CN116421745A - 一种腹腔出血点延时显像造影剂 - Google Patents
一种腹腔出血点延时显像造影剂 Download PDFInfo
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Abstract
本发明属于造影诊断技术领域,具体涉及一种腹腔出血点延时显像造影剂。本发明要解决的技术问题是出血发生时间窗和图像采集时间窗不重合造成的漏诊。本发明的技术方案是一种腹腔出血点延时显像造影剂,包括A组分和B组分;A组分为Nb‑PEG‑PTIB或BSA‑TIB‑Nb;B组分为HA‑Tz或4‑arm PEG5000‑Tz。A组分含有碘造影剂,经静脉注射;B组分直接注射至腹腔;血液中的A组分由血管出血点进入腹腔后与B组分相遇,快速形成水凝胶固定位置而非自由扩散,实现在X光/CT成像中的持续显影,指示出血位置。
Description
技术领域
本发明属于造影诊断技术领域,具体涉及一种腹腔出血点延时显像造影剂。
背景技术
失血是腹部创伤伤员死亡的主要原因。目前主流的腹腔出血点探明方案是剖腹探查、X射线透视下腹腔动脉介入造影和增强CT。
剖腹探查止血能够快速探明动脉、门脉、静脉等多种出血点和多发出血点,但是创伤大,同时腹腔脏器多,急诊情况下患者未做肠道准备,肠管鼓影响手术视野,在无的放矢的情况下快速明确出血位置难度高,需要专业技能较高的外科医生,另外腹腔出血患者常常伴有低血压、休克,腹腔出血点可以随着血压的变化间歇出现、隐匿出现,术前无明确的影像学指示出血点容易造成出血点的遗漏,进而二次开腹手术止血,给患者带来很大的损伤。
X射线透视下腹腔动脉介入造影更适宜单发的动脉性出血。X射线透视下腹腔动脉介入造影需要经动脉穿刺进针,经导丝送至腹腔出血动脉的向心端,释放造影剂后,下游动脉充盈造影剂,下游出血点在释放造影剂的短暂时间窗内会出现造影剂外泄的“云雾影”,从而探明出血点。对于门静脉系统出血可以经肝动脉肝内穿刺到门静脉系统逆血流造影或者经肠系膜微循环对门静脉系统造影,不过该方法难度较大。但是腹部创伤常包括动脉、门静脉、静脉、创面或者复合出血点,即使是动脉性出血点也可以呈现多发、间歇出血等特点,X射线透视下腹腔动脉介入造影需要逐支动脉排查,同时反复多次注射造影剂,否则容易遗漏多发的出血点、遗漏低血压时间歇性出血。
增强CT探明出血点是经静脉注射水溶性造影剂,造影剂在血管破口溢出时如果在该时间窗采集图像,就能在出血点附近看到高信号影,这依赖影像医生恰好捕捉到溢出的时间窗。不过该水溶性造影剂腹腔弥散快,如果出血发生时间窗和图像采集时间窗不重合,则容易漏诊。
综上三种主流的腹腔出血点探明方案各有合适的使用场景和利弊,三种方法并未覆盖所有的腹腔出血场景,临床上仍然有相当多的腹腔出血的患者,找不到明确的出血点,贻误病情。
发明内容
本发明要解决的技术问题是出血发生时间窗和图像采集时间窗不重合造成的漏诊。
本发明的技术方案是一种腹腔出血点延时显像造影剂,包括A组分和B组分;A组分为Nb-PEG-PTIB(单降冰片烯聚乙二醇-嵌段聚甲基丙烯酸(三碘苯甲酰氧基乙酯)共聚物)或BSA-TIB-Nb(三碘苯甲酰胺-降冰片烯酰胺修饰白蛋白);B组分为HA-Tz(四嗪修饰透明质酸)或4-arm PEG5000-Tz(四臂聚乙二醇四嗪);Nb-PEG-PTIB如式I所示,BSA-TIB-Nb如式II所示,HA-Tz如式III所示,4-arm PEG5000-Tz如式IV所示;
进一步的, A组分含有碘造影基团经静脉注射,B组分经腹腔注射。
特别的,所述Nb-PEG-PTIB的制备包括如下步骤:
步骤s1、Nb-PEG-OH(单降冰片烯聚乙二醇)制备:将Nb-COOH(降冰片烯羧酸)、NHS(N-羟基琥珀酰亚胺)和EDCI(1-乙基-3(3-二甲基丙胺)碳二亚胺)溶解在三氯甲烷中,搅拌活化得到反应液a;将NH2-PEG-OH(氨基聚乙二醇羟基)溶解在三氯甲烷中,加入至反应液a中;加入三乙胺,搅拌反应;停止反应后用饱和NaCl溶液清洗,无水硫酸镁干燥,过滤,收集有机相用旋蒸浓缩,再将其滴入冰乙醚中沉淀,收集白色沉淀真空干燥,得到Nb-PEG-OH;
步骤s2、Nb-PEG-Br(单降冰片烯聚乙二醇溴)制备:将步骤s1制备得到的Nb-PEG-OH溶解于四氢呋喃中,加入三乙胺得到反应液b;将溴异丁酰溴溶于四氢呋喃,冰浴下滴加到反应液b中,室温搅拌过夜;过滤去除杂质,旋蒸浓缩,在冰的正己烷中沉淀,真空干燥,得到Nb-PEG-Br;
步骤s3、TIBMA(三碘苯甲酰氧基甲基丙烯酸乙酯)的制备:称取三碘苯甲酸溶解于在三氯甲烷中得到三碘苯甲酸溶液;将二氯亚砜溶解在三氯甲烷中,在冰浴条件下将其滴加至三碘苯甲酸溶液中,滴加完毕后转移至搅拌回流装置中反应,待反应溶液变澄清后旋蒸去除未反应的二氯亚砜,收集旋干后的固体,将其溶解在四氢呋喃中得到溶液c;称量HEMA(甲基丙烯酸羟乙酯)溶解在四氢呋喃中,同时加入三乙胺,得到溶液d,然后冰浴下缓慢将溶液c滴加至溶液d中,滴加完毕后,将其转移至室温下搅拌过夜;过滤,通过硅胶色谱柱分离纯化产物,旋干浓缩,真空干燥,得到TIBMA;
步骤s4、制备聚合物Nb-PEG-PTIB(单降冰片烯聚乙二醇-嵌段聚甲基丙烯酸(三碘苯甲酰氧基乙酯)):取Nb-PEG-Br聚合物、TIBMA、CuBr和四氢呋喃加入聚合瓶中,真空/氮气条件下冻融除去氧气,加入2,2-联吡啶反应;反应结束后加入四氢呋喃稀释,过中性氧化铝柱除去铜盐,正己烷沉淀后真空干燥得到终产物Nb-PEG-PTIB。
步骤s1的反应式如下:
步骤s2的反应式如下:
步骤s3的反应式如下:
步骤s4的反应式如下:
特别的, 步骤s1中,活化为在室温下活化6h。
进一步的,步骤s1中,反应温度40℃,反应时间24h。
特别的,步骤s1中,饱和NaCl洗2~3次,无水硫酸镁干燥1h,冰乙醚中沉淀2~3次。
其中,步骤s2中,在冰的正己烷中沉淀4~5次。
进一步的,步骤s3中,于50℃下搅拌并回流4h。
其中,步骤s4中,于60℃反应12h。
具体的,所述BSA-TIB-Nb的制备包括如下步骤:
步骤s5、将三碘苯甲酸和二氯亚砜分别溶解到三氯甲烷中,然后将二氯亚砜溶液缓慢加入三碘苯甲酸溶液中,充分混合,回流装置中反应至溶液澄清;旋蒸除去二氯亚砜和三氯甲烷,收集固体溶于四氢呋喃中,得到溶液d;
步骤s6、将Nb-COOH和二氯亚砜分别溶解到三氯甲烷中,然后将二氯亚砜溶液缓慢加入Nb-COOH溶液中,充分混合,回流装置中反应;旋蒸除去二氯亚砜和溶剂,收集固体溶于四氢呋喃中,得到溶液e;
步骤s7、将BSA溶解在PBS溶液中,置于冰浴中;将溶液d与溶液e充分混合,缓慢滴入BSA溶液;滴加完毕后,室温搅拌反应,期间用饱和碳酸钠溶液调整其pH为8;反应完毕后旋蒸除去四氢呋喃,加入水稀释后,在pH为8的碳酸钠溶液中透析,冻干得到BSA-TIB-Nb。
反应式如下:
进一步的,步骤s5和s6中,50℃回流4h。
其中,所述HA-Tz的制备包括如下步骤:将HA-TBA(透明质酸)和Dowex 50 W×8-100酸性离子交换树脂混合在室温下搅拌过夜,之后过滤冻干得到四丁基铵盐化的透明质酸;将透明质酸溶解于无水二甲基亚砜中,然后在氮气保护条件下加入pyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)和Tz-NH2(4-(1,2,4,5-四嗪-3-基)苯基)甲胺盐酸盐),在室温下避光搅拌反应;反应结束后用蒸馏水透析,最后冷冻干燥得到HA-Tz。
反应式如下:
进一步的,透明质酸和Dowex 50 W×8-100酸性离子交换树脂树脂的重量比为1︰50。
具体的,蒸馏水透析3天。
其中,所述4-arm PEG5000-Tz的制备方法如下:将4-arm PEG5000-COOH(四臂聚乙二醇羧基)、NHS、Tz-NH2((4-(1,2,4,5-四嗪-3-基)苯基)甲胺盐酸盐)、三乙胺0.4g溶于二氯甲烷中,加入EDCI(1-乙基-3(3-二甲基丙胺)碳二亚胺),氮气保护下室温搅拌反应,结束后加入二氯甲烷稀释,冰盐水洗有机相,无水硫酸镁干燥后过滤,旋蒸浓缩,用冰乙醚沉淀,真空干燥得到4-arm PEG5000-Tz。
反应式如下:
进一步的,冰盐水洗有机相3次,冰乙醚沉淀3次。
本发明的有益效果:本发明提供了一种可以静脉给药的血管造影剂,长时间滞留于血管破损处,让出血点在影像条件下持续显影,这对于多发、隐匿、间隙出现、复杂或者创面出血都能起到很好的探明作用,军地应用价值佳。本发明造影剂包含A、B两个组分,用于外伤或手术后腹腔出血的X光/CT造影。其中A组分含有碘造影剂,经静脉注射;B组分直接注射至腹腔。在腹腔血管破损处,血液中的A组分由血液进入腹腔后与B组分相遇,将含碘纳米颗粒交联,快速形成水凝胶固定位置而非自由扩散,实现在X光/CT成像中的持续显影,指示出血位置,引导后续治疗。动脉、门静脉、静脉和创面渗血等多种出血各类均可显影,可观察多个出血部位,一次给药后还可以动态观察,间歇性出血也可以被捕捉到。适应多发伤、复杂伤的平战时腹部创伤救治。延长造影剂出血部位留置时间快速探明多发出血、容易发现隐匿和间歇出血、应对复杂出血。本发明的造影剂可以实现对目前主流的剖腹探查、X射线透视下腹腔动脉介入造影和增强CT三种方法的有效补充。让剖腹探查止血有的放矢,让经动脉介入栓塞提高效率,防止遗漏出血点。采用本发明造影剂一次性检测腹腔多发的出血点位后,根据出血位置、数量和严重程度制定后续止血方案。
附图说明
图1、模拟出血实验结果,大分子对比组即为本发明的产品。
图2、模拟出血实验CT成像结果。
实施方式
基于现有技术存在的问题,申请人设想如果存在一种造影剂,长时间滞留于血管破损处,让出血点在影像条件下持续显影,这对于多发、隐匿、间隙出现、复杂或者创面出血都能起到很好的探明作用。
单一组分的设计方案一般需要生理或者病理情况下的酶触发的反应,该类反应速度慢无法达到点化学反应的速度,以至于造成造影剂还未聚集就在腹腔中弥散开,无法留滞于腹腔出血点附近。因此申请人考虑将造影剂设计成包含A、B两个组分的组成。其中A组分含有碘造影基团,经静脉注射;B组分水溶性好,直接注射腹腔并弥散开。在腹腔血管破损处,血液中的A组分由血液进入腹腔后与B组分相遇,快速形成水凝胶固定位置而非自由扩散。
A组分(Nb-PEG-PTIB, BSA-TIB-Nb)与B组分(HA-Tz, 4-arm PEG5000-Tz)可任选其一,两两配对使用,实现腹腔出血造影。在本发明的一个实施方式中采用了A组分为BSA-TIB-Nb和B组分为HA-Tz进行搭配使用。
本发明中涉及到的试剂的中文名称及简写见表1。
表1本发明中涉及到的试剂的中文名称及简写
试剂 | 简写 |
降冰片烯羧酸 | Nb-COOH |
N-羟基琥珀酰亚胺 | NHS |
1-乙基-3(3-二甲基丙胺)碳二亚胺 | EDCI |
二氯甲烷 | DCM |
三氯甲烷 | TCM |
三乙胺 | TEA |
四氢呋喃 | THF |
2,2-联吡啶 | Bpy |
甲苯 | MB |
甲基丙烯羟乙酯 | HEMA |
四丁基铵 | TBA |
二甲基亚砜 | DMSO |
六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷 | pyBOP |
(4-(1,2,4,5-四嗪-3-基)苯基)甲胺盐酸盐 | Tz-NH2 |
牛血清白蛋白 | BSA |
降冰片烯单端修饰聚乙二醇 | Nb-PEG-OH |
透明质酸 | HA-TBA |
三碘苯甲酰氧基甲基丙烯酸乙酯 | TIBMA |
氨基聚乙二醇羟基 | NH2-PEG-OH |
单降冰片烯聚乙二醇 | Nb-PEG-OH |
单降冰片烯聚乙二醇溴 | Nb-PEG-Br |
单降冰片烯聚乙二醇-嵌段聚甲基丙烯酸(三碘苯甲酰氧基乙酯) | Nb-PEG-PTIB |
四嗪修饰透明质酸 | HA-Tz |
三碘苯甲酰胺-降冰片烯酰胺修饰白蛋白 | BSA-TIB-Nb |
四臂聚乙二醇羧基 | 4-arm PEG5000-COOH |
四臂聚乙二醇四嗪 | 4-arm PEG5000-Tz |
步骤1:Nb-PEG-OH聚合物制备
称取Nb-COOH 0.207g,NHS 0.288g及EDCI 2.98g将其完全溶解在4mL TCM,室温下搅拌活化6h得到反应液a;称取0.5g NH2-PEG -OH 将其溶解在1mL TCM中,然后加入至反应液a中,同时加入0.35mL TEA,在40℃下搅拌反应24h。停止反应后用饱和NaCl洗2~3遍,无水硫酸镁干燥1h,过滤后收集已有机相用旋蒸浓缩至2~5mL,再将其滴入冰乙醚中沉淀2~3遍,收集白色沉淀真空干燥。
步骤2: Nb-PEG-Br聚合物制备
称取已制备的OH-PEG-Nb 0.5g溶于8mL THF中,加入0.1mL TEA得到反应液b;将溴异丁酰溴0.0414g溶于2mLTHF,冰浴下滴加到反应液b中,室温搅拌过夜。停止反应后,将其过滤去除杂质,然后旋蒸浓缩至2~5mL左右,然后将其在冰的正己烷中沉淀4~5次,真空干燥。
步骤3: TIBMA的制备
称取1.17g三碘苯甲酸溶解于15mL在TCM中,然后将量取二氯亚砜0.141mL溶解在3mLTCM中,在冰浴条件下将其匀速缓慢的滴加至三碘苯甲酸溶液中,滴加完毕后转移至50℃下搅拌并回流4h,反应溶液逐渐变澄清。停止反应后旋蒸去除未反应的二氯亚砜,收集旋干后的固体,将其溶解在5mLTHF中得到溶液I。称量HEMA 0.234g溶解在10mLTHF中,同时加入0.5mLTEA,得到溶剂II,然后冰浴下缓慢将备好的溶液I滴加至溶剂II中,滴加完毕后,将其转移至室温下搅拌过夜。停止反应后,将其过滤,通过硅胶色谱柱分离纯化产物,旋干浓缩,真空干燥,即得到TIBMA。
步骤4: ATRP(原子转移自由基聚合法)制备聚合物Nb-PEG-PTIB
Nb-PEG-Br 0.5g、TIBMA 0.7g、CuBr 28.6mg、5mLTHF加入聚合瓶中,真空/氮气条件下冻融3次除去氧气,加入Bpy 62.4mg,无氧条件下60℃反应12h。反应结束后加入20mLTHF稀释,过中性氧化铝柱除去铜盐,正己烷沉淀后真空干燥得到终产物Nb-PEG-PTIB。终产物的核磁氢谱表征结果如下:氘代氯仿中的化学位移δppm: 8.3 (13H), 7.7 (13H),6.2 (1H), 5.9 (1H), 4.5 (26H), 4.3 (26H), 3.3-3.7 (460H), 1.8 (26H), 1.0(39H)。
称取2.63g三碘苯甲酸,将其溶解于25mLTCM中,之后称取1.13g二氯亚砜溶解在5mLTCM中,将二氯亚砜溶液缓慢加入三碘苯甲酸溶液中,充分混合后加热至50℃回流4h,反应液逐渐澄清。旋蒸除去二氯亚砜和溶剂,收集固体溶于5mL THF中,得到溶液I。
称取0.726g Nb-COOH,将其溶解于10mL TCM中,之后称取1.13g二氯亚砜溶解在5mL TCM中,将二氯亚砜溶液缓慢加入Nb-COOH溶液中,充分混合后加热至50℃回流4h。旋蒸除去二氯亚砜和溶剂,收集固体溶于3mL THF中,得到溶液II。
将1g BSA溶解在10mL 3× PBS溶液,并置于冰浴中。将溶液I与溶液II充分混合,缓慢滴入BSA溶液。滴加完毕后升至室温,继续搅拌6h,期间用饱和碳酸钠溶液调整其pH值,使其维持在pH8。反应完毕后旋蒸除去THF,加入20mL水稀释后,在pH8的碳酸钠溶液中透析3天。冻干得到BSA-TIB-Nb。
将HA-TBA和Dowex 50 W×8-100酸性离子交换树脂树脂1︰50(w/w)混合在室温下搅拌过夜,之后过滤冻干得到四丁基铵盐化的透明质酸(HA-TBA)。将已制备的HA-TBA 200mg 溶解于无水DMSO 20 mL中,然后在氮气保护条件下加入PyBop 20 mg和Tz-NH2盐酸盐10mg,在室温下避光搅拌反应24 h。反应结束后用蒸馏水透析3天,最后冷冻干燥得到HA-Tz。终产物的核磁氢谱表征结果如下:重水中的化学位移δppm: 10.4 (1H), 8.6 (2H), 7.7(2H), 3.2-4.5 (90H)。
将4-arm PEG5000-COOH 1g、NHS 0.322g、Tz-NH20.3g、TEA 0.4g溶于7mL DCM中,之后加入EDCI 0.382g,氮气保护下室温搅拌24h。反应结束后加入50mL DCM稀释,冰盐水洗有机相3次,无水硫酸镁干燥后过滤,旋蒸浓缩至5~10mL,用冰乙醚沉淀3次,真空干燥得到4-arm PEG5000-Tz。终产物的核磁氢谱表征结果如下:重水中的化学位移δppm: 10.4(1H), 8.6 (2H), 7.7 (2H), 4.4 (2H), 3.6 (110H)。
A组分为BSA-TIB-Nb,B组分为HA-Tz。将A、B两个组分分别用PBS缓冲液配置成1%浓度的溶液(溶液A与溶液B),溶液A中加入0.1%的荧光染料罗丹明B模拟血液。作为对照,另配置参比溶液A’,其中含有0.1%的罗丹明B 和1%的小分子对比剂碘海醇以代替组分A。
将溶液B置于玻璃瓶中,模拟腹腔液体环境;玻璃瓶中放入细管模拟血管,并使其有一处破损,模拟出血点。溶液A(或溶液A’)在细管中流动模拟血液。当两组分直接接触后,B组分与A组分发生快速的点击化学反应,从而将含碘纳米颗粒交联,交联反应后造影集团形成胶状物留置于血管破损处附近。之后分别用光学成像和小动物活体CT(Hiscan XM)观察模拟出血情况。
光学成像结果显示,含有A、B两种组分的系统能够很好地指示出血点位置,并能长时间示踪。作为对照,含有小分子对比剂碘海醇的系统,对比剂渗出血管后会迅速弥散,无法准确清晰地指示出血点(图1)。CT成像显示了相同的结果,本发明设计的对比剂能够清晰地指示出血点位置,而小分子碘海醇无法指示出血点(图2)。
Claims (10)
2.根据权利要求1所述腹腔出血点延时显像造影剂,其特征在于:A组分含有碘造影基团,经静脉注射;B组分注射至腹腔。
3.根据权利要求1所述腹腔出血点延时显像造影剂,其特征在于:所述Nb-PEG-PTIB的制备包括如下步骤:
步骤s1、Nb-PEG-OH(单降冰片烯聚乙二醇)制备:将Nb-COOH(降冰片烯羧酸)、NHS (N-羟基琥珀酰亚胺)和EDCI(1-乙基-3(3-二甲基丙胺)碳二亚胺)溶解在三氯甲烷中,搅拌活化得到反应液a;将NH2-PEG-OH(氨基聚乙二醇羟基)溶解在三氯甲烷中,加入至反应液a中;加入三乙胺,搅拌反应;停止反应后用饱和NaCl溶液清洗,无水硫酸镁干燥,过滤,收集有机相用旋蒸浓缩,再将其滴入冰乙醚中沉淀,收集白色沉淀真空干燥,得到Nb-PEG-OH;
步骤s2、Nb-PEG-Br(单降冰片烯聚乙二醇溴)制备:将步骤s1制备得到的Nb-PEG-OH溶解于四氢呋喃中,加入三乙胺得到反应液b;将溴异丁酰溴溶于四氢呋喃,冰浴下滴加到反应液b中,室温搅拌过夜;过滤去除杂质,旋蒸浓缩,在冰的正己烷中沉淀,真空干燥,得到Nb-PEG-Br;
步骤s3、TIBMA(三碘苯甲酰氧基甲基丙烯酸乙酯)的制备:称取三碘苯甲酸溶解于在三氯甲烷中得到三碘苯甲酸溶液;将二氯亚砜溶解在三氯甲烷中,在冰浴条件下将其滴加至三碘苯甲酸溶液中,滴加完毕后转移至搅拌回流装置中反应,待反应溶液变澄清后旋蒸去除未反应的二氯亚砜,收集旋干后的固体,将其溶解在四氢呋喃中得到溶液c;称量HEMA(甲基丙烯酸羟乙酯)溶解在四氢呋喃中,同时加入三乙胺,得到溶液d,然后冰浴下缓慢将溶液c滴加至溶液d中,滴加完毕后,将其转移至室温下搅拌过夜;过滤,通过硅胶色谱柱分离纯化产物,旋干浓缩,真空干燥,得到TIBMA;
步骤s4、制备聚合物Nb-PEG-PTIB(单降冰片烯聚乙二醇-嵌段聚甲基丙烯酸(三碘苯甲酰氧基乙酯)):取Nb-PEG-Br聚合物、TIBMA、CuBr和四氢呋喃加入聚合瓶中,真空/氮气条件下冻融除去氧气,加入2,2-联吡啶反应;反应结束后加入四氢呋喃稀释,过中性氧化铝柱除去铜盐,正己烷沉淀后真空干燥得到终产物Nb-PEG-PTIB。
4.根据权利要求3所述腹腔出血点延时显像造影剂,其特征在于: 步骤s1中,活化为在室温下活化6h;步骤s1中,反应温度40℃,反应时间24h;步骤s1中,饱和NaCl洗2~3次,无水硫酸镁干燥1h,冰乙醚中沉淀2~3次。
5.根据权利要求3所述腹腔出血点延时显像造影剂,其特征在于:步骤s2中,在冰的正己烷中沉淀4~5次。
6.根据权利要求3所述腹腔出血点延时显像造影剂,其特征在于:步骤s3中,于50℃下搅拌并回流4h;步骤s4中,于60℃反应12h。
7.根据权利要求1所述腹腔出血点延时显像造影剂,其特征在于:所述BSA-TIB-Nb的制备包括如下步骤:
步骤s5、将三碘苯甲酸和二氯亚砜分别溶解到三氯甲烷中,然后将二氯亚砜溶液缓慢加入三碘苯甲酸溶液中,充分混合,回流装置中反应至溶液澄清;旋蒸除去二氯亚砜和三氯甲烷,收集固体溶于四氢呋喃中,得到溶液d;
步骤s6、将Nb-COOH和二氯亚砜分别溶解到三氯甲烷中,然后将二氯亚砜溶液缓慢加入Nb-COOH溶液中,充分混合,回流装置中反应;旋蒸除去二氯亚砜和溶剂,收集固体溶于四氢呋喃中,得到溶液e;
步骤s7、将BSA溶解在PBS溶液中,置于冰浴中;将溶液d与溶液e充分混合,缓慢滴入BSA溶液;滴加完毕后,室温搅拌反应,期间用饱和碳酸钠溶液调整其pH为8;反应完毕后旋蒸除去四氢呋喃,加入水稀释后,在pH为8的碳酸钠溶液中透析,冻干得到BSA-TIB-Nb。
8.根据权利要求1所述腹腔出血点延时显像造影剂,其特征在于:所述HA-Tz的制备包括如下步骤:将HA-TBA(透明质酸)和Dowex 50 W×8-100酸性离子交换树脂混合在室温下搅拌过夜,之后过滤冻干得到四丁基铵盐化的透明质酸;将透明质酸溶解于无水二甲基亚砜中,然后在氮气保护条件下加入pyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)和Tz-NH2(4-(1,2,4,5-四嗪-3-基)苯基)甲胺盐酸盐),在室温下避光搅拌反应;反应结束后用蒸馏水透析,最后冷冻干燥得到HA-Tz。
9.根据权利要求8所述腹腔出血点延时显像造影剂,其特征在于:HA-TBA和Dowex 50 W×8-100酸性离子交换树脂树脂的重量比为1︰50。
10.根据权利要求1所述腹腔出血点延时显像造影剂,其特征在于:所述4-armPEG5000-Tz的制备方法如下:将4-arm PEG5000-COOH(四臂聚乙二醇羧基)、NHS、Tz-NH2((4-(1,2,4,5-四嗪-3-基)苯基)甲胺盐酸盐)、三乙胺0.4g溶于二氯甲烷中,加入EDCI(1-乙基-3(3-二甲基丙胺)碳二亚胺),氮气保护下室温搅拌反应,结束后加入二氯甲烷稀释,冰盐水洗有机相,无水硫酸镁干燥后过滤,旋蒸浓缩,用冰乙醚沉淀,真空干燥得到4-armPEG5000-Tz。
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