CN112494664A - 一种多糖类磁共振及荧光双模式成像诊断剂及其制备方法和诊断试剂 - Google Patents
一种多糖类磁共振及荧光双模式成像诊断剂及其制备方法和诊断试剂 Download PDFInfo
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Abstract
本发明属于医药学、化学技术领域,具体涉及一种多糖类磁共振及荧光双模式成像诊断剂及其制备方法和诊断试剂。该诊断剂以含有罗丹明B基的五肽(酪氨酰‑异亮氨酰‑甘氨酰‑丝氨酰‑精氨酸,YIGSR)、九肽色氨酸‑异亮氨酸‑苯丙氨酸‑脯氨酸‑色氨酸‑异亮氨酸‑谷氨酰胺‑亮氨酸‑赖氨酸,WIFPWIQL)衍生物作为肿瘤靶向性、荧光成像基团与侧链含有开链或环状多氨多羧酸的多糖类大分子化合物通过化学反应偶联为配体,再与顺磁性金属离子作用形成的顺磁性金属配合物构成的,可用于人体或其他哺乳动物体内肿瘤的磁共振(MRI)‑荧光双模式成像等医学成像诊断。
Description
技术领域
本发明属于医药学、化学技术领域,具体涉及一种多糖类磁共振及荧光双模式成像诊断剂及其制备方法和诊断试剂。
背景技术
我国肺癌发病率与死亡率高、转移病灶难以早期发现。CT检查是常用的影像诊断方法,对骨骼、钙化敏感,具有成像速度快、价格便宜等优点,然而对软组织成像较差,难以实现对肿瘤等疾病的早期检测与诊断,对癌症转移的病灶检出率低。
磁共振成像(MRI)对软组织具有高成像分辨率,活体荧光成像(FI)可从分子及细胞生物学水平检测肿瘤,灵敏度高。MRI、FI可较好地分辨软组织的各种病变,对肿瘤等疾病的检出率较高。尤其对于早期比较细小肿瘤、癌症转移的病灶,MRI、FI比CT具有更出色的检出率,能更好地帮助医生制订更精准的治疗方案。
国际上已有多种广谱的应用于全身的MRI诊断剂、FI探针分别进入商业应用,然而,目前这些诊断剂均需在体内引入高浓度剂量(0.1mmol/kg)才能获得有效的成像信号,不具有肿瘤靶向性,对肿瘤显像较差,难以早期发现癌症微小病灶,不能对癌症进行早期的诊断与及时治疗。临床使用的磁共振成像、荧光成像诊断剂均不具有肺癌靶向性,对肿瘤显像效果较差,且目前磁共振/荧光成像(MRI/FI)一体化技术应用不足,缺乏靶向性MRI/FI双模式诊断剂,存在不能满足联合成像的要求等问题。因此研制肺癌靶向增强型磁共振/荧光双模式成像(MRI/FI)诊断剂,用于肿瘤MRI/FI联合靶向成像检测与诊断,提高肿瘤的早期诊断水平与癌症治愈率,从而解决当前传统临床医学影像诊断技术对肿瘤显像效果较差、转移病灶难以早期发现等难题,最终使广大患者受益,具有重要的科学理论意义与良好的实际应用价值,以及鲜明的引领性或开创性,也是亟待解决的关键问题。
发明内容
为解决现有技术的不足,克服现有目前临床所使用的广谱应用于全身的MRI造影剂、FI探针存在的缺点,本发明提供了一种多糖类磁共振及荧光双模式成像诊断剂及其制备方法和诊断试剂。该诊断剂以含有罗丹明B基的五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR)、九肽(色氨酸-异亮氨酸-苯丙氨酸-脯氨酸-色氨酸-异亮氨酸-谷氨酰胺-亮氨酸-赖氨酸,WIFPWIQL)衍生物作为肿瘤靶向性、荧光成像基团与侧链含有开链或环状多氨多羧酸的多糖类大分子化合物通过化学反应偶联为配体,与顺磁性金属离子作用形成的顺磁性金属配合物构成的,可用于人体或其他哺乳动物体内肿瘤的磁共振(MRI)-荧光双模式成像等医学成像诊断。
本发明所提供的技术方案如下:
一种多糖类磁共振及荧光双模式成像诊断剂,为顺磁性金属离子与配体形成的配合物,所述配体具有式1结构式:
其中,B为COO-、CH2OSO3 -、CH2OPO3 -或OA;C为NHC(=O)CH3、OH、CH3、OCH3、OSO3 -、NHSO3 -、OPO3 -或OA;D为NHC(=O)CH3、CH3、OCH3、OSO3 -、NHSO3 -、OPO3 -或OA;
A具有式2或式3代表的化学结构式:
其中R1、R3、Q分别独立选自CO、O、CH2CO、SO、-(CR4R5)m-、-(SR6)m-、-(SOR7)m-、或者-(NR8)m-;R2、R4、R5、R6、R7、R8分别独立选自氢原子、烷基、芳基,或者,为由一个或多个羟基、一个或多个烷氧基、一个或多个胺基、一个或多个芳基、一个或多个芳氧基取代的烷基或芳基;m、n、y为1到10的自然数;r是0到10的整数;
E具有式4或式5代表的化学结构式:
其中R6选自亚烷基、亚芳基、CO、SO、CO(CH2)zCO,或者,选自由一个或多个羟基、一个或多个烷氧基、一个或多个胺基、一个或多个芳基或一个或多个芳氧基取代的亚烷基或亚芳基,z为1到10的自然数;
式1中,a为1~100000,b为1~100000;
所述多糖类磁共振及荧光双模式成像诊断剂的数均分子量范围为5000至108。
优选的,其分子量范围为5000-2000000。
具体的,所述的顺磁性金属离子为Gd、Mn、Cr、Fe、Co、Ni、La、Tc、Dy或Cu金属元素的各正价离子。
具体的,其分子量范围为5000-2000000。
具体的,式1配体中的E具有以下结构:
具体的,式1配体中的E具有以下结构:
本发明还提供了一种多糖类磁共振及荧光双模式成像诊断剂的制备方法,包括以下步骤:
1)将H-A与多糖大分子进行偶联反应,所述的多糖具有式6的结构式
2)将步骤1)得到的产物与H-E进行偶联反应,得到所述的配体;
3)将所述的配体与顺磁性金属离子进行配位反应,得到多糖类磁共振及荧光双模式成像诊断剂。
具体的,步骤1)中,反应温度为室温;反应时间不低于4h;溶剂为水、二甲亚砜或N,N-二甲基甲酰胺;
步骤2)中,反应温度为室温;反应时间不低于48h;溶剂为水、二甲亚砜或N,N-二甲基甲酰胺;采用沉淀法从反应得到的混合物中分离出所述配体,沉淀剂为无水乙醇与无水乙醚的混合沉淀剂;
步骤3)中,反应温度为室温;反应时间不低于1h;溶剂为水;将反应得到的混合物调节pH至5~8,然后采用沉淀法从反应得到的混合物中分离出所述多糖类磁共振及荧光双模式成像诊断剂,沉淀剂为无水乙醇与无水乙醚的混合沉淀剂。
E为罗丹明B基的五肽(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR)、九肽(色氨酸-异亮氨酸-苯丙氨酸-脯氨酸-色氨酸-异亮氨酸-谷氨酰胺-亮氨酸-赖氨酸,WIFPWIQL)的活性衍生物,活性衍生物类型为单环酸酐、双环酸酐、混合酸酐、活性酯、酰氯或酰溴。
步骤1)得到的为含有开链或环状多氨多羧酸的多糖类大分子化合物,可参考中国发明专利“多糖类大分子顺磁性金属配合物及合成方法和用途.ZL 200910063629.X”所述的含有开链或环状多氨多羧酸化合物的多糖类大分子化合物。
本发明还提供了一种肺癌靶向磁共振及荧光双模式成像诊断试剂,为药用载体和/或赋形体与本发明所提供的多糖类磁共振及荧光双模式成像诊断剂的水溶液,其中,所述多糖类磁共振及荧光双模式成像诊断剂的重量百分含量为0.1-50%,所述药用载体的浓度为0.001-5.0摩尔/升,所述赋形体的浓度为0.001-5.0摩尔/升,所述药用载体为氯化钠和/或葡萄糖,所述的赋形体为磷脂、明胶、淀粉或糖浆。
本发明与已有技术相比较,已达到的技术效果:
当前癌症治愈的关键在于临床上早期发现、早期诊断、早期治疗,即是否能较早地发现微小病灶,并进行及时有效的治疗。目前临床磁共振成像(MRI)、活体荧光成像(FI)技术均需要在体内引入高浓度的各自相应的成像诊断剂(如磁共振成像造影剂钆二乙烯三胺五乙酸(Gd-DTPA)、FI探针5-氨基乙酰丙酸(ALA),使用剂量大于0.1mmol/kg)才能获得有效的成像信号,而高浓度诊断剂会对动物的生理和病理过程产生影响与干扰,具有在体内存留时间短,在体内代谢速度快,利用率低,不具有组织或器官选择性或靶向性,尤其对肿瘤缺乏选择性等问题。而且目前磁共振/荧光成像(MRI/FI)一体化技术应用不足,缺乏MRI/FI诊断剂,难以满足联合成像的要求等问题。
针对我国肿瘤发病率与死亡率高、转移病灶难以早期发现的特点,以及临床使用的磁共振成像、荧光成像诊断剂存在的不足,本发明者发明的多糖类磁共振-荧光双模式成像诊断剂保持了相应的多氨多羧酸配合物的结构特点,因而具有良好的稳定性、水溶性和弛豫率,同时含有罗丹明B荧光基团与肿瘤靶向基团,对肿瘤具有靶向性,从而实现靶向磁共振、荧光联合成像,提高成像对比度和清晰度,对提高肿瘤的早期诊断水平具有较好的效果。
与临床广泛常用的MRI造影剂、FI探针,以及目前已报道的相关诊断剂相比,本项目研制的肿瘤靶向磁共振/荧光(MRI/FI)双模式成像诊断剂具有以下特色与创新点:
(1)兼具备MRI、FI成像诊断的功能,可实行MRI/FI一体化同步扫描与双模式联合成像;同时可抑制与杀死肿瘤细胞,实现诊疗一体化、可视化。
在肿瘤靶向MRI/FI诊断剂的分子结构中,Gd-DTPA结构可作为MRI成像基团,可用于肿瘤靶向磁共振成像,显示肿瘤等组织精细的解剖结构,并研究肿瘤的产生、发展的规律。
罗丹明B结构可作为荧光成像基团,用于肿瘤靶向FI成像,能探查局部组织代谢的异常,提供病灶详尽的功能与代谢等分子信息,揭示肿瘤等组织的功能状态,为病变定位和诊断、致病机理与发展过程提供更多的信息。
本发明研制肿瘤靶向MRI/FI双模式成像诊断剂,用于MRI/FI对肺癌联合靶向成像诊断,所提供的影像不仅可以反映肿瘤的生化、生理及功能,而且还可反映解剖形态,得到肿瘤的局部或全身更真实、清晰的三维图像,使代谢显像与形态显像联合,优势互补,灵敏度与分辨率同时提高,靶向性好,将显著提高肿瘤检测与诊断的准确度。
同时,肿瘤靶向双模式成像诊断剂还可以解决体内高使用剂量的MRI造影剂覆盖FI探针作用的活性位点,从而影响或降低FI探针显像性能等问题。
(2)具有肿瘤靶向性与特异选择性,提高成像的精准性与灵敏度。肿瘤靶向MRI/FI双模式成像诊断剂采用五肽化合物(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR)、九肽化合物(色氨酸-异亮氨酸-苯丙氨酸-脯氨酸-色氨酸-异亮氨酸-谷氨酰胺-亮氨酸-赖氨酸,WIFPWIQL)两种靶向基团,具有肿瘤靶向与特异选择性,提高成像的精准性与灵敏度。
医学研究发现,在肿瘤转移形成过程中,肿瘤细胞通过基底膜侵入是一个关键性步骤。层粘蛋白(Laminin,亦称层粘素)是基底膜所特有的非胶原糖蛋白,是基底膜基质的重要组成部分与粘附分子的配体,在恶性肿瘤细胞的浸润、粘着、铺展、增殖及转移中起着重要的促进作用。
多种恶性肿瘤细胞表面有大量的层粘素受体,即高度表达或过度表达67kDa层粘连蛋白受体(67kDa laminin receptor,67LR),其中一种来源于Lamininβ-1链顺序的合成九肽配体已被鉴定为主要的细胞结合位点,与这种层粘连蛋白受体具有特异亲和性作用,能更多、更快地与层粘素结合。在这个九肽序列中含有一段活性片段,即五肽化合物(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,Tyr-Ile-Gly-Ser-Arg-NH2,YIGSR),能够与肿瘤相关的层粘素受体高亲和性结合,因此放射性核素标记YIGSR是一种很有发展潜力的、能评估活体内肿瘤细胞转移潜能的、具有受体特异性的放射性药物。利用配体-受体反应特异性的原理,含有五肽化合物YIGSR结构的配体能经过受体介导的内吞途径进入肿瘤细胞,可被肿瘤细胞特异性摄取。因此五肽化合物YIGSR对肿瘤细胞,尤其对转移性肿瘤细胞具有较好的靶向性,可用作为肿瘤靶向MRI造影剂、FI成像探针、药物控制释放体系的肿瘤靶向基团。
九肽化合物WIFPWIQLK是免疫球蛋白重链结合蛋白GRP78特异性靶向肽,而GRP78在肺癌等肿瘤细胞膜上高表达,但不在大多数正常细胞上表达,因此,GRP78可被认为是可区分癌细胞与正常细胞的理想靶点,九肽化合物WIFPWIQLK在双模式成像诊断剂可用作为良好的肺癌靶向基团。同时由于肿瘤细胞具有旺盛的代谢能力,ACE2、整合素受体分子会在肿瘤细胞中高度表达,致使含有RGD基团的双模式成像诊断剂分子可以通过相应的受体介导而进入肿瘤细胞,进一步被肿瘤组织特异性摄取与富集,可以实现肿瘤靶向成像。
而且,双模式成像诊断剂根据WIFPWIQLK、YIGSR化合物对肿瘤、正常细胞、肺炎或炎症肿块等其它组织的亲和性作用存在的较大差异,可以在体内根据正常肺细胞、肿瘤细胞、肺炎细胞、炎症肿块以及其它病变细胞中ACE2、整合素受体数量的多少,对不同的细胞呈现选择性摄取量的差异,即在不同的细胞中诊断剂的富集量不同,进行不同程度的增强显像,实现不同成像增强对比度的明显区别,进行定性、定量的检测与诊断,从而可以比较MRI/FI对早期肺癌肿瘤的发现、肺炎、癌症转移病灶和良恶性肿瘤的鉴别与诊断差异,揭示癌症发生与发展规律。
(3)实现大分子化,具有良好的水溶性、生物相容性与可生物降解性能。
多糖类大分子侧链含有丰富的羟基,易进行化学修饰,在体内可降解,且降解产物对人体无害,已广泛地用作为药物载体。本发明采用水溶性多糖类大分子作为诊断剂的高分子载体,通过接枝比率双重调控弛豫率和荧光强度,可以自组装成纳米结构,采用主动靶向和被动靶向(EPR效应)相结合作用,渗透到肿瘤组织中,提高弛豫率、荧光强度及稳定性,降低血液清除率和毒副作用,不需要频繁服药,可减小用药剂量,降低毒性。可在肿瘤组织内相对长时间内保持稳定的浓度,有利于较长时间的成像检测。而且双模式成像诊断剂具有良好的生物相容性与可生物降解性,在体内可以完全降解,其降解终产物可被体内吸收或排出体外。从而提高MRI/FI联合成像技术对肿瘤的早期诊断水平,实现联合分子成像与诊疗一体化、可视化,最终使广大患者受益。
(4)实验研究结果表明,多糖类磁共振-荧光双模式成像诊断剂对肿瘤具有较好的靶向性,可被肿瘤选择性摄取与富集,在肿瘤中的浓度较高,从而实现肿瘤MRI/FI联合靶向成像,提高成像对比度和清晰度,实现MRI、FI对肿瘤成像增强信号(以实施例1得到的诊断剂进行试验,效果在5倍以上,如图一、图二、图三所示)明显优于临床诊断剂的图像信号,清晰度与对比度明显提高,进一步提高MRI/FI联合成像对早期肿瘤发现、癌症转移病灶,以及良恶性肿瘤、炎症的鉴别与诊断水平。且降低毒副作用与使用剂量(0.05mmol/kg,达到临床剂量的50%),具有较长停留时间,便于较长时间实现靶向成像(3小时以上)。
附图说明
图1是本发明所提供的多糖类磁共振及荧光双模式成像诊断剂(0.05mmol/kg)对C57小鼠体内B16F10肿瘤的荧光成像试验。
图2是本发明所提供的钆二乙烯三胺五乙酸(Gd-DTPA)(0.1mmol/kg)对C57小鼠体内B16F10肿瘤的荧光成像试验。
图3是本发明所提供的多糖类磁共振及荧光双模式成像诊断剂(0.05mmol/kg)对C57小鼠体内B16F10肿瘤的磁共振成像试验。
具体实施方式
以下对本发明的原理和特征进行描述,所举实施例只用于解释本发明,并非用于限定本发明的范围。
实施例1:
1.62g葡聚糖(分子量为2万)与5mL三乙胺溶于100mL二甲亚砜中,在室温、磁力搅拌条件下,缓慢滴加入含0.98g溴乙烷代1,4,7,10-氮杂环十二烷四乙酸DOTA的30mL二甲亚砜溶液,室温反应4h。再缓慢滴加入0.51g丁二酸酰胺罗丹明B基五肽化合物(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR-RhB)的30mL二甲亚砜溶液,在室温继续反应48h,过滤,减压蒸除部分溶剂,冷却至室温,残留液于搅拌下倒入600mL无水乙醇-无水乙醚(体积比为1:2)的混合溶剂中,产生浅黄色沉淀,过滤,抽干,所得固体再用蒸馏水溶解,用无水乙醇/无水乙醚重沉淀,收集浅黄色固体,真空干燥,得到2.33g固体,产率75%。
2.33g所得固体溶于20mL二次蒸馏水中,搅拌下,加入0.36g氧化钆GdCl3,反应液室温反应1h,用稀氢氧化钠溶液调节pH为7,继续搅拌12h,过滤,滤液用乙醇/乙醚沉淀,真空干燥,得到2.15g多糖类磁共振及荧光双模式成像诊断剂,可用于淋巴系统靶向多糖类大分子造影剂,产率80%。
实施例2:
8.08g琼胶(分子量为4万)与10mL三乙胺溶于200mL二甲亚砜中,在室温、磁力搅拌条件下,缓慢搅拌下滴加含3.84g对硫氰酸苯甲基-DO3A的60mL二甲亚砜溶液,室温反应4h。再缓慢滴加入0.72g丁二酸酰胺罗丹明B基九肽化合物(色氨酸-异亮氨酸-苯丙氨酸-脯氨酸-色氨酸-异亮氨酸-谷氨酰胺-亮氨酸-赖氨酸,WIFPWIQL),室温继续反应48h,过滤,减压蒸除部分溶剂,冷却至室温,残留液于搅拌下倒入1000mL无水乙醇-无水乙醚(体积比为1:2)的混合溶剂中,产生浅黄色沉淀,过滤,抽干,所得固体再用蒸馏水溶解,用无水乙醇/无水乙醚重沉淀,收集浅黄色固体,真空干燥,得到8.85g固体,产率70%。
8.85g所得固体溶于100mL二次蒸馏水中,搅拌下,加入1.96g氯化镧LaCl3,反应液室温反应1h,用稀氢氧化钠溶液调节pH为6,继续搅拌12h,过滤,滤液用乙醇/乙醚沉淀,真空干燥,得到7.57g多糖类磁共振及荧光双模式成像诊断剂,可用于淋巴系统靶向多糖类大分子造影剂,产率70%。
实施例3:
1.14g透明质酸(分子量为8万)与5mL三乙胺溶于50mL二甲亚砜中,在室温、磁力搅拌条件下,搅拌下分批加入含量为1.47g二乙三胺五乙酸(DTPA)单N-羟基琥珀酰亚胺活性酯的二甲亚砜溶液,室温反应4h。再缓慢滴加入0.10g溴乙酰胺罗丹明B基五肽化合物(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR-RhB)的30mL二甲亚砜溶液,在室温继续反应48h,过滤,减压蒸除部分溶剂,冷却至室温,残留液于搅拌下倒入500mL无水乙醇-无水乙醚(体积比为1:4)的混合溶剂中,产生浅黄色沉淀,过滤,抽干,所得固体再用蒸馏水溶解,用无水乙醇,也可以用无水乙醚重沉淀,收集浅黄色固体,真空干燥,得到1.63g固体,产率60%。
1.63g所得固体溶于50mL二次蒸馏水中,搅拌下,加入0.79g氯化GdCl3,反应液室温反应1h,用稀氢氧化钠溶液调节pH为5,继续搅拌12h,过滤,滤液用乙醇/乙醚沉淀,真空干燥,得到1.94g多糖类磁共振及荧光双模式成像诊断剂,可用于淋巴系统靶向多糖类大分子造影剂,产率80%。
实施例4:
5.46g壳聚糖(分子量为20万)与5mL三乙胺溶于100mL二甲亚砜中,在室温、磁力搅拌条件下,缓慢滴加入含6.01gDOTA单N-羟基琥珀酰亚胺酯的80mL二甲亚砜溶液,室温反应4h。再缓慢滴加入0.19g溴乙酰胺罗丹明B基九肽化合物(色氨酸-异亮氨酸-苯丙氨酸-脯氨酸-色氨酸-异亮氨酸-谷氨酰胺-亮氨酸-赖氨酸,WIFPWIQL),室温继续反应48h,过滤,减压蒸除部分溶剂,冷却至室温,残留液于搅拌下倒入1200mL无水乙醇-无水乙醚(体积比为1:3)的混合溶剂中,无水乙醇:无水乙醚的体积比为1:3,产生浅黄色沉淀,过滤,抽干,所得固体再用蒸馏水溶解,用无水乙醇/无水乙醚重沉淀,收集浅黄色固体,真空干燥,得到7.0g固体,产率60%。
7.0g所得固体溶于200mL二次蒸馏水中,搅拌下,加入2.80g氯化镝DyCl2,反应液室温反应1h,用稀氢氧化钠溶液调节pH为7.4,继续搅拌12h,过滤,滤液用乙醇/乙醚沉淀,真空干燥,得到7.84g多糖类磁共振及荧光双模式成像诊断剂,可用于淋巴系统靶向多糖类大分子造影剂,产率80%。
实施例5:
7.08g硫酸软骨素(分子量为50万)与15mL三乙胺溶于250mL二甲亚砜中,在室温、磁力搅拌条件下,缓慢滴加入含13.5g硫氰酸苯甲基-二乙三胺五乙酸的150mL二甲亚砜溶液,室温反应4h。再缓慢滴加入0.08g溴乙基罗丹明B基五肽化合物(酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸,YIGSR-RhB)的30mL二甲亚砜溶液,在室温继续反应48h,过滤,减压蒸除部分溶剂,冷却至室温,残留液于搅拌下倒入2000mL无水乙醇-无水乙醚(体积比为1:5)的混合溶剂中,产生浅黄色沉淀,过滤,抽干,所得固体再用蒸馏水溶解,用无水乙醇,也可以用无水乙醚重沉淀,收集浅黄色固体,真空干燥,得到12.4g固体,产率60%。
12.4g所得固体溶于200mL二次蒸馏水中,搅拌下,加入3.18g氯化铁FeCl2,反应液室温反应1h,用稀氢氧化钠溶液调节pH为6,继续搅拌12h,过滤,滤液用乙醇/乙醚沉淀,真空干燥,得到多糖类磁共振及荧光双模式成像诊断剂,可用于10.9g淋巴系统靶向多糖类大分子造影剂,产率70%。
实施例6:
29.82g肝素(分子量为100万)与20mL三乙胺溶于300mL二甲亚砜中,在室温、磁力搅拌条件下,缓慢滴加入含20.21g二乙三胺五乙酸的单异丁酯的200mL二甲亚砜溶液,室温反应4h。再缓慢滴加入0.32g溴乙基罗丹明B基九肽化合物(色氨酸-异亮氨酸-苯丙氨酸-脯氨酸-色氨酸-异亮氨酸-谷氨酰胺-亮氨酸-赖氨酸,WIFPWIQL),室温继续反应48h,过滤,减压蒸除部分溶剂,冷却至室温,残留液于搅拌下倒入2500mL无水乙醇-无水乙醚(体积比为1:6)的混合溶剂中,产生浅黄色沉淀,过滤,抽干,所得固体再用蒸馏水溶解,用无水乙醇/无水乙醚重沉淀,收集浅黄色固体,真空干燥,得到25.18g固体,产率50%。
25.18g所得固体溶于200mL二次蒸馏水中,搅拌下,加入5.67g氯化锰MnCl2,反应液室温反应1h,用稀氢氧化钠溶液调节pH为8,继续搅拌12h,过滤,滤液用乙醇/乙醚沉淀,真空干燥,得到18.51g多糖类磁共振及荧光双模式成像诊断剂,可用于淋巴系统靶向多糖类大分子造影剂,产率60%。
实施例7:
取0.01摩尔的实施例1的多糖类磁共振-荧光双模式成像诊断剂溶于常规的氯化钠注射液中,用调节pH值到7.4,制成肿瘤靶向性肿瘤靶向性诊断剂。
实施例8:
取0.02摩尔的实施例2的多糖类磁共振-荧光双模式成像诊断剂溶于常规的葡萄糖注射液中,用调节pH值到7.4,制成肿瘤靶向性肿瘤靶向性诊断剂。
实施例9:
取0.03摩尔的实施例3的多糖类磁共振-荧光双模式成像诊断剂溶于常规的氯化钠-葡萄糖注射液中,用调节pH值到7.4,制成肿瘤靶向性肿瘤靶向性诊断剂。
实施例10:
取0.04摩尔的实施例4的多糖类磁共振-荧光双模式成像诊断剂溶于注射用蒸馏水中,用调节pH值到7.4,制成肿瘤靶向性诊断剂。
实施例11:
取0.005摩尔的实施例5的多糖类磁共振-荧光双模式成像诊断剂溶于常规的葡萄糖注射液中,用调节pH值到7.4,制成肿瘤靶向性肿瘤靶向性诊断剂。
实施例12:
取0.2摩尔的实施例6的多糖类磁共振-荧光双模式成像诊断剂溶于常规的氯化钠注射液中,调节pH值到7.4,制成肿瘤靶向性肿瘤靶向性诊断剂。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种多糖类磁共振及荧光双模式成像诊断剂,其特征在于,为顺磁性金属离子与配体形成的配合物,所述配体具有式1结构式:
其中,B为COO-、CH2OSO3 -、CH2OPO3 -或OA;C为NHC(=O)CH3、OH、CH3、OCH3、OSO3 -、NHSO3 -、OPO3 -或OA;D为NHC(=O)CH3、CH3、OCH3、OSO3 -、NHSO3 -、OPO3 -或OA;
A具有式2或式3代表的化学结构式:
其中R1、R3、Q分别独立选自CO、O、CH2CO、SO、-(CR4R5)m-、-(SR6)m-、-(SOR7)m-、或者-(NR8)m-;R2、R4、R5、R6、R7、R8分别对应的独立选自氢原子、烷基、芳基,或者,为由一个或多个羟基、一个或多个烷氧基、一个或多个胺基、一个或多个芳基、一个或多个芳氧基取代的烷基或芳基;m、n、y为1到10的自然数;r是0到10的整数;
E具有式4或式5代表的化学结构式:
其中R6选自亚烷基、亚芳基、CO、SO、CO(CH2)zCO,或者,选自由一个或多个羟基、一个或多个烷氧基、一个或多个胺基、一个或多个芳基或一个或多个芳氧基取代的亚烷基或亚芳基,z为1到10的自然数;
式1中,a为1~100000,b为1~100000;
所述多糖类磁共振及荧光双模式成像诊断剂的数均分子量范围为5000至108。
2.根据权利要求1所述的多糖类磁共振及荧光双模式成像诊断剂,其特征在于:所述的顺磁性金属离子为Gd、Mn、Cr、Fe、Co、Ni、La、Tc、Dy或Cu金属元素的各正价离子。
3.根据权利要求1所述的多糖类磁共振及荧光双模式成像诊断剂,其特征在于:其分子量范围为5000-2000000。
7.根据权利要求6所述的多糖类磁共振及荧光双模式成像诊断剂的制备方法,其特征在于:
步骤1)中,反应温度为室温;反应时间不低于4h;溶剂为水、二甲亚砜或N,N-二甲基甲酰胺;
步骤2)中,反应温度为室温;反应时间不低于48h;溶剂为水、二甲亚砜或N,N-二甲基甲酰胺;采用沉淀法从反应得到的混合物中分离出所述配体,沉淀剂为无水乙醇与无水乙醚的混合沉淀剂;
步骤3)中,反应温度为室温;反应时间不低于1h;溶剂为水;将反应得到的混合物调节pH至5~8,然后采用沉淀法从反应得到的混合物中分离出所述多糖类磁共振及荧光双模式成像诊断剂,沉淀剂为无水乙醇与无水乙醚的混合沉淀剂。
8.一种肺癌靶向磁共振及荧光双模式成像诊断试剂,其特征在于,为药用载体和/或赋形体与权利要求1至5任一所述的多糖类磁共振及荧光双模式成像诊断剂的水溶液,其中,所述多糖类磁共振及荧光双模式成像诊断剂的重量百分含量为0.1-50%,所述药用载体的浓度为0.001-5.0摩尔/升,所述赋形体的浓度为0.001-5.0摩尔/升,所述药用载体为氯化钠和/或葡萄糖,所述的赋形体为磷脂、明胶、淀粉或糖浆。
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