析,得到理论加载5000Fe的超顺磁性铁蛋白纳米笼 (M-HFn)。
除了脱气硫酸亚铁铵、脱气过氧化氢溶液、NaOH溶液的注入量调整为 313μL外,以与制备理论加载5000Fe的M-HFn相同方法制备得到理论加载1000 Fe的超顺磁性铁蛋白纳米笼。
除了脱气硫酸亚铁铵、脱气过氧化氢溶液、NaOH溶液的注入量改为939μL 外,以以与制备理论加载5000Fe的M-HFn相同方法制备得到理论加载3000Fe 的超顺磁性铁蛋白纳米笼。
(3)Cy5.5-M-HFn的制备
取1.2μmol Cy5.5-N-羟基琥珀酰亚胺酯溶于60μL DMSO中,加入到50nmol 溶于1mL PBS和0.1M碳酸氢盐/碳酸盐缓冲液的超顺磁性四氧化三铁的铁蛋白 纳米笼(M-HFn)溶液中(pH=8.3),混合轻轻震荡室温孵育过夜,样品然后通过 GE superose 6层析柱从功能化HFn上除去未结合的Cy5.5,制得Cy5.5-M-HFn。
(4)RGD-聚乙二醇-磷脂分子的制备
配制中性PBS溶液(2%体积百分含量0.5M EDTA)通氩气30min除氧(氩 气在后续实验中持续通入)干燥后称取约3mg TCEP,40.5mg DSPE-PEG2000-MAL(D163619-500mg,购自阿拉丁),待PBS除氧结束后取8mL PBS于烧杯中,加热搅拌(盖上保鲜膜)使DSPE-PEG-MAL溶解,同时分别用 1mL PBS使10mg(一瓶)RGD(M2976-10mg,购自北京拜尔迪生物技术有限公 司),3mg TCEP溶解(等待时持续通入氩气)。将含有RGD溶液与 MAL-PEG-DSPE溶液混合,室温搅拌4h(盖上保鲜膜)4℃静置过夜。离心三次, 用不含EDTA的PBS洗涤,除去其中的EDTA。超滤(MW=3500)洗涤2次,收 集产品冻干。
(5)黑色素瘤靶向Cy5.5-M-HFn/RBC的制备
将人O型血的全血经过处理得到的生物膜10mg溶于1mL水和100μL生理 盐水中(包括红细胞膜、白细胞膜和血小板膜),利用红细胞在低渗膨胀溶血时, 细胞膜上会短暂形成许多直径20~50nm的膜孔,加入5mg步骤(2)制得的 Cy5.5-M-HFn,孵育30min后离心,收集沉淀,最终获得负载Cy5.5-M-HFn的红 细胞血影悬浮液。接下来,将红细胞血影依次通过400nm,200nm,100nm或 50nm的脂质体制备仪器(Avanti mini extruder)的反复挤压成型;接下来上述 的纳米血影与步骤(3)制得的靶向RGD-聚乙二醇-磷脂分子混合孵育30min,最终获得黑色素瘤靶向的生物膜包裹的多模态肿瘤造影剂。
通过透射电子显微镜(TEM)显示红细胞膜中磁性M-HFn纳米粒子包封状 态,结果如图1所示,干燥后纳米粒子的尺寸约为80nm,继续增加放大倍数, 可清楚地看到磷脂双层的纳米颗粒包裹状态,每个细胞膜载体含有约10个超顺 磁性铁蛋白纳米笼(M-HFn)。另外,M-HFn纳米颗粒的多个磁铁矿纳米晶体也有 助于提高核磁成像对比度效应。
实施例2脑胶质瘤靶向造影剂的制备实例
(1)制备超顺磁性四氧化三铁的铁蛋白纳米笼:
制备超顺磁性四氧化三铁的铁蛋白纳米笼:将脱气8.0mL,100mM NaCl溶 液加到反应瓶中(氩气保护,严格无氧操作),随后将2.0mg,3.9nmol超顺磁 性铁蛋白纳米笼(HFn1mg/mL)加进去,温度控制在65℃,pH=8.5 12.5mM,1566 μL脱气硫酸亚铁铵,以化学计量比H2O2:Fe2+=1:3配制4.17mM,1566μL脱气 过氧化氢溶液,25mM,1566μL NaOH溶液用于中和反应过程中产生的H+以维 持pH=8.5;三者同时以恒速31.3μL/min加入,理论加载5000Fe;全部加进去 之后反应持续5min;反应完成后,200μL(300mM)柠檬酸钠被加进去蟄合游离 铁;超滤离心/透析。
(2)Cy5.5-M-HFn的制备
取1.2μmol Cy5.5-N-羟基琥珀酰亚胺酯溶于60μL DMSO中,加入到50nmol 溶于1mL PBS和0.1M碳酸氢盐/碳酸盐缓冲液的HFn溶液中(pH=8.3),混合 轻轻震荡室温孵育过夜,样品然后通过GE superose 6层析柱从功能化HFn上除 去未结合的Cy5.5。
(3)Angiopep-2-聚乙二醇-磷脂分子的制备
配制中性PBS溶液(2%体积百分含量0.5M EDTA)通氩气30min除氧(氩 气在后续实验中持续通入)干燥后称取约3mg TCEP,40.5mg DSPE-PEG-MAL, 待PBS除氧结束后取8mLPBS于烧杯中,加热搅拌(盖上保鲜膜)使 DSPE-PEG-MAL溶解,同时分别用1mL PBS使10mg(一瓶)Angiopep-2,3mg TCEP溶解(等待时持续通入氩气)。将含有Angiopep-2溶液与MAL-PEG-DSPE 溶液混合,室温搅拌4h(盖上保鲜膜)4℃静置过夜。离心三次,用不含EDTA 的PBS洗涤,除去其中的EDTA。超滤(MW=3500)洗涤2次,收集产品冻干。
(4)脑胶质瘤靶向Cy5.5-M-HFn/RBC的制备
将人O型血的全血经过处理得到生物膜,利用红细胞在低渗膨胀溶血时,细 胞膜上会短暂形成许多直径20~50nm的膜孔,加入5mg Cy5.5-M-HFn,孵育一 定时间30min后离心,收集沉淀,最终获得负载Cy5.5-M-HFn的红细胞血影悬 浮液。接下来,将红细胞血影依次通过400nm,200nm,100nm或50nm的脂 质体制备仪器(Avanti mini extruder)的反复挤压成型;接下来上述的纳米血影 与及靶向Angiopep-2-聚乙二醇-磷脂分子混合孵育,最终获得黑色素瘤靶向的生 物膜包裹的多模态肿瘤造影剂。
实施例3纳米粒子的稳定性测试
分别用实施例1制得的理论加载1000Fe、3000Fe、5000Fe的超顺磁性铁蛋 白纳米笼,将人O型血的全血经过处理得到生物膜10mg溶于1mL水和100μL 生理盐水中(包括红细胞膜、白细胞膜和血小板膜),利用红细胞在低渗膨胀溶 血时,细胞膜上会短暂形成许多直径20~50nm的膜孔,加入M-HFn,孵育30min 后离心,收集沉淀,最终获得负载不同理论加载量的M-HFn的红细胞血影悬浮 液。接下来,将红细胞血影依次通过400nm,200nm,100nm或50nm的脂质 体制备仪器(Avanti mini extruder)的反复挤压成型,分别制得RBC-1000Fe,RBC-3000Fe和RBC-5000Fe水溶液。
分别取RBC-1000Fe,RBC-3000Fe和RBC-5000Fe水溶液各1mL,室温下 使用激光纳米粒度仪定时测定其粒径。
结果如图2所示,RBC-1000Fe,RBC-3000Fe和RBC-5000Fe的DLS分析显 示纳米粒子的平均粒径随时间变化轻微,表明M-HFn纳米粒子在体内长循环中 具有优势。
实施例4纳米粒子的细胞毒性测试
对实施例1制得的理论加载1000Fe、3000Fe、5000Fe的超顺磁性铁蛋白纳 米笼用CCK8法对细胞毒性进行测试,结果如图3所示,本发明的超顺磁性铁蛋 白纳米笼均无明显的细胞毒性。
实施例5造影剂的超顺磁特性测试
分别测试纳米颗粒红细胞膜包裹Cy5.5-M-HFn之后(RBC-3000Fe)的超顺磁 特性,在1.5-T磁场下测量不同M-HFn的铁浓度的(T2)弛豫时间,实施例1制 得的Cy5.5-M-HFn/RBC的T2加权松弛率(R2)计算为198mM-1S-1。M-HFn (3000Fe)比RBC-M-HFn(RBC-3000Fe)的R2值更高,是由于HFn纳米笼对 附近铁核周围水分子的强烈扰动作用。3000Fe的浓度梯度T2成像如图4所示, 可明显看出随浓度变高颜色变黑,即成像效果更好。
实施例6动物实验
将以对数生长期肿瘤细胞B16F10制备单细胞悬液,以无血清培养基洗涤3 次,并调整细胞浓度至1*107/mL,在超净工作台内进行动物试验。以TB空针将 细胞悬液注入试验裸鼠大腿内侧皮下(选取血管丰富处),每只小鼠接种0.1mL, 含细胞数1*106,待皮下移植瘤粟粒大小(约10天,大小约60~80mm3)进行肿 瘤双模态成像实验,所述的双模态成像即磁共振成像(MRI),近红外荧光成像 (NIR)双重成像。
选取B16F10的荷瘤小鼠,尾静脉注射Cy5.5-M-HFn/RBC,注射量25mg Fe/kg,Cy5.5.8nmol Fe/kg进行肿瘤双模态成像,验证实施例1制得的Cy5.5-M-HFn/RBC 在皮下肿瘤中的成像效果。结果如图6和图7所示,MRI图像显示的肿瘤在注射 造影剂前后造影效果明显增加;NIR结果显示肿瘤部位荧光明显,表明该造影剂 能很好地富集于肿瘤部位,用于肿瘤的成像定位。图5为B16F10细胞的激光共聚 焦显微镜照片。
在注射药物24h后将其处死,分别取心脏、肝脏、脾脏、肺部、肾脏、肿瘤 组织进行HE染色切片,结果如图8所示,各组脏器的生理形态正常,未见明显病 理改变。与PBS对照组相比,本发明的Cy5.5-M-HFn/RBC在细胞中没有明显的坏 死或细胞凋亡,在器官或组织中无任何损伤。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施 例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替 代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
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<110> 暨南大学
<120> 一种生物膜包裹的多模态肿瘤造影剂及其制备方法与应用
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<210> 1
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
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<211> 26
<212> DNA
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gccggatcct tagctttcat tatcac 26
Claims (10)
1.一种生物膜包裹的多模态肿瘤造影剂,其特征在于:
包括生物膜和包裹于生物膜中的超顺磁性四氧化三铁的铁蛋白纳米笼和荧光染料,其中的超顺磁性四氧化三铁的铁蛋白纳米笼与荧光染料连接形成荧光染料-M-HFn复合物。
2.根据权利要求1所述的生物膜包裹的多模态肿瘤造影剂,其特征在于,所述的超顺磁性四氧化三铁的铁蛋白纳米笼通过如下方法制备得到:
在惰性气氛下,将人FTH1蛋白与脱气NaCl溶液混合在65℃±3℃下反应,然后同时恒速加入pH 8±1的脱气硫酸亚铁铵、脱气过氧化氢溶液与NaOH溶液,反应至少持续5min,加入柠檬酸钠;超滤离心或透析,制得所述的载铁铁蛋白纳米粒子。
3.根据权利要求1所述的生物膜包裹的多模态肿瘤造影剂,其特征在于:
所述的生物膜为红细胞膜、白细胞膜、血小板膜中的至少一种。
4.根据权利要求1所述的生物膜包裹的多模态肿瘤造影剂,其特征在于:
所述的生物膜为红细胞膜;
所述的荧光染料为Cy5.5。
5.根据权利要求1~4任一项所述的生物膜包裹的多模态肿瘤造影剂,其特征在于:
所述的生物膜包裹的多模态肿瘤造影剂的表面连接磷脂-聚乙二醇-靶向分子。
6.根据权利要求5所述的所述的生物膜包裹的多模态肿瘤造影剂,其特征在于:
所述的靶向分子为Angiopep-2、RGD多肽、叶酸、整合素、新生血管靶向肽中的至少一种。
7.权利要求1~6任一项所述的生物膜包裹的多模态肿瘤造影剂的制备方法,其特征在于,包括如下步骤:
(1)将荧光染料与超顺磁性四氧化三铁的铁蛋白纳米笼混合孵育过夜,纯化后得到所述的荧光染料-M-HFn复合物;
(2)将步骤(1)制得的荧光染料-M-HFn复合物加入到红细胞膜的低渗溶液中孵育,离心取沉淀,得到负载荧光染料-M-HFn复合物的红细胞血影悬浮液,将红细胞血影依次通过400nm,200nm,100nm或50nm脂质体制备仪器反复挤压成型,即得所述的生物膜包裹的多模态肿瘤造影剂。
8.根据权利要求7所述的生物膜包裹的多模态肿瘤造影剂的制备方法,其特征在于:
步骤(1)中所述的纯化为柱层析纯化。
9.根据权利要求7或8任一项所述的生物膜包裹的多模态肿瘤造影剂的制备方法,其特征在于:
当所述的生物膜包裹的多模态肿瘤造影剂表面还连接磷脂-聚乙二醇-靶向分子时,将所述的生物膜包裹的多模态肿瘤造影剂混合孵育,得到靶向生物膜包裹的多模态肿瘤造影剂。
10.所述的生物膜包裹的多模态肿瘤造影剂作为载体材料或制备靶向药物中的应用。
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