CN116650661B - PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料及其制备和应用 - Google Patents
PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料及其制备和应用 Download PDFInfo
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Abstract
本发明涉及新材料领域,具体涉及一种PAA‑BaSO4@Zn‑MOF/TRF复合人造纳米巨噬细胞材料,包括PAA‑BaSO4核,包覆在核上的Zn‑MOF中间层,以及修饰在中间层上的转铁蛋白;所述的PAA‑BaSO4核包括PAA聚合骨架以及修饰在PAA聚合骨架上的BaSO4。本发明还涉及所述的材料的制备和应用。本发明所述的材料,得益于结构和成分的联合协同,能够赋予材料优异的模拟巨噬细胞的功能和效果。
Description
技术领域
本发明属于纳米材料领域,具体涉及具有巨噬细胞类似作用的人造纳米巨噬细胞材料领域。
背景技术
免疫疗法已被公认为最有希望的根除肿瘤的方法。巨噬细胞是抗肿瘤免疫过
程中最重要的免疫细胞。然而,肿瘤微环境中的巨噬细胞不仅有限,而且主要作为免疫抑制性M2表型存在,导致免疫监视异常。此外,M2巨噬细胞抑制T细胞渗透,并通过分泌抗炎细胞因子驱动肿瘤中的T细胞衰竭。因此,免疫疗法仅对临床中不到30%的肿瘤患者有效。为了逆转肿瘤免疫抑制,研究人员付出了巨大的努力,通过细胞工程开发嵌合抗原受体(CAR)细胞,如CAR-T、CAR-巨噬细胞和CAR-自然杀伤细胞。CAR细胞被设计成通过基因编辑技术表达免疫细胞上的肿瘤特异性受体,但其应用受到高成本和肿瘤异质性的限制。因此,开发新的替代策略对于抗肿瘤免疫治疗是非常迫切的。
人造细胞由合成材料构成,模仿天然细胞的生物学功能。人造细胞的合成和可调结构使它们能够充分发挥与肿瘤的各种物理化学相互作用。此外,人工细胞的功能可以根据实际需要灵活设计和调整。除此之外,人造细胞很容易以低成本大规模生产。所有这些优点使人造细胞成为天然细胞的有效替代品。然而,人造巨噬细胞很少被制造出来模仿天然巨噬细胞,可能是由于以下挑战。首先,天然巨噬细胞的生物学功能与TNF-α、IL-6和IL-1等促炎因子高度相关,可介导肿瘤凋亡和抗肿瘤先天/适应性免疫。释放细胞因子以启动免疫的能力是设计人造巨噬细胞的先决条件。其次,在抗肿瘤免疫治疗中,抗原捕获是天然巨噬细胞介导抗肿瘤免疫治疗中抗原呈递和T细胞识别的关键步骤。在大多数情况下,抗原捕获是由天然巨噬细胞通过非特异性吞噬作用完成的。迄今为止,很少有人造巨噬细胞被成功构建以满足上述要求。
发明内容
针对现有人造巨噬细胞材料匮乏,且免疫诱导性能不理想等问题,本发明第一目的在于,提供一种PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料(本发明也简称为人造巨噬细胞),旨在提供一种能够模拟巨噬细胞功能的材料。
本发明第二目的在于,提供所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料的制备和应用。
本发明第三目的在于,提供一种包含所述PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料的抗肿瘤药物。
一种PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,包括PAA-BaSO4核,包覆在核上的Zn-MOF中间层,以及修饰在中间层上的转铁蛋白;
所述的PAA-BaSO4核包括PAA聚合骨架以及修饰在PAA聚合骨架上的BaSO4。
本发明提供了一种全新的人造巨噬细胞材料,其得益于所述的材料和结构的联合控制,可以表现出类似于天然巨噬细胞的功能。例如,对于肿瘤而言,其能够有效识别肿瘤,并高效捕获和呈递肿瘤抗原,激活肿瘤免疫,逆转肿瘤免疫抑制,诱导免疫因子释放,从而诱导肿瘤失巢凋亡。
本发明中,所述的材料的物质和结构的联合是协同赋予其巨噬细胞模拟作用,改善抗原识别,抗原捕获-呈递效果,改善免疫作用的关键。
本发明中,所述的核为多孔核,其中,PAA(指聚丙烯酸)聚合骨架和BaSO4的重量比为1:5~50,进一步优选为1:10~20。
本发明中,所述的Zn-MOF为ZIF-8。
本发明中,PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料中,TRF的重量百分含量为10~40%,优选为25~35%,所述的Zn-MOF的重量含量为10~40%,优选为20~30%,余量为PAA-BaSO4。
优选地,PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料的粒径为300~500nm。
本发明还提供了一种项所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料的制备方法,步骤包括:
步骤(1):将PAA和Ba源复合进行络合,制得PAA-Ba;随后再将其和水溶性硫化物进行混合,反应得到PAA-BaSO4;所述的PAA和Ba源的重量比为1:5~50;所述的Ba源和水溶性硫化物的重量为1:1~10:
步骤(2):在PAA-BaSO4核上包覆Zn-MOF中间层,制得PAA-BaSO4@Zn-MOF中间产物;
步骤(3):在PAA-BaSO4@Zn-MOF中间产物上修饰TRF,制得所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料。
本发明所述的材料的制备难点主要在于如何成功实现中间层的有效复合,以及如何改善产物的抗原富集以及呈递效率,改善材料的免疫模拟性能。针对本发明所述的材料的制备难点,本发明创新地发现,预先将PAA和Ba化合交联络合,随后再配合硫化物的处理,进一步配合制备参数的联合控制,能够意外地构建人造巨噬细胞适配的网络结构,并在其中化学修饰有硫酸钡物相,如此利于材料的抗原呈递效果,不仅如此,还利于Zn-MOF的原位有效复合,进一步和TRF层联合,能够协同改善材料的模拟免疫能力。
本发明中,PAA和Ba源的化学络合、配合后续硫化物的物相转型处理以及处理参数如成分比例的联合控制是调控核结构,利于Zn-MOF复合,并利于抗原呈递,改善模拟巨噬细胞性能的关键。
步骤(1)中,所述的Ba源为Ba2+的水溶性化合物,优选为氢氧化钡;
优选地,所述的PAA和Ba源的重量比为1:10~15。
优选地,所述的水溶性硫化物为硫化钠、硫化钾中的至少一种。
优选地,Ba源和水溶性硫化物的重量为1:3~6。
本发明中,步骤(2)中,将制得的PAA-BaSO4分散在溶剂中,加入水溶性锌盐和MOF配体,进行配位反应,在PAA-BaSO4上沉积Zn-MOF材料,制得PAA-BaSO4@Zn-MOF;
优选地,所述的MOF配体为2-甲基咪唑;
优选地,所述的水溶性锌盐和MOF配体的摩尔比为1:10~40,优选为1:10~20。
优选地,所述的PAA-BaSO4和锌源的重量比为1:0.1~1;优选为1:0.5~0.8。
本发明中,步骤(3)中,将PAA-BaSO4@Zn-MOF和TRF进行液相混合,组装修饰,制得所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料;
优选地,所述的PAA-BaSO4@Zn-MOF和TRF的重量比为1:0.1~1;优选为1:0.4~0.6。
本发明还提供了一种所述PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料在制备抗肿瘤药物中的应用。
本发明中,得益于所述的材料优异的巨噬细胞模拟效果,可以激活肿瘤免疫,诱导肿瘤细胞凋亡,从而实现肿瘤的靶向治疗,且具有优异的普适性。
本发明还提供了一种抗肿瘤药物,其包含药学有效量的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料。
优选地,所述的抗肿瘤药物还包括药学上可接受的辅料;
优选地,所述的抗肿瘤药物具有药学上可接受的剂型;
优选地,所述的抗肿瘤药物为注射制剂;进一步优选为药学上可接受的局部注射制剂。
有益效果:
(1)本发明提供了一种PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,其具有天然巨噬细胞类似的功能,能够高效识别抗原,且能够捕获和呈递抗原,诱导免疫应答,促使炎性作用。
例如,PAA-BaSO4@ZIF-8/TRF纳米材料可以识别肿瘤,促进细胞信息交换;不仅可以诱导肿瘤免疫性死亡,而且可以逆转肿瘤免疫抑制。此外,与天然巨噬细胞相似,其选择性地捕获和呈递肿瘤抗原以进行免疫激活。因此,纳米巨噬细胞成功地模拟了巨噬细胞的基本生物学功能,以建立全身抗肿瘤免疫。
(2)本发明创新地基于PAA-Ba以及硫化物的作用,能够调控核结构,诱导Zn-MOF的形成,另外,还能够利于抗原的捕获和呈递,改善免疫应答。
附图说明
图1为实施例1制得的PAA-BaSO4@ZIF-8纳米材料的透射电镜图(TEM图,上左图)、PPS缓冲液中处理后的材料的TEM图(上右图),以及X射线衍射图(XRD图,图1下图,其中,1为BaSO4,2为ZIF-8,3为PAA-BaSO4@ZIF-8纳米材料,4为PAA-BaSO4@ZIF-8纳米材料在PPS缓冲液中浸泡后的材料);
图2为实施例1制得的PAA-BaSO4@ZIF-8/TRF纳米材料在不同pH条件下离子释放检测结果;
图3为细胞层面抗肿瘤效果研究;
PAA-BaSO4@ZIF-8/TRF细胞毒性图:(a)blank control,(b)PAA-BaSO4@ZIF-8/TRF(60μg mL-1),(c)PAA-BaSO4@ZIF-8/TRF(90μg mL-1),(d)PAA-BaSO4@ZIF-8/TRF(150μg mL-1),(e)PAA-BaSO4@ZIF-8/TRF(150μgmL-1)+CQ(3μg mL-1)。
图4为动物层面体内肿瘤治疗效果研究;
不同条件下不同时间小鼠存活率图:(1)control,(2)BaSO4,(3)αPD-1,(4)ZIF-8/TRF,(5)PAA-BaSO4@ZIF-8,(6)PAA-BaSO4@ZIF-8/TRF,(7)ZIF-8/TRF+αPD-1,(8)PAA-BaSO4@ZIF-8/TRF+αPD-1.*p<0.05,**p<0.01(n=6)。
具体实施方式
下面结合具体的实施例对本发明作进一步说明。这些实施例应理解为仅用于说明本发明而不用于限制本发明的保护范围。在阅读了本发明记载的内容之后,基于本发明的原理对本发明所做出的各种改动或修改同样落入本发明权利要求书所限定。
本发明所述的PAA-BaSO4@ZIF-8/TRF纳米材料的制备方法,包括以下步骤:
首先将PAA加入Ba(OH)2·8H2O溶液中,搅拌,随后离心洗涤得到PAA-Ba;其次将PAA-Ba分散在水中与Na2S·9H2O溶液混合,搅拌,随后离心洗涤得到PAA-BaSO4;将PAA-BaSO4分散在异丙醇中,加入Zn(NO3)2·6H2O后与2-甲基咪唑溶液混合,搅拌,随后离心洗涤得到PAA-BaSO4@ZIF-8纳米材料;最后将PAA-BaSO4@ZIF-8纳米材料分散在水中,加入TRF,搅拌,随后离心洗涤得到PAA-BaSO4@ZIF-8/TRF纳米材料。
所述的制备方法,
所述PAA优选质量为1~10mg,优选质量为2~5mg;
所述Ba(OH)2·8H2O溶液优选浓度为0.5~2mg/ml,优选体积为20~100mL;
所述Na2S·9H2O溶液优选浓度为10~30mg/ml,优选体积为5~20mL;
所述PAA-BaSO4溶液优选浓度为0.5~3mg/ml,优选体积为10~50mL;
所述Zn(NO3)2·6H2O优选质量为5~30mg,优选质量为10~20mg;
所述2-甲基咪唑溶液优选浓度为50~100mM,优选体积为5~20mL;
所述TRF优选质量为1~30mg,优选质量为5~20mg;
所述PAA-BaSO4@ZIF-8优选浓度为0.5~3mg/ml,优选体积为10~30mL。
本发明中,可对制备的材料进行亲水聚合物包覆。
本发明中,可将所述的材料用于人造材料,用于识别和诱导肿瘤细胞的免疫应答。
本发明对肿瘤具有良好的普适性,例如,所述的肿瘤可以是良性和/或恶性肿瘤。
本发明中,可通过尾静脉注射的方法对小鼠进行施药。
例如,在使用过程中,可采用生理盐水对PAA-BaSO4@ZIF-8/TRF纳米球进行分散;将得到的分散溶液再通过静脉注射施药。优选的施药剂量为1.5~10mg kg1。每只施药对象(例如小鼠)优选施加PAA-BaSO4@ZIF-8/TRF纳米球的剂量为5mg kg-1。
实施例1
PAA-BaSO4@ZIF-8/TRF纳米球的制备:
首先将3.6mg PAA加入到50ml Ba(OH)2·8H2O(1mg mL-1)溶液中,搅拌30min,随后离心洗涤得到PAA-Ba;其次将PAA-Ba分散在50ml水中与10ml Na2S·9H2O(20mg mL-1)溶液混合,室温(20~35℃)搅拌7h,随后离心洗涤得到PAA-BaSO4;将20mg PAA-BaSO4分散在30ml异丙醇中,加入14.8mg Zn(NO3)2·6H2O后与10ml 2-甲基咪唑溶液(80mM)混合,搅拌,随后离心洗涤得到PAA-BaSO4@ZIF-8纳米材料;
最后将20ml PAA-BaSO4@ZIF-8纳米材料分散液(1mg mL-1)与10mg TRF混合,搅拌,随后离心洗涤得到PAA-BaSO4@ZIF-8/TRF纳米材料。
PAA-BaSO4@ZIF-8纳米材料的TEM以及XRD图;图2为PAA-BaSO4@ZIF-8/TRF纳米材料在pH为6.5的PPS缓冲液中浸泡3h后的材料的TEM图,可以看出其具有丰富的微观孔结构。
实施例2
PAA-BaSO4@ZIF-8/TRF纳米材料(实施例1制备)在细胞层面毒性的检测:
小鼠乳腺癌细胞4T1、小鼠胚胎成纤维细胞3T3和正常肝细胞L02在PAA-BaSO4@ZIF-8/TRF不同处理组下孵育相同时间,检测细胞活性
本发明人将相同浓度的不同处理组与不同细胞(每孔均为104个细胞,细胞购于湘雅医学院)孵育24h。不同处理组分别为:(a)blank control,(b)PAA-BaSO4@ZIF-8/TRF(60μg mL-1),(c)PAA-BaSO4@ZIF-8/TRF(90μg mL-1),(d)PAA-BaSO4@ZIF-8/TRF(150μg mL-1),(e)PAA-BaSO4@ZIF-8/TRF(150μgmL-1)+CQ(氯喹,3μg mL-1)。
由图3(b)可知将不同处理组的纳米材料和小鼠乳腺癌细胞及小鼠胚胎成纤维细胞和正常肝细胞进行孵育24h后,细胞活性发生了明显的变化,而与癌细胞共孵育24h后,细胞存活率低于30%,正常细胞存活率高于80%,说明纳米材料对癌细胞的杀伤能力非常强。
实施例3
PAA-BaSO4@ZIF-8/TRF纳米材料(实施例1制备)在动物层面抗肿瘤能力的检测:
以4T1细胞为模型细胞,BALB/C雌性小鼠为模型小鼠,构建肿瘤模型,采用本发明所提供的PAA-BaSO4@ZIF-8/TRF作为抗肿瘤材料。本实验设置8组实验组(每组6只小鼠):(1)control,(2)BaSO4,(3)αPD-1,(4)ZIF-8/TRF,(5)PAA-BaSO4@ZIF-8,(6)PAA-BaSO4@ZIF-8/TRF,(7)ZIF-8/TRF+αPD-1,(8)PAA-BaSO4@ZIF-8/TRF+αPD-1.*p<0.05,**p<0.01(n=6),将材料注入小鼠体内(5mg kg-1),连续观察监测60天。
由图4可知PAA-BaSO4@ZIF-8/TRF组小鼠存活率达到83%,表明PAA-BaSO4@ZIF-8/TRF具有优异的抗肿瘤效果。
Claims (24)
1.一种PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,其特征在于,包括PAA-BaSO4核,包覆在核上的Zn-MOF中间层,以及修饰在中间层上的转铁蛋白;
所述的PAA-BaSO4核包括PAA聚合骨架以及修饰在PAA聚合骨架上的BaSO4。
2.如权利要求1所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,其特征在于,所述的核中,PAA聚合骨架和BaSO4的重量比为1:5~50。
3.如权利要求2所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,其特征在于,所述的核中,PAA聚合骨架和BaSO4的重量比为1:10~20。
4.如权利要求1所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,其特征在于,所述的Zn-MOF为ZIF-8。
5.如权利要求1~4任一项所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,其特征在于,TRF的重量百分含量为10~40%,所述的Zn-MOF的重量含量为10~40%,余量为PAA-BaSO4。
6.如权利要求5所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,其特征在于,TRF的重量百分含量为25~35%,所述的Zn-MOF的重量含量为20~30%,余量为PAA-BaSO4。
7.如权利要求5所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,其特征在于,PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料的粒径为300~500 nm。
8.一种权利要求1~7任一项所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料的制备方法,其特征在于,步骤包括:
步骤(1):将PAA和Ba源复合进行络合,制得PAA-Ba;随后再将其和水溶性硫化物进行混合,反应得到PAA-BaSO4;所述的PAA和Ba源的重量比为1:5~50;所述的Ba源和水溶性硫化物的重量为1:1~10;
步骤(2):在PAA-BaSO4核上包覆Zn-MOF中间层,制得PAA-BaSO4@Zn-MOF中间产物;
步骤(3):在PAA-BaSO4@Zn-MOF中间产物上修饰TRF,制得所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料。
9.如权利要求8所述的制备方法,其特征在于,步骤(1)中,所述的Ba源为氢氧化钡。
10.如权利要求8所述的制备方法,其特征在于,所述的PAA和Ba源的重量比为1:10~15。
11.如权利要求8所述的制备方法,其特征在于,所述的水溶性硫化物为硫化钠、硫化钾中的至少一种。
12.如权利要求8所述的制备方法,其特征在于,Ba源和水溶性硫化物的重量比为1:3~6。
13.如权利要求8所述的制备方法,其特征在于,步骤(2)中,将制得的PAA-BaSO4分散在溶剂中,加入水溶性锌盐和MOF配体,进行配位反应,在PAA-BaSO4上沉积Zn-MOF材料,制得PAA-BaSO4@Zn-MOF。
14.如权利要求13所述的制备方法,其特征在于,所述的MOF配体为2-甲基咪唑。
15.如权利要求13所述的制备方法,其特征在于,所述的水溶性锌盐和MOF配体的摩尔比为1:10~40。
16.如权利要求13所述的制备方法,其特征在于,所述的PAA-BaSO4和水溶性锌盐的重量比为1:0.1~1。
17.如权利要求8所述的制备方法,其特征在于,步骤(3)中,将PAA-BaSO4@Zn-MOF和TRF进行液相混合,组装修饰,制得所述的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料。
18.如权利要求17所述的制备方法,其特征在于,所述的PAA-BaSO4@Zn-MOF和TRF的重量比为1:0.1~1。
19.如权利要求17所述的制备方法,其特征在于,所述的PAA-BaSO4@Zn-MOF和TRF的重量比为1:0.4~0.6。
20.一种权利要求1~7任一项所述PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料或权利要求8~19任一项制备方法制得的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料在制备抗肿瘤药物中的应用,其特征在于,所述的抗肿瘤药物为抗乳腺癌药物。
21.一种抗肿瘤药物,其特征在于,包含药学有效量的权利要求1~7任一项所述PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料或权利要求8~19任一项制备方法制得的PAA-BaSO4@Zn-MOF/TRF复合人造纳米巨噬细胞材料,所述的抗肿瘤药物为抗乳腺癌药物。
22.如权利要求21所述的抗肿瘤药物,其特征在于,所述的抗肿瘤药物还包括药学上可接受的辅料。
23.如权利要求21所述的抗肿瘤药物,其特征在于,所述的抗肿瘤药物具有药学上可接受的剂型。
24.如权利要求23所述的抗肿瘤药物,其特征在于,所述的抗肿瘤药物为注射制剂。
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