CN107213479B - 一种包含过氧化氢酶的组合物及用途 - Google Patents
一种包含过氧化氢酶的组合物及用途 Download PDFInfo
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
本发明公开了一种包含过氧化氢酶的组合物及其用途，包含有标记在生物大分子上的放射性核素，可溶性海藻酸盐及过氧化氢酶。该组合物可以通过介入治疗的方式注入肿瘤内，当组合物中的海藻酸根离子进入肿瘤后遇到钙离子时会形成凝胶，从而将放射性核素及过氧化氢酶均匀的限定在肿瘤内。本发明公开的包含过氧化氢酶的组合物，利用过氧化氢酶分解瘤内过氧化氢产生的溶解氧改善肿瘤细胞乏氧状态，同时利用放射性射线对乏氧改善后的肿瘤细胞进行杀伤，具有良好的肿瘤治疗应用前景。
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种用于制备抗肿瘤药剂的组合物及用途。
背景技术
放射性核素因为其在不同器官组织中的富集效应不同，如甲状腺细胞对碘化物具有特殊的亲和力，口服一定量的碘-131后，能被甲状腺大量吸收，碘-131在衰变为氙-131时，能放射出β射线(占99％)和γ射线(占1％)，前者的有效射程3.63mm，平均射程为0.48mm，能选择性地破坏甲状腺腺泡上皮而不影响邻近组织，但是富集效应也限制了放射性核素应用于其他组织中。现有技术中，通过放射粒子的微创植入疗法是目前较为理想的方式之一，将放射性材料放置于微型载体中，再通过微创手术在超声或CT的引导下将放射性籽源植入病灶处，通过粒子衰变发出的射线来杀伤肿瘤细胞。这种方式会将载体粒子永久的留在患者体内，对患者的身体会造成长期的影响，该植入方法还存在分布不均匀和覆盖性差等问题，难以达到预期的效果。
另一方面，由于肿瘤的无序生长,血管生成不充分,所以人体实体瘤大多存在氧缺乏问题,乏氧状态的肿瘤细胞抵抗电离辐射的能力超过含氧量正常的肿瘤细胞的数倍,主要原因是减少了氧自由基对DNA的损伤，因此放射线对乏氧肿瘤细胞的杀伤性有限，导致现有放射粒子的治疗效果并不明显。现有技术中一类解决方式是通过高压氧仓的方式提高体内的溶解氧浓度；另一类方法通常采用乏氧细胞增敏剂以降低放射线的剂量或增强放射性治疗的效果，但放射性增敏剂通常具有较强的毒性，会对患者身体造成不良影响。如一类具有亲电子活性结构的硝基芳烃化合物,能参与乏氧细胞的生物还原代谢，减弱硝基对氧的模拟作用,能够在乏氧条件下固定DNA损伤,使DNA损伤不能进行修复，然而由于其副反应大而在临床使用中受到很大的限制。
发明内容
本发明针对现有技术中的上述问题，提供一种包含过氧化氢酶的组合物及其用于制备抗肿瘤药剂的用途。可改善肿瘤细胞乏氧问题，提高放射性粒子分布的均匀性及放射线对肿瘤细胞的杀伤能力，且不会影响周围的正常组织。
本发明公开了一种包含过氧化氢酶的组合物，包含过氧化氢酶，可溶性海藻酸盐，以及标记在生物大分子上的放射性核素。组合物中的海藻酸根离子进入肿瘤后，遇到钙离子时形成凝胶而附着在肿瘤内部，同时会将放射性核素标记的生物大分子及过氧化氢酶均匀限定在肿瘤内部。利用过氧化氢酶分解肿瘤内的过氧化氢可以产生溶解氧，从而改善肿瘤细胞的乏氧状态，同时利用放射性射线电离溶解氧产生氧自由基，该氧自由基会对肿瘤细胞进行杀伤，极大的增强了放射线对肿瘤细胞的杀伤作用。另一方面，可溶性海藻酸盐与氧化氢酶以及放射性核素标记的生物大分子能够因应肿瘤内部的结构形态，形成网络状均匀分布的凝胶结构，且过氧化氢酶和放射性核素标记的生物大分子因体型结构合适，能够被限定在海藻酸盐的凝胶结构中，而不会被血液带到患者的正常组织区域，同时也保证了病灶区域的放射线强度。此外，海藻酸钠在生物体内数周内逐渐降解，不会留下任何微粒。
可选的，该包含过氧化氢酶的组合物中，可溶性海藻酸盐为海藻酸钠。
可选的，该包含过氧化氢酶的组合物中，可溶性海藻酸盐为海藻酸钾，钾离子可促进血管的收缩，降低注入液在瘤体内的流动性。
可选的，该包含过氧化氢酶的组合物中，可溶性海藻酸盐为海藻酸钠与海藻酸钾的混合物，可依据肿瘤内血管的不同情况，调整混合物的比例关系，从而调整血管的收缩程度，进而调整组合物在血管中的分布状态。
可选的，该包含过氧化氢酶的组合物中，放射性核素可为碘-131，碘-125。
可选的，该包含过氧化氢酶的组合物中，放射性核素标记的生物大分子为蛋白质、核酸或多糖。
可选的，该包含过氧化氢酶的组合物中，放射性核素标记在该过氧化氢酶，将放射性核素标记在过氧化氢酶上，可以进一步限定放射线与过氧化氢酶产生的溶解氧的相对距离分布的均匀性，不会因为分子量的差异导致空间分布上的不均匀，从而提高氧自由基生成的几率和对肿瘤细胞的杀伤效果。
可选的，该包含过氧化氢酶的组合物中，过氧化氢酶浓度为5mg/mL-10mg/mL，海藻酸盐浓度为5mg/mL-10mg/mL，放射性核素剂量为200Ci/mL-500Ci/mL。
可选的，该包含过氧化氢酶的组合物中，还包含免疫刺激CpG寡聚脱氧核苷酸，可联合细胞毒T淋巴细胞相关抗原-4(CTLA-4)，为免疫治疗制造适量的抗原，在组合物中加入免疫佐剂更好地产生肿瘤相关抗原，然后联用CTLA-4调节免疫反应，利用自身免疫杀伤远端的肿瘤或者转移瘤，在治疗原位肿瘤的同时实现治疗远端或者转移瘤的目的。
本发明解决了现有技术中存在的乏氧肿瘤细胞的耐放射线辐射的问题，同时改善了现有技术中放射线核素事先容置与载体颗粒中，但介入病灶区后分布不均匀和覆盖性差的问题。此外杀死肿瘤细胞的同时可产生抗原，与T淋巴细胞抗原-4抗体(CTLA-4)，治疗原位肿瘤的同时实现治疗远端或者转移瘤
附图说明
下面结合附图及实施例对本发明作进一步描述：
图1是放射线核素在小鼠瘤内48小时动向的成像监测图；
图2是小鼠瘤内血氧浓度的光声监测图；
图3是肿瘤生长曲线图；
图4是小鼠存活曲线图；
图5是原位肿瘤生长曲线图
图6是远端肿瘤生长曲线图
图7是小鼠体内免疫相关细胞因子含量图
图8是不同浓度的海藻酸钠在肿瘤内的渗透行为切片图
具体实施方式
实施例一：
制备海藻酸钠溶液。称取50毫克的海藻酸钠溶于10毫升的去离子水中，充分震荡使得海藻酸钠充分溶解，从而得到5毫克每毫升的海藻酸钠溶液。
制备碘-131标记的过氧化氢酶。将碘-131原液50微升和0.1毫克每毫升的氯胺-T溶液100微升混合并加入加入500微升的PBS或者生理盐水，随后将碘-131和氯胺-T的混合液加入500微升浓度为5毫克每毫升的人过氧化氢酶中，在涡旋振荡器上震荡混匀5分钟后，室温静置15分钟，15分钟后将混合液转移至15毫升超滤管中4000转离心处理15分钟，加分散介质洗涤3次后取出上层清液，用活度计测量其活度。
将海藻酸钠溶液与碘-131标记的过氧化氢酶混合均匀，得到包含过氧化氢酶的组合物，其中过氧化氢酶浓度为5mg/mL-10mg/mL，海藻酸钠浓度为5mg/mL-10mg/mL，放射性核素剂量为200Ci/mL-500Ci/mL。
实施例二：
制备海藻酸钠溶液。称取50毫克的海藻酸钠溶于10毫升的去离子水中，充分震荡使得海藻酸钠充分溶解，从而得到5毫克每毫升的海藻酸钠溶液。
制备碘-131标记的人血清白蛋白。将碘-131原液50微升和100微升0.1毫克每毫升的氯胺-T混合并加入500微升分散介质，随后将碘-131和氯胺-T的混合液加入500微升浓度为5毫克每毫升的人血清白蛋白中，在涡旋振荡器上震荡混匀5分钟后，室温静置15分钟，15分钟后将混合液转移至15毫升超滤管中4000转离心处理15分钟，加分散介质洗涤3次后取出上层清液，用活度计测量其活度。
将海藻酸钠溶液、碘-131标记的人血清白蛋白和过氧化氢酶溶液混合均匀，得到包含过氧化氢酶的组合物，其中过氧化氢酶浓度为5mg/mL-10mg/mL，海藻酸盐浓度为5mg/mL-10mg/mL，放射性核素剂量为200Ci/mL-500Ci/mL。
实施例三：
制备海藻酸钾溶液。称取50毫克的海藻酸钾溶于10毫升的去离子水中，充分震荡使得海藻酸钾充分溶解，从而得到5毫克每毫升的海藻酸钾溶液。
制备碘-125标记的过氧化氢酶。将碘-125原液550微升和100微升0.1毫克每毫升的氯胺-T混合并加入500微升分散介质，随后将碘-125和氯胺-T的混合液加入500微升浓度为5毫克每毫升的过氧化氢酶中，在涡旋振荡器上震荡混匀5分钟后，室温静置15分钟，15分钟后将混合液转移至15毫升超滤管中4000转离心处理15分钟，加分散介质洗涤3次后取出上层清液，用活度计测量其活度。
将海藻酸钾溶液和碘-125标记的过氧化氢酶混合均匀，得到包含过氧化氢酶的组合物，其中过氧化氢酶浓度为5mg/mL-10mg/mL，海藻酸盐浓度为5mg/mL-10mg/mL，放射性核素剂量为200Ci/mL-500Ci/mL。
实施例四：
图1是放射线核素在小鼠瘤内48小时动向的成像监测图，在小鼠身上做系列实验，验证海藻酸盐的凝胶可将标记在生物大分子上的放射性核素限定在肿瘤内：
其中海藻酸钠浓度5mg/mL，过氧化氢酶浓度5mg/mL，碘131剂量200Ci/mL，分散介质为PBS液，每只小鼠注射50μl。将6只乳腺癌荷瘤小鼠分为6组，分别瘤内注射A:游离的碘-131；
B:碘-131标记的人血清白蛋白；
C:碘-131标记的过氧化氢酶；
D:海藻酸钠联合游离的碘-131；
E:海藻酸钠联合碘-131标记的人血清白蛋白；
F:海藻酸钠联合碘-131标记的过氧化氢酶。瘤内注射后，分别在0、4、12、24和48小时用核素小动物成像仪观察注射后的组合物动向。利用碘131核素放出的射线，实时监控海藻酸钠和碘131标记的过氧化氢酶直接注射进小鼠瘤内后的动向。从图1中可以看出，在没有海藻酸钠的对照组中，注射后的组合物在24小时基本已经泄露出肿瘤从静脉途径代谢出小鼠身体。而海藻酸钠可以非常好的将碘-131标记的生物大分子保留在肿瘤内，从而可以说明海藻酸钠在注射到肿瘤内后，遇到肿瘤内微量的钙离子能形成胶体，将生物大分子很好的包覆其中并限定在肿瘤内。
实施例五：
图2是小鼠瘤内血氧浓度的光声监测图，进一步验证包含过氧化氢酶的组合物在小鼠4T1肿瘤模型上改善乏氧的能力。将4只乳腺癌荷瘤小鼠分别瘤内注射人血清白蛋白，过氧化氢酶，海藻酸钠联合人血清白蛋白和海藻酸钠联合过氧化氢酶。利用光声来监测肿瘤的血氧浓度，图中灰白部分为超声成像显示出肿瘤的形状，而白色的部分为溶解氧的分布情况。从图2中可以看出海藻酸钠和过氧化氢酶联合使用可以长时间的改善肿瘤乏氧状况。由于海藻酸钠凝胶的存在，将过氧化氢酶很好的固定在肿瘤内，从而获得长时间的乏氧改善效果。
实施例六：
图3和图4分别为小鼠肿瘤生长曲线和小鼠存活曲线。
将乳腺癌荷瘤小鼠分为5组，每组5只做平行性的实验治疗。小鼠分别瘤内注射生理盐水，碘-131标记的人血清白蛋白，碘-131标记的过氧化氢酶，海藻酸钠联合碘-131标记的人血清白蛋白和海藻酸钠联合碘-131标记的过氧化氢酶。在瘤内注射后，每隔两天用游标卡尺测量肿瘤的长和宽，肿瘤的体积为(长×(宽×宽))÷2。从肿瘤生长曲线和小鼠存活曲线(图3和图4)可以看出，该体系增强了碘-131的治疗能力，表现出很好的治疗效果，并且联合使用海藻酸钠和过氧化氢酶的实验组小鼠存活时间最久。其中,control代表对照组单纯注射生理盐水，没有治疗效果；131I-HSA代表单纯碘131标记的人血清蛋白，只有碘131的治疗效果；131I-Cat代表碘131标记的过氧化氢酶，表示改善乏氧后的碘131的治疗；131I-HSA/ALG表示海藻酸钠联合碘131标记的人血清白蛋白；最后131I-Cat/ALG代表海藻酸钠联合碘131标记的过氧化氢酶。
实施例七：
图5和图6分别为小鼠原位肿瘤生长曲线和远端肿瘤生长曲线。
将屁股两边都种有小鼠结肠癌的荷瘤小鼠分为5组，每组5只做联合免疫的治疗实验。小鼠分别瘤内注射A生理盐水，B海藻酸钠联合的碘131标记的过氧化氢酶，C海藻酸钠联合的碘131标记的过氧化氢酶联用细胞毒T淋巴细胞相关抗原-4抗体，D海藻酸钠联合的碘131标记的过氧化氢酶和CpG寡聚核苷酸组合物以及E海藻酸钠联合的碘131标记的过氧化氢酶和CpG寡聚核苷酸组合物联用细胞毒T淋巴细胞相关抗原-4抗体。在瘤内注射原位肿瘤后，每隔两天用游标卡尺测量原位肿瘤和远端肿瘤的长和宽，肿瘤的体积为(长×(宽×宽))÷2。从原位肿瘤生长曲线和远端肿瘤生长曲线(图5和图6)可以看出，海藻酸钠联合碘-131标记的过氧化氢酶实现的内放疗可以很好的近乎达到消除原位肿瘤的目的从而产生相关抗原，在联用了免疫刺激核苷酸和细胞毒T淋巴细胞相关抗原-4抗体以后能很好地抑制远端瘤的生长，实现完整的治疗癌症的目的。在治疗20天后，从小鼠眼球取血并解剖取小鼠肿瘤，取出的血室温静置一个半小时后3000转离心20分钟分离出血清。通过酶联免疫法测量血清和肿瘤内的免疫相关细胞因子。
从图7中可以看出，相对于A,B,C和D这四个对照组，关键实验组小鼠由于瘤内注射了海藻酸钠与碘-131标记的过氧化氢酶和免疫佐剂寡核苷酸的组合物，并且静脉给药抗细胞毒T淋巴细胞相关抗原，其原位肿瘤被内放射治疗清除产生大量相关抗原，配合免疫佐剂和免疫刺激剂导致小鼠体内相关的免疫因子中细胞毒性T细胞有相应的增加而调节性T细胞减少，表示小鼠体内对肿瘤有杀伤性能的淋巴细胞增多而保护肿瘤的淋巴细胞减少。而进一步对远端肿瘤内细胞因子的检测发现，γ干扰素有相应的提升也表明肿瘤内部杀伤肿瘤的淋巴细胞的增加同时肿瘤坏死因子α的提升表明远端肿瘤受到淋巴细胞攻击而坏死严重。这一系列的现象都表明内放疗在清除了原位瘤之后配合免疫佐剂和免疫刺激剂使小鼠体内杀伤肿瘤的淋巴细胞显著提升，而这些淋巴细胞识别并攻击小鼠体内远端的肿瘤细胞使其坏死，从而有力的解释了内放射治疗配合免疫疗法有很好的效果。
实施例八：
为进一步研究不同浓度的海藻酸钠在小鼠肿瘤内的渗透行为。在过氧化氢酶上标记荧光素染料，标记方法为在5毫克每毫升过氧化氢酶1毫升加入10微升荧光素染料，然后加入10毫克1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐，搅拌12小时后将反应液1.1毫升转移到14800分子量的透析袋中于水透析两天，12小时换一次水。透析完得到荧光素染料标记的过氧化氢酶。将该过氧化氢酶和不同浓度的海藻酸钠分别为1、5、10、20毫克每毫升混合，瘤内注射到荷瘤小鼠的肿瘤内。分别在4小时和72小时取出肿瘤，将肿瘤切片染色。从图8中可以看出，5毫克每毫升的海藻酸钠其适当的成胶能力，可以使得组合物很好的在肿瘤内扩散，相比较而言，低于5毫克每毫升，其成胶能力不足，在72小时组合物已经流出肿瘤，而大于10毫克每毫升，太快的成胶导致组合物停留在肿瘤的某个部分。综上可以得出结论，5-10毫克每毫升是海藻酸钠的最适浓度。
小鼠体内钙离子浓度大概在1.5*10-3～1.8*10-3M，而人体内大概也是1.5*10-3～1.8*10-3M这个量级，所以对人体的海藻酸钠浓度也在5～10毫克每毫升。
此外，应当理解，虽然本说明书按照实施方式加以描述，但并非每个实施方式仅包含一个独立的技术方案，说明书的这种叙述方式仅仅是为清楚起见，本领域技术人员应当将说明书作为一个整体，各实施例中的技术方案也可以经适当组合，形成本领域技术人员可以理解的其他实施方式。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
Claims (8)
1.一种包含过氧化氢酶的组合物，其特征在于：包含过氧化氢酶，可溶性海藻酸盐，以及标记在生物大分子上的放射性核素。
2.根据权利要求1所述的组合物，其特征在于该可溶性海藻酸盐为海藻酸钠、海藻酸钾或其混合物。
3.根据权利要求1所述的组合物，其特征在于该放射性核素为碘-131或碘-125。
4.根据权利要求1所述的组合物，其特征在于该放射性核素标记在该过氧化氢酶上。
5.根据权利要求1-4任意一项所述的组合物，其特征在于该过氧化氢酶浓度为5mg/mL-10mg/mL；
该海藻酸盐浓度为5mg/mL-10mg/mL；以及
该放射性核素剂量为200Ci/mL-500Ci/mL。
6.根据权利要求1所述的组合物，其特征在于该组合物还包含免疫佐剂CpG寡聚脱氧核苷酸。
7.权利要求1-6任意一项所述的组合物用于制备抗肿瘤药剂的用途。
8.根据权利要求7所述的用途，其特征在于该组合物与细胞毒T淋巴细胞相关抗原-4联用。
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| EP18819947.5A EP3643315B1 (en) | 2017-06-22 | 2018-06-19 | Composition comprising catalase, preparation method and use thereof and method for killing tumor cells |
| ES18819947T ES2924183T3 (es) | 2017-06-22 | 2018-06-19 | Composición que comprende catalasa, método de preparación y uso de la misma y método para eliminar células tumorales |
| PCT/CN2018/091841 WO2018233605A1 (zh) | 2017-06-22 | 2018-06-19 | 一种包含过氧化氢酶的组合物、其制备方法及用途和一种杀死肿瘤细胞的方法 |
| US16/606,976 US11173220B2 (en) | 2017-06-22 | 2018-06-19 | Composition comprising catalase, preparation method and use thereof and method for killing tumor cells |
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| CN114652862A (zh) * | 2020-12-23 | 2022-06-24 | 成都纽瑞特医疗科技股份有限公司 | 一种放射性树脂微球注射剂及制备方法和用途 |
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