CN114522241A - 一种铝纳米晶复合免疫药物及其制备方法和应用 - Google Patents
一种铝纳米晶复合免疫药物及其制备方法和应用 Download PDFInfo
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- CN114522241A CN114522241A CN202210152866.9A CN202210152866A CN114522241A CN 114522241 A CN114522241 A CN 114522241A CN 202210152866 A CN202210152866 A CN 202210152866A CN 114522241 A CN114522241 A CN 114522241A
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Abstract
本发明涉及生物医药技术与疫苗技术领域,尤其涉及一种铝纳米晶复合免疫药物及其制备方法和应用。其中铝纳米晶作为载体,在铝纳米晶表面覆盖有聚乙二醇,并通过聚乙二醇端位基团链接功能多肽序列和细胞因子分子,形成类病毒颗粒免疫药物,提升细胞因子稳定性以及在肿瘤组织停留时间,有效提升细胞因子辅助抗肿瘤效果。
Description
技术领域
本发明涉及生物医药技术与疫苗技术领域,特别涉及一种铝纳米晶复合免疫药物及其制备方法和应用。
背景技术
截止目前,虽然临床医学上理论研究以及相关技术已经有了较大的进步,但是肿瘤(癌症)仍然是难以治愈和高致死率的疾病。临床上,肿瘤主要有手术、化学和放射三种传统治疗方案。手术疗法通过外科手术直接切除患病部位,对于早期肿瘤或扩散能力较低的良性肿瘤治疗效果较好,但是对于已经发生转移的癌症患者,其疗效和预后生活质量较差。化学疗法由于缺乏特异性,在治疗肿瘤的同时,对于患者自身免疫系统和干细胞也有较大伤害。近些年来,随着对肿瘤生长发展过程不断深入的研究,提出了免疫疗法这一创新性治疗方案,极大促进了癌症治疗的发展,并于2013年被Science杂志评为当年的十大科技突破之首,是近些年来癌症临床治疗的最重要的研究方向之一。
免疫疗法是一大类通过激活人体的免疫系统达到治疗癌症目的的治疗手段的统称。人体内的免疫系统一直充当着“警务人员”的角色,驱除像体内的外来入侵者。肿瘤免疫疗法可通过以下三种方式起作用:(1)设计单克隆抗体来增强免疫反应以破坏癌细胞;(2)使用免疫检查点抑制剂来帮助免疫系统识别和攻击癌细胞;(3)合成癌症疫苗以激发免疫应答以治疗和预防癌症。与其他治疗癌症手段不同,免疫疗法主要是通过激活免疫系统来赋予人体攻击肿瘤细胞的能力,由于人体免疫系统的记忆功能,其过程在初始治疗后可能会持续很长时间。此外,免疫系统还具备区分癌细胞与正常细胞的能力,并可通过激活免疫反应,从而选择性攻击癌细胞并避免损坏正常细胞。
细胞因子是调节免疫反应的主要参与者之一,基于细胞因子的方法为癌症免疫治疗提供了另一种策略。在过去的几十年中,细胞因子和细胞因子受体作为癌症治疗的靶点已被广泛研究。细胞因子是由免疫细胞(如单核、巨噬细胞、T细胞、B细胞、NK细胞等)和某些特定的非免疫细胞(内皮细胞、表皮细胞、纤维母细胞等)经刺激而表达、分泌的一类具有广泛生物学活性的小分子蛋白质,并可通过结合相应受体调节固有免疫和适应性免疫、血细胞生成、细胞生长、APSC多能细胞以及损伤组织修复等多种功能。细胞因子可被分为白细胞介素、干扰素、肿瘤坏死因子超家族的部分成员、集落刺激因子、趋化因子、生长因子等。在肿瘤微环境中,细胞因子是细胞通讯的关键介质。恶性细胞、免疫细胞和基质细胞的细胞因子产生失调参与肿瘤发生和发展的所有阶段。某些细胞因子与肿瘤的发展、进展和转移密切相关,并且炎性细胞因子的异常产生是非恶性细胞中致癌变化的常见下游结果。因此,利用细胞因子的免疫刺激作用和细胞因子失调时中和它们的作用,能够有效实现肿瘤组织的治疗。然而,全身给予细胞因子由于缺乏靶向性,具有一定的全身毒性,并对胚胎组织也有潜在的不良作用,因此细胞因子药物进行局部给药是一种比较有效和安全的方式。
因此,研制一种基于铝纳米晶的复合免疫药物,解决细胞因子机体稳定性以及局部蓄积时间,提升细胞因子在肿瘤组织内与细胞作用时间,充分发挥调节免疫的作用,将极具实用价值。
发明内容
本发明提供了一种铝纳米晶复合免疫药物及其制备方法和应用,以及基于铝纳米晶复合免疫药物中的铝纳米晶表面链接的功能多肽序列和细胞因子。本发明所提供的铝纳米晶能够通过聚乙二醇分子有效结合功能多肽序列和细胞因子,构建复合免疫药物,通过功能多肽序列有效提升复合免疫药物在肿瘤部位与肿瘤细胞的结合能力,并增加复合免疫药物在肿瘤部位的蓄积时间;同时增强细胞因子稳定性和在肿瘤部位发挥免疫调节能力的时间窗口,有效改善机体对肿瘤组织的免疫反应,抑制肿瘤组织的增长。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种铝纳米晶复合免疫药物,基于铝纳米晶通过聚乙二醇分子结合功能多肽序列和细胞因子分子构建而成。
进一步的,所述构建方式为铝纳米晶表面M-PEG-NH2的氨基与细胞因子分子上的羧基形成共价酰胺键。
进一步地,所述铝纳米晶通过以下步骤制备:
将铝盐溶液与聚乙二醇溶液搅拌充分混合,并加入NaOH水溶液调节pH为5.0~8.0后,静置得沉淀,离心洗涤纯化后得聚乙二醇修饰的铝纳米晶。
进一步地,所述铝盐溶液的溶质为氯化铝、硝酸铝、硫酸铝和醋酸铝中的一种及以上;所述铝盐溶液所用溶剂为纯水或浓度为0.01mol/L的醋酸钠溶液;
进一步地,所述聚乙二醇为磷酸丝氨酸修饰的聚乙二醇(PS-PEG)与马来酰亚胺基团和末端羧酸的聚乙二醇(M-PEG-NH2)的混合试剂。
进一步地,加入NaOH水溶液调节所述pH为5.0~8.0。
本发明还提供了上述铝纳米晶复合免疫药物的制备方法,包括如下步骤:
(1)将铝纳米晶和功能多肽序列加入磷酸盐缓冲液或0.1M醋酸铵缓冲液中,搅拌反应,并离心洗涤提纯,得到功能多肽序列修饰的铝纳米晶;
(2)将细胞因子分子加入50mM MES缓冲液中,并加入EDC/NHS活化分子上的羧基,之后加入步骤(1)得到的纳米晶的溶液,使M-PEG-NH2的氨基与细胞因子分子上的羧基形成共价酰胺键,得到细胞因子分子进一步修饰的铝纳米晶复合免疫药物。
进一步地,所述功能多肽序列包括可特异性结合肿瘤细胞表面高表达蛋白的多肽序列。
更进一步地,所述功能多肽序列为环形RGD序列或可协助免疫药物进入细胞的TAT序列中的一种或多种。
进一步地,所述细胞因子分子选自白细胞介素类因子,所述白细胞介素类因子包括IL-2、IL-7、IL-12、IL-15、IL-18、IL-21、伽马干扰素IFN-γ、肿瘤坏死因子TNFα中的一种或多种。
本发明还提供了上述铝纳米晶复合免疫药物或所述制备方法制得的铝纳米晶复合免疫药物在肿瘤模型免疫治疗中的应用。
所述应用为静脉注射使用、粘膜施用、皮下注射使用、皮内注射使用、瘤周注射使用或瘤内注射使用。
本发明具有的技术效果为:
本发明所提供的聚乙二醇辅助制备的铝纳米晶能够有效结合功能多肽序列和细胞因子,有效增强了细胞因子稳定性和在肿瘤部位发挥免疫调节能力的时间窗口,改善了机体对肿瘤组织的免疫反应,抑制了肿瘤组织的增长。
附图说明
为了更清楚地说明本申请实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1为本发明实施例2、3所构建的铝纳米晶复合免疫药物抑制肿瘤生长的效果分析;
图2为本发明实施例2、3所构建的铝纳米晶复合免疫药物在小鼠肿瘤模型中细胞因子蓄积和稳定性情况分析;
图3为本发明实施例2、3所构建的铝纳米晶复合免疫药物在小鼠肿瘤模型中调节肿瘤组织中CD8 T细胞增殖情况;
图4为本发明实施例2、3所构建的铝纳米晶复合免疫药物抑制远端肿瘤组织生长的效果分析;
图5为本发明铝纳米晶复合免疫药物构建过程示意图。
具体实施方式
本发明公开了一种铝纳米晶复合免疫药物及其制备方法以及基于铝纳米晶复合免疫药物中的铝纳米晶表面链接的功能多肽序列和细胞因子。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
下面结合实施例及附图,进一步阐述本发明:
实施例1
将AlCl3·6H2O溶于0.01mol/L NaAc中,配制成铝离子含量0.05mol/L的铝盐溶液;向得到的铝盐溶液加入总分子浓度为0.05mol/L的PS-PEG与M-PEG-NH2摩尔比例为1:1的混合溶液,其中Al3+与磷酸丝氨酸之间的摩尔比为1:2;反应完成后,静置7小时,离心后洗涤,最后高压蒸汽灭菌或经过滤膜除菌,制得铝纳米晶,命名为Al-PEG。
实施例2铝纳米晶复合免疫药物Al-RGD-IL12制备:
(1)将铝纳米晶和可特异性结合肿瘤细胞表面高表达的功能蛋白整合素的多肽序列c(RGDfC)加入0.1M磷酸盐缓冲液或0.1M醋酸铵缓冲液中,其中多肽序列与铝纳米晶表面PEG分子中含有的马来酰亚胺的比例为1.2:1,搅拌反应24小时,并离心洗涤提纯,得到RGD肽序列修饰的铝纳米晶;
(2)将细胞因子IL-12分子加入50mM MES缓冲液中,并加入EDC/NHS活化分子上的羧基,之后加入步骤(1)得到的纳米晶的溶液,其中铝纳米晶表面M-PEG-NH2的与细胞因子分子比例为1.5:1,得到细胞因子分子进一步修饰的铝纳米晶复合免疫药物,命名为Al-RGD-IL12。
实施例3铝纳米晶复合免疫药物Al-TAT-TNFα:
(1)将铝纳米晶和可有效载带纳米颗粒进入细胞内部的穿膜肽序列TAT加入0.1M磷酸盐缓冲液或0.1M醋酸铵缓冲液中,其中多肽序列与铝纳米晶表面PEG分子中含有的马来酰亚胺的比例为1.5:1,搅拌反应24小时,并离心洗涤提纯,得到TAT肽序列修饰的铝纳米晶;
(2)将肿瘤坏死因子TNFα分子加入50mM MES缓冲液中,并加入EDC/NHS活化分子上的羧基,之后加入步骤(1)得到的纳米晶的溶液,其中铝纳米晶表面M-PEG-NH2的与细胞因子分子比例为1.3:1,得到细胞因子分子进一步修饰的铝纳米晶复合免疫药物。
实施例4
对所述铝纳米晶或铝纳米晶复合免疫药物进行粒径和表面电荷进行表征
25℃条件下,将铝纳米晶的浓度稀释至10μg/ml,用纳米粒度仪测试铝纳米晶的粒径和Zeta电位(购自Malvern公司,Zetasizer Nano ZS型号),结果如表1所示。
实施例1、2、3制备的铝纳米晶或铝纳米晶复合免疫药物的理化性质如下表所示。
由表1可知,本发明所有实施例均得到纳米尺寸的铝纳米晶。
实施例5
将上述对所构建的铝纳米晶复合免疫药物应用于肿瘤模型免疫治疗中,进行肿瘤生长抑制评估。
A)在遵循国家动物保健协议的前提下,选取6-8周龄的BALB/c小鼠进行后侧皮下肿瘤种植,肿瘤模型选取B16F10小鼠黑色素瘤高转移细胞,待所种植的肿瘤组织生长至100mm3左右时,将小鼠随机分为5组,并于瘤内注射如下药物:①、注射盐水(Ctrl);②、商业铝佐剂Alum与含有0.25微克IL-12的简单混合样(Alum-IL12);③、实施例2构建的含有0.25微克IL-12的Al-RGD-IL12复合免疫药物;④、商业铝佐剂Alum与含有0.25微克TNFα的简单混合样(Alum-IL12);⑤、实施例2构建的含有0.25微克IL-12的Al-TAT-TNFα复合免疫药物。并记录小鼠肿瘤体积变化情况。
结果如图1所示,图1为所构建的铝纳米晶复合免疫药物抑制肿瘤生长的效果分析。
由图1可知,20天时,对照组小鼠肿瘤平均大小为1942mm3;Alum-IL12组肿瘤体积平均大小为1364mm3;而Al-RGD-IL12组肿瘤体积平均大小为183mm3;Alum-TNFα组肿瘤体积平均大小为1540mm3;而Al-TAT-TNFα组肿瘤体积平均大小为204mm3;可得所构建的载带细胞因子的铝纳米晶复合免疫药物能够有效抑制肿瘤的生长。
实施例6
针对实施例5中的各组小鼠,分析其肿瘤组织中细胞因子的积累和蓄积情况,分别在瘤内注射药物后的24小时和48小时后,分别于实施例5的②、③、④、⑤四个组别内随机各取出一只小鼠,人道主义处死后解剖获取其肿瘤组织,并按照白细胞介素12(IL-12)或肿瘤坏死因子(TNFα)的ELISA试剂盒说明书的操作对肿瘤组织中的IL-12或TNFα的存量水平进行分析。
结果如图2所示,图2为实施例5中小鼠肿瘤模型中细胞因子蓄积情况分析。由图2可知所构建的铝纳米晶复合免疫药物能够显著提升细胞因子在肿瘤环境中的稳定性和蓄积时间。
实施例7
对实施例6提取的注射药物后小鼠的肿瘤组织,进行CD8+T细胞增值情况研究。将部分肿瘤组织称重并研磨,然后通过100μm细胞过滤器过滤。用抗CD8对细胞悬液进行表面标记染色,然后在流式细胞仪上进行分析。结果如图3所示,图3为实施例5中小鼠肿瘤模型中,肿瘤组织中CD8 T细胞增殖情况。由图3可知所构建的铝纳米晶复合免疫药物能够显著提升CD8 T细胞的增殖能力,有效调节肿瘤组织的免疫反应。
实施例8
铝纳米晶复合免疫药物抑制远端肿瘤生长
将B16F10小鼠黑色素瘤细胞接种到Balb/c小鼠右后腿皮下,记为原位肿瘤,将一半细胞数目的B16F10小鼠黑色素瘤细胞接种到Balb/c小鼠左后腿皮下,记为远端肿瘤。待原位肿瘤平均体积长到100mm3时,远端肿瘤体积平均大小约50mm3,然后将小鼠随机分为5组,并于原位瘤内注射如下药物:①、注射盐水(Ctrl);②、商业铝佐剂Alum与含有0.25微克IL-12的简单混合样(Alum-IL12);③、实施例2构建的含有0.25微克IL-12的Al-RGD-IL12复合免疫药物;④、商业铝佐剂Alum与含有0.25微克TNFα的简单混合样(Alum-IL12);⑤、实施例2构建的含有0.25微克IL-12的Al-TAT-TNFα复合免疫药物。每3天治疗一次,并记录小鼠远端肿瘤体积变化情况。
结果如图4所示,图4为所构建的铝纳米晶复合免疫药物抑制远端肿瘤组织生长的效果分析。由图4可知,20天时,对照组小鼠远端肿瘤平均大小为1286mm3;Alum-IL12组远端肿瘤体积平均大小为984mm3;而Al-RGD-IL12组远端肿瘤体积平均大小为253mm3;Alum-TAT-TNFα组远端肿瘤体积平均大小为880mm3;而Al-TAT-TNFα组远端肿瘤体积平均大小为382mm3;可得所构建的载带细胞因子的铝纳米晶复合免疫药物能够有效抑制远端肿瘤的生长。说明所构建的铝纳米晶复合免疫药物除了可以对已有肿瘤的生长产生明显抑制效果,对于新生肿瘤的生长也有明显的抑制作用。
以上所述,仅是本发明的较佳实施例,并非对本发明作任何形式上的限制,凡是依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属本发明技术方案的保护范围。
Claims (12)
1.一种铝纳米晶复合免疫药物,其特征在于,由铝纳米晶通过聚乙二醇分子结合功能多肽序列和细胞因子分子构建而成。
2.根据权利要求1所述的铝纳米晶复合免疫药物,其特征在于,所述铝纳米晶通过以下步骤制备:
将铝盐溶液与聚乙二醇溶液搅拌混合,并加入NaOH水溶液调节pH后静置得沉淀,离心洗涤纯化后得聚乙二醇修饰的铝纳米晶。
3.根据权利要求2所述的铝纳米晶复合免疫药物,其特征在于,所述铝盐溶液的溶质为氯化铝、硝酸铝、硫酸铝和醋酸铝中的一种或多种;所述铝盐溶液所用溶剂为纯水或浓度为0.01mol/L的醋酸钠溶液。
4.根据权利要求2所述的铝纳米晶复合免疫药物,其特征在于,所述聚乙二醇溶液为磷酸丝氨酸修饰的聚乙二醇与马来酰亚胺基团和末端羧酸的聚乙二醇的混合试剂。
5.根据权利要求2所述的铝纳米晶复合免疫药物,其特征在于,加入NaOH水溶液调节所述pH为5.0~8.0。
6.一种铝纳米晶复合免疫药物的制备方法,其特征在于,包括如下步骤:
(1)将铝纳米晶和功能多肽序列加入溶剂中,搅拌反应,并离心洗涤提纯,重悬至超纯水得到功能多肽序列修饰的铝纳米晶溶液;
(2)将细胞因子分子加入MES缓冲液中,并加入EDC/NHS活化细胞因子分子上的羧基,之后加入所述铝纳米晶溶液,使M-PEG-NH2的氨基与细胞因子分子上的羧基形成共价酰胺键,得到细胞因子分子修饰的铝纳米晶复合免疫药物。
7.根据权利要求6所述的铝纳米晶复合免疫药物的制备方法,其特征在于,所述溶剂为0.1M磷酸盐缓冲液或0.1M醋酸铵缓冲液。
8.根据权利要求6所述的铝纳米晶复合免疫药物的制备方法,其特征在于,所述功能多肽序列包括可特异性结合肿瘤细胞表面高表达蛋白的多肽序列。
9.根据权利要求6所述的铝纳米晶复合免疫药物的制备方法,其特征在于,所述细胞因子分子选自白细胞介素类因子,所述白细胞介素类因子包括IL-2、IL-7、IL-12、IL-15、IL-18、IL-21、伽马干扰素IFN-γ或肿瘤坏死因子TNFα中的一种或多种。
10.根据权利要求8所述的铝纳米晶复合免疫药物的制备方法,其特征在于,所述功能多肽序列为环形RGD序列或可协助免疫药物进入细胞的TAT序列中的一种或多种。
11.权利要求1~5任意一项铝纳米晶复合免疫药物或权利要求6~9任意一项所述制备方法制得的铝纳米晶复合免疫药物在肿瘤模型免疫治疗中的应用。
12.权利要求11所述的应用,其特征在于,所述应用为静脉注射使用、粘膜施用、皮下注射使用、皮内注射使用、瘤周注射使用或瘤内注射使用。
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