CN110974962B - 肿瘤免疫凝胶制剂的合成方法 - Google Patents
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Abstract
本发明公布一种肿瘤免疫凝胶制剂的合成方法。主要步骤包括:1)PLGA‑PEG‑PLGA凝胶溶液的制备；2)混合法制备SEV‑4I1@ICG肿瘤免疫凝胶。仙台病毒(SEV)可全身性激活机体免疫功能，形成肌体对肿瘤的免疫反应，并形成免疫记忆，对肿瘤杀伤和清除。吲哚菁绿(ICG)的荧光效应使疫苗接种的过程可视化，其产生的光热效应也可清除剩余的病毒及肿瘤细胞。PLGA‑PEG‑PLGA无毒，生物相容性好，在常温下呈液态，35度左右相变为凝胶，可以很好地用于体内注射，延长药物在体内的滞留，从而提高效果。这种病毒介导的肿瘤免疫凝胶可很好地预防肿瘤的产生。
Description
技术领域
本发明涉及免疫凝胶制剂制备方法，具体为一种通过PLGA-PEG-PLGA包裹仙台病毒(SEV)、吲哚菁绿(ICG)和4T1肿瘤细胞的策略,合成肿瘤免疫凝胶制剂的方法。
背景技术
目前，肿瘤是世界上对人类威胁最大的疾病之一。免疫治疗通过激活人体免疫系统，依靠自身免疫机能杀灭癌细胞和肿瘤组织，从而达到治疗癌症的作用。鉴于灭活的仙台病毒(SEV)可以作为异物在体内可以激发全身免疫系统产生细胞因子风暴(如干扰素、肿瘤坏死因子和各种白细胞介素等)，并使在抗肿瘤治疗过程中具有重要作用的树突状细胞(DC细胞，提呈肿瘤抗原)，巨噬细胞(细胞，吞噬肿瘤细胞)和自然杀伤细胞(NK细胞，杀伤肿瘤细胞)等被大量激活，随后大幅提高T细胞的增值效率。这种基于仙台病毒的免疫凝胶通过激活患者自身免疫系统，利用肿瘤细胞或肿瘤抗原物质诱导机体的特异性细胞免疫和体液免疫反应，增强机体的抗癌能力，阻止肿瘤的生长、扩散和复发，以达到清除或控制肿瘤的目的。
ICG化学名为吲哚菁绿，是一种感光染料，是美国食品药品监督管理局(FDA)惟一批准的体内应用染料。它注入血液后会迅速与清蛋白及α1-脂蛋白结合(98％)，随血液经过肝脏时，90％以上被肝细胞摄取，再以原形由胆道排泄，不参与体内化学反应，无肠肝循环，无淋巴逆流，不从肾脏等肝外脏器排泄，无辐射，无毒副作用。
PLGA-PEG-PLGA是一种三嵌段聚合物。其中PLGA由两种单体——乳酸和羟基乙酸随机聚合而成，是一种可降解的功能高分子有机化合物，其降解产物是乳酸和羟基乙酸，同时也是人代谢途径的副产物，所当它应用在医药和生物材料中时不会有毒副作用，具有良好的生物相容性、无毒、良好的成囊和成膜的性能。PEG具有良好的水溶性，生物相容性好，并赋予了聚合物温敏相变的性质。
发明内容
本发明为克服现有技术的不足，提供一种通过PLGA-PEG-PLGA包裹仙台病毒(SEV)、吲哚菁绿(ICG)和4T1肿瘤细胞的策略,合成肿瘤免疫凝胶制剂的方法。利用肿瘤细胞或肿瘤抗原物质诱导机体的特异性细胞免疫和体液免疫反应，增强机体的抗癌能力，阻止肿瘤的生长、扩散和复发，以达到清除或控制肿瘤的目的。
本发明的技术方案是一种肿瘤免疫凝胶制剂的合成方法，通过PLGA-PEG-PLGA包裹仙台病毒(SEV)吲哚菁绿(ICG)和4T1肿瘤细胞的策略,具体步骤如下：
1)称取PLGA-PEG-PLGA材料，加入水中溶解，得到浓度为0.2-0.5mg/ml的PLGA溶液；
2)称取ICG材料，加入水中溶解，得到浓度为5-10mg/ml的ICG溶液；
3)各取适量混合成肿瘤免疫凝胶。
所述步骤3)具体如下：
(1)在室温下将盛有1ml的PLGA-PEG-PLGA溶液的单口瓶置于旋转搅拌器上，搅拌速度设定为500r/min；
(2)边搅拌边逐滴加入8uL的ICG水溶液和20uL4T1肿瘤细胞溶液和20uLSEV溶液，继续搅拌直至完全混匀，最终得到SEV-4I1@ICG免疫凝胶。
本发明的优势在于：
1)仙台病毒SEV可以激活细胞免疫,增强机体的抗癌能力，阻止肿瘤的生长、扩散和复发，以达到清除或控制肿瘤的目的。
2)吲哚菁绿(ICG)的荧光效应使疫苗接种的过程可视化，其产生的光热效应也可清除剩余的病毒及肿瘤细胞。
3)PLGA-PEG-PLGA无毒，生物相容性好，在常温下呈液态，35度左右相变为凝胶，可以很好地用于体内注射，延长药物在体内的滞留，从而提高效果。
附图说明
图1：PLGA-PEG-PLGA的1H NMR图。
图2：SEV-4I1@ICG免疫凝胶光热效应曲线图。
具体实施方式
以下结合附图和具体实施例来对本发明作进一步的说明。
实施例1：
1)准确称取0.25mg的PLGA-PEG-PLGA材料，加入1mL水溶解，得到浓度为0.25mg/ml的PLGA-PEG-PLGA水溶液。
2)准确称取5mg的ICG材料，加入1mL水溶解，得到浓度为5mg/ml的ICG水溶液。
3)混合法合成SEV-4I1@ICG免疫凝胶的方法如下：
(1)在室温下将盛有1ml的PLGA-PEG-PLGA溶液的单口瓶置于旋转搅拌器上，搅拌速度设定为500r/min；
(2)边搅拌边逐滴加入8uL的ICG水溶液和20uL4T1肿瘤细胞溶液和20uLSEV溶液，继续搅拌直至完全混匀，最终得到SEV-4I1@ICG免疫凝胶。
实施例2：
1)准确称取0.2mg的PLGA材料，加入1mL水溶解，得到浓度为0.2mg/ml的PLGA-PEG-PLGA水溶液。
2)准确称取8mg的ICG材料，加入1mL水溶解，得到浓度为8mg/ml的ICG水溶液。
3)混合法合成SEV-4I1@ICG免疫凝胶的方法如下：
(1)在室温下将盛有1ml的PLGA-PEG-PLGA溶液的单口瓶置于旋转搅拌器上，搅拌速度设定为500r/min；
(2)边搅拌边逐滴加入6uL的ICG水溶液和20uL4T1肿瘤细胞溶液和20uLSEV溶液，继续搅拌直至完全混匀，最终得到SEV-4I1@ICG免疫凝胶。
实施例3：
1)准确称取0.5mg的PLGA-PEG-PLGA材料，加入1mL水溶解，得到浓度为0.5mg/ml的PLGA-PEG-PLGA水溶液。
2)准确称取10mg的ICG材料，加入1mL水溶解，得到浓度为10mg/ml的ICG水溶液。
3)混合法合成SEV-4I1@ICG免疫凝胶的方法如下：
(1)在室温下将盛有1ml的PLGA-PEG-PLGA溶液的单口瓶置于旋转搅拌器上，搅拌速度设定为500r/min；
(2)边搅拌边逐滴加入10uL的ICG水溶液和20uL4T1肿瘤细胞溶液和20uLSEV溶液，继续搅拌直至完全混匀，最终得到SEV-4I1@ICG免疫凝胶。
Claims (1)
1.肿瘤免疫凝胶制剂的合成方法，其特征是，通过PLGA-PEG-PLGA包裹仙台病毒(SEV)、吲哚菁绿(ICG)和4T1肿瘤细胞的策略,具体步骤如下：
1)称取PLGA-PEG-PLGA材料，加入水中溶解，得到浓度为0.2-0.5mg/ml的PLGA-PEG-PLGA溶液；
2)称取ICG材料，加入水中溶解，得到浓度为5-10mg/ml的ICG溶液；
3)混合成肿瘤免疫凝胶；
所述步骤3)具体如下：(1)在室温下将盛有1ml的PLGA-PEG-PLGA溶液的单口瓶置于旋转搅拌器上，搅拌速度设定为500r/min；
(2)边搅拌边逐滴加入6-10uL的ICG水溶液和20uL4T1肿瘤细胞溶液和20uLSEV溶液，继续搅拌直至完全混匀，最终得到SEV-4I1@ICG免疫凝胶。
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| Title |
|---|
| "希罗达对4T1乳腺癌小鼠肿瘤血管生成的影响";杨芳等;《现代生物医学进展》;20071231;第7卷(第9期);第1294-1296页 * |
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