CN110292641B - 一种磁热触发级联酶反应超分子凝胶及其制备方法和应用 - Google Patents
一种磁热触发级联酶反应超分子凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种磁热触发级联酶反应超分子凝胶及其制备方法和应用,制备包括:富含氧气的PFOB纳米乳和包载葡萄糖的PLGA纳米囊混合形成溶液A;在Fe3O4@PEI溶液加入α‑环糊精、葡萄糖氧化酶和甘露醇得到溶液B;将溶液A和B混合得到磁热触发级联酶反应超分子凝胶。本发明制备的凝胶具有剪切变稀可注射和温敏可逆相转变的性质,其多级结构可携带葡萄糖、氧气、葡萄糖氧化酶和甘露醇,该凝胶注射至肿瘤组织,四氧化三铁纳米颗粒在交变磁场下产热使肿瘤组织升温并促进凝胶液化弥散填充肿瘤细胞间隙,同时四氧化三铁纳米颗粒作为类过氧化物酶参与后续级联酶反应产生自由基ROS,发挥磁感应热疗和纳米酶催化治疗双重功效。
Description
技术领域
本发明属于生物与医学纳米材料及技术领域,具体涉及一种磁热触发级联酶反应超分子凝胶及其制备方法和应用。
背景技术
磁感应热疗作为新型肿瘤治疗策略,为肿瘤治疗带来了新突破,尤其是基于磁性纳米材料的磁感应热疗,它利用磁性纳米颗粒为磁介质,以静脉注射或原位介入等方式进入肿瘤组织后,在外加交变磁场的作用下,磁介质由于尼尔弛豫(Néel Relaxation) 和布朗弛豫(Brownian Relaxation)等效应而发热,使肿瘤组织快速达到一定的温度而杀灭或诱导肿瘤细胞凋亡,并且磁场穿透深度强,副作用小,更适合深部肿瘤组织治疗与临床转化。肿瘤组织温度达到50度以上的磁感应热消融治疗时间短,治疗效果好,却也容易对周围正常组织带来损伤。因此,进一步探索常规温热疗法下肿瘤治疗新方法至关重要。
肿瘤组织通常具有复杂的生物微结构和特定微环境。肿瘤微环境(TME)表现出许多独有的特征。 比如由于肿瘤细胞的快速代谢及代谢产物乳酸的过量产生,使得TME通常具有温和的酸性条件(酸中毒);癌细胞中的细胞内谷胱甘肽(GSH)浓度约是正常细胞内的4倍;癌细胞和肿瘤组织中不完整血管的快速生长导致实体瘤内为缺氧环境。 此外,由于癌细胞的快速代谢和血液供应不足,肿瘤内的H2O2水平升高并过度表达。以肿瘤微环境为靶点的肿瘤治疗一直是研究热点并不断取得突破。比如肿瘤酸性环境响应的酸敏感药物释放,过氧化氢通过歧化反应产生ROS破坏肿瘤组织等。
作为生物医用纳米材料临床转化的典型代表,磁性四氧化三铁纳米颗粒除了在肿瘤磁感应热疗、磁共振成像、药物载体和体外磁分离等领域的广泛应用,科学家还发现了其全新的功能,氧化铁纳米颗粒具有类似天然酶的催化能力,继而开辟了纳米酶这一新兴领域。氧化铁纳米粒子在体外和体内以pH依赖性方式表现出双酶活性,在中性或碱性pH条件下将H2O2催化分解成无毒的H2O和O2,呈现出过氧化氢酶的活性清除ROS;在酸性条件下,可以催化H2O2发生歧化反应产生高毒性的活性氧自由基(·OH),显示出类过氧化物酶的活性。因此,氧化铁纳米颗粒被认为是潜在的可治疗肿瘤的纳米酶。
发明内容
发明目的:针对现有技术中基于氧化铁纳米颗粒的磁感应热疗中存在的问题,本发明提供一种磁热触发级联酶反应超分子凝胶及其制备方法和应用,本发明制备的磁热触发级联酶反应超分子凝胶是一种磁热响应的智能超分子凝胶,该凝胶可在肿瘤磁热疗的基础上进一步提升肿瘤组织氧化还原水平,并使之超越阈值而达到促氧化治疗的目的,以单一磁性纳米颗粒发挥磁热和纳米酶双重功效来协同治疗肿瘤。
本发明制备得到的凝胶可以应用在制备抗肿瘤药物中,该凝胶被注射至肿瘤组织,四氧化三铁磁性纳米颗粒在交变磁场下产热启动连锁治疗模式,磁热首先对肿瘤组织给予温热治疗,同时促进凝胶液化弥散填充肿瘤细胞间隙,接着,四氧化三铁磁性纳米颗粒作为类过氧化物酶参与后续级联酶反应产生自由基ROS杀伤肿瘤细胞,为实体肿瘤新型协同治疗提供了新的产品和方法。
技术方案:为了实现上述目的,如本发明所述的一种磁热触发级联酶反应超分子凝胶(MHZ)的制备方法,包括如下步骤:
(1)用二硬脂酰磷脂酰乙醇胺-甲氧基聚乙二醇(DSPE-MPEG2000)制备富含氧气的全氟溴辛烷(PFOB)纳米乳,聚乳酸-羟基乙酸共聚物-甲氧基聚乙二醇(PLGA11K -MPEG5K)制备包载葡萄糖(Glucose)的聚乳酸-羟基乙酸共聚物(PLGA)纳米囊,两者混合形成溶液A;
(2)用聚乙烯亚胺(PEI)修饰四氧化三铁(Fe3O4)纳米颗粒得到Fe3O4@PEI溶液,并将α-环糊精(α-CD)、葡萄糖氧化酶(GOD)和甘露醇(D-Mannitol)加入其中,混匀溶解,得到溶液B;
(3)将溶液A和溶液B混合,搅拌均匀,室温静置,得到磁热触发级联酶反应超分子凝胶(MHZ)。
作为优选,步骤(1)所述二硬脂酰磷脂酰乙醇胺-甲氧基聚乙二醇(DSPE-MPEG2000)在溶液A中的终浓度为50~100mg/mL;全氟溴辛烷(PFOB)在溶液A中的终体积百分数为10%~30%。
作为优选,步骤(1)所述的聚乳酸-羟基乙酸共聚物-甲氧基聚乙二醇(PLGA11K -MPEG5K)在溶液A中的终浓度为100~300mg/mL,葡萄糖(Glucose)在溶液A中的终浓度为1~5mg/mL。
作为优选,步骤(1)所述的PFOB纳米乳和PLGA纳米囊按体积比1:1~3:1混合形成溶液A。
作为优选,步骤(2)所述的四氧化三铁(Fe3O4)纳米颗粒尺寸在5~50纳米之间,B溶液中铁元素含量1~8mg/mL。
作为优选,步骤(2)所述的聚乙烯亚胺(PEI)与四氧化三铁纳米颗粒质量比为1:1~5:1。
作为优选,步骤(2)所述溶液B中的α-CD浓度为100~300mg/mL、GOD浓度为1~5mg/mL, D-Mannitol浓度为1~3mg/mL。
进一步地,步骤(3)所述的溶液A和溶液B混合,其混合的体积比例为3:1~0.5:1,搅拌均匀后,室温静置时间为10s~30min。
本发明所述磁热触发级联酶反应超分子凝胶的制备方法所制备的磁热触发级联酶反应超分子凝胶。
本发明所述磁热触发级联酶反应超分子凝胶的制备方法所制备的磁热触发级联酶反应超分子凝胶在制备抗肿瘤药物中的应用。
本发明中所使用的二硬脂酰磷脂酰乙醇胺-甲氧基聚乙二醇(DSPE-MPEG2000);聚乳酸-羟基乙酸共聚物-甲氧基聚乙二醇(PLGA11K -MPEG5K);聚乙烯亚胺(PEI,MW=10000);全氟溴辛烷(PFOB);聚乙烯亚胺(PEI);四氧化三铁(Fe3O4)纳米颗粒;α-环糊精;葡萄糖氧化酶;甘露醇等原料均可市售获得。
本发明将聚乙二醇(PEG2000)修饰的全氟溴辛烷(PFOB)纳米乳、聚乳酸-羟基乙酸共聚物-聚乙二醇(PLGA-PEG)纳米囊与分散有磁性四氧化三铁纳米颗粒的α-环糊精(α-CD)水溶液以一定比例混合,搅拌均匀,室温静置,即获得超分子凝胶;其成胶机理为纳米颗粒表面的PEG链可以穿过α-环糊精的内部空腔形成项链式串珠模式,环糊精之间通过氢键相互作用形成凝胶基本结点,进而促进整个体系成胶。
本发明制备的磁热触发级联酶反应超分子凝胶,其设计思路为以介入方式将其注射至肿瘤组织内,通过施加交变磁场,四氧化三铁磁性纳米颗粒通过弛豫效应将磁能转化为热能,凝胶升温至相变温度42℃,热疗作用的同时,促进凝胶均匀扩散至肿瘤组织间隙,D-Mannitol可通过使细胞脱水作用进一步增强纳米颗粒在肿瘤细胞间隙的扩散能力,凝胶水相中负载的GOD和肿瘤组织中丰富的葡萄糖分子及PLGA纳米囊中包裹的可缓慢释放的Glucose反应生成H2O2,外加肿瘤组织本身较高浓度的过氧化氢,在肿瘤组织酸性环境下,氧化铁纳米颗粒发挥类过氧化物酶性质,通过芬顿反应催化过氧化氢产生羟自由基杀伤肿瘤细胞,携氧的PFOB纳米乳可改善肿瘤组织乏氧环境,进一步缓解肿瘤恶性程度。此外,本发明制备的磁热触发级联酶反应超分子凝胶在肿瘤的轻度酸性微环境下特异性产生的羟基自由基诱导快速的脂质和蛋白质氧化和DNA损伤,进一步引起癌细胞的凋亡和死亡,而正常细胞不受伤害。
有益效果:与现有技术相比,本发明具有如下有益效果:
本发明中制备的磁热触发级联酶反应超分子凝胶(MHZ),其制备优势为通过双乳化法制备了表面PEG化,中心载有Glucose的PLGA纳米囊,超声破碎法制备了DSPE-MPEG为表面活性剂,携氧PFOB为油相的纳米乳;α-CD的引入,与PEG分子通过氢键等相互作用获得凝胶结点,该制备方法操作简便,绿色易重复,室温静置即可快速成胶。PEI修饰的具有较大比表面积的四氧化三铁纳米颗粒的引入赋予凝胶磁性,同时可发挥四氧化三铁纳米颗粒在酸性条件下类过氧化物酶的特性。本发明制备的磁热触发级联酶反应超分子凝胶本身所具备的优势为,在室温时,为剪切变稀可注射凝胶,当达到相转变温度时,即可实现固液转变开始流动,并且这个过程是可逆的,反复多次不出现明显异常。该凝胶多级结构可携带葡萄糖(Glucose)、氧气、葡萄糖氧化酶(GOD)和甘露醇(D-Mannitol);
本发明在应用中将MHZ通过注射器注射至肿瘤组织内,将肿瘤部位置于交变磁场线圈内,施加交变磁场,四氧化三铁磁性纳米颗粒升温至凝胶相变温度42℃,肿瘤组织得到常规温热疗的同时凝胶液化促进四氧化三铁纳米颗粒、PFOB纳米乳、PLGA纳米囊和凝胶中负载的GOD在肿瘤细胞间隙扩散,凝胶中负载的D-Mannitol也促进了凝胶的扩散;此时,GOD和肿瘤组织中富含及PLGA中缓慢释放的葡萄糖反应生成H2O2,外加肿瘤组织本身较高浓度的H2O2,Fe3O4颗粒在肿瘤微酸性环境中发挥模拟酶功效,通过芬顿反应催化H2O2产生·OH,使肿瘤组织超越可耐受氧化还原阈值。热疗升温促进Fe3O4纳米酶酶活性增强而产生更多·OH,·OH进一步损伤热疗中高表达的热休克蛋白HSP 70等,使得热疗效果提升,同时携氧的PFOB纳米乳可改善肿瘤组织乏氧环境,进一步缓解肿瘤恶性程度。基于磁性纳米颗粒的磁感应热疗和促氧化协同治疗使得肿瘤治疗效果显著,42°C温热疗即可消退小鼠乳腺癌皮下瘤。本发明中磁性氧化铁颗粒发挥双重功效来损伤肿瘤细胞,为肿瘤热疗注入了新鲜血液。
附图说明
图1为磁热触发级联酶反应超分子凝胶基本组成部分示意图及应用过程说明图;
图2为磁热触发级联酶反应超分子凝胶基本成分的表征;其中,图2a为双乳化法制备载葡萄糖分子的MPEG化PLGA纳米囊透射电镜图,图2b为超声破碎法制备全氟溴辛烷携氧纳米乳透射电镜图,图2c为高温热分解法合成的有机相四氧化三铁纳米颗粒透射电镜图,图2d为凝胶实物图,图2e为凝胶的SEM形貌观察图;
图3磁热触发级联酶反应超分子凝胶基本性能的表征,其中,图3a为凝胶成胶机理XRD表征图谱,图3b为凝胶粘度随温度变化图,图3c为凝胶模量随温度变化图,图3d为凝胶磁感应升温曲线图;
图4为磁热触发级联酶反应超分子凝胶酶学性能检测图,其中,图4a表示不同温度下MHZ产生羟自由基催化能力的比较,图4b模拟在肿瘤被热疗42度PH=4.8条件下催化能力随时间变化曲线;
图5是不同实验组分类情况示意图,分别为磁性凝胶治疗组,单纯氧化铁纳米酶治疗组,单纯热疗组,和空白对照组;
图6为不同实验组治疗效果图,图6a为四周后肿瘤组织拍照图,图6b为各个组对应的HE染色图,图6c为不同实验组热休克蛋白HSP70检测图。
具体实施方式
以下结合实施例和附图作进一步说明。
本发明磁热触发级联酶反应超分子凝胶的制备方法的主要步骤是:用二硬脂酰磷脂酰乙醇胺-甲氧基聚乙二醇(DSPE-MPEG2000)制备富含氧气的PFOB纳米乳,聚乳酸-羟基乙酸共聚物-甲氧基聚乙二醇(PLGA11K -MPEG5K)制备包载葡萄糖(Glucose) 的PLGA纳米囊,两者混合形成溶液A;用聚乙烯亚胺(PEI)修饰高温热分解法合成的四氧化三铁纳米颗粒得到Fe3O4@PEI溶液,并将α-环糊精(α-CD)、葡萄糖氧化酶(GOD)和甘露醇(D-Mannitol)加入其中,涡旋混匀溶解,得到溶液B;将溶液A和溶液B以一定比例混合,搅拌均匀,室温静置,得到磁性超分子凝胶。
图1中,在室温及小鼠体温37℃时,磁热触发级联酶反应超分子凝胶因剪切变稀可注射性质而可以被注射,并可以其粘滞性停留在肿瘤组织内;当凝胶温度因磁性纳米颗粒产热热达到相转变温度时,凝胶即可实现固液转变开始流动,并在肿瘤组织间隙扩散,凝胶中负载的葡萄糖氧化酶和PLGA纳米囊中包裹的葡萄糖等也开始扩散,并启动后续级联酶反应产生羟自由基,和磁热结合联合治疗肿瘤。
实施例1
双乳溶剂蒸发法制备载葡萄糖PLGA纳米囊
3mg葡萄糖加入250微升超纯水中,超声溶解充分混匀,将其作为内水相; 300mgPLGA11K-MPEG5K粉末加入到5ml氯仿中,超声使之溶解,并作为油相;准备1.0% (w/v, g/mL) PVA溶液15 mL作为外水相。将内水相加入油相内,冰浴80W超声30s,获得初乳。将初乳加入15ml 1% PVA中,80W 冰浴超声2min,形成水包油包水复乳体系。混合液加入250ml0.3% PVA中,500r/min搅拌3h, 使氯仿缓慢挥发。收集反应溶液,10000r/min 离心洗涤2次去除多余PVA,纯水定容至1.5mL于4℃保存。
图2a为上述方法制备得到的载葡萄糖PLGA纳米囊透射电镜负染图,纳米囊平均尺寸50纳米,形貌良好,球形度高,尺寸均一,其疏水PLGA壳层为8纳米左右,中间为载药水相。
实施例2
超声分散法制备携氧PFOB纳米乳
在100mL三颈瓶中加入20毫升超纯水作为水相,300毫克DSPE-MPEG2000作为表面活性剂加入到水相中,油浴加热水相使之温度升至100℃,并以600r/min速率搅拌,此时逐滴加入0.9mLPFOB作为油相,关闭热源,继续搅拌30min获得纳米乳,30K超滤管超滤离心浓缩至1.5mL体积,4℃保存。
图2b为PFOB携氧纳米乳透射电镜负染图,纳米乳呈球形,尺寸在30-50纳米之间,分散良好。
实施例3
高温热分解法制备四氧化三铁纳米颗粒及其表面PEI修饰
实验装置为在100毫升斜口三颈烧瓶和程序控温装置,向三颈瓶中加入铁前驱物乙酰丙酮铁2mmol,反应溶剂二苄醚20mL,表面活性剂油酸和油胺总共12mmol。程序控温以3.3℃/min的加热速率使反应体系升温至220℃,纳米颗粒成核持续一小时,之后,仍以3.3℃/min的加热速率升温到290℃纳米颗粒生长温度并持续30min。实验过程中持续通入氮气以去除体系中的氧气并起到搅拌作用,同时冷凝回流。待反应结束,移去热源,待反应体系自然冷却至室温后转移至烧杯中,无水乙醇磁分离进行洗涤三次,去除溶液中残留的油酸、油胺、二苄醚和未反应完全的前驱物,最后将磁性四氧化三铁纳米颗粒定容于三氯甲烷中保存。首先利用二巯基丁二酸(DMSA)通过配体交换法取代纳米颗粒表面油酸油胺,使之亲水,再通过静电吸附法将不同质量比带正电荷的聚乙烯亚胺(PEI)修饰在纳米颗粒表面,得到Fe3O4@PEI胶体溶液。
图2c为有机相氧化铁纳米颗粒透射电镜图,纳米颗粒平均尺寸为8纳米,颗粒大小均一,形貌球形,分散良好。
实施例4
磁热触发级联酶反应超分子凝胶将实施例1中制得的载葡萄糖PLGA纳米囊与实施例2中所得携氧PFOB纳米乳按1:1体积混合为溶液A,其中,PFOB其体积百分数为30%,DSPE-MPEG2000的浓度为100mg/mL,PLGA11K -MPEG5K的浓度为100mg/mL,Glucose用量为1mg/mL。实施例3中所得PEI修饰的5nm四氧化三铁纳米颗粒(mPEI:mFe=5:1)与α-环糊精(α-CD)、葡萄糖氧化酶(GOD)和甘露醇(D-Mannitol)混合为溶液B,其中α-CD浓度为100mg/mL,GOD浓度为1mg/mL,D-Mannitol浓度为1mg/mL,铁元素含量1mg/ml。溶液A和溶液B混合,其混合的体积比例为3:1,搅拌均匀后,室温静置时间范围30min,得到磁热触发级联酶反应超分子凝胶。
实施例5
磁热触发级联酶反应超分子凝胶以实施例1中所述方法制备各组分比例与实施例1不同的载葡萄糖PLGA纳米囊,以实施例2中所述方法制备各组分比例与实施例2不同的携氧PFOB纳米乳,将二者按2:1体积混合为溶液A,其中,PFOB其体积百分数为20%, DSPE-MPEG2000的浓度为80mg/mL,PLGA11K -MPEG5K的浓度为200mg/mL,Glucose用量为3mg/mL。实施例3中所得PEI修饰的50nm四氧化三铁纳米颗粒(mPEI:mFe=1:1)与α-环糊精(α-CD)、葡萄糖氧化酶(GOD)和甘露醇(D-Mannitol)混合为溶液B,其中α-CD浓度为200mg/mL,GOD浓度为4mg/mL,D-Mannitol浓度为3mg/mL,铁元素含量8mg/ml。溶液A和溶液B混合,其混合的体积比例为2:1,搅拌均匀后,室温静置时间范围5min,得到磁热触发级联酶反应超分子凝胶。
实施例6
磁热触发级联酶反应超分子凝胶以实施例1中所述方法制备各组分比例与实施例1不同的载葡萄糖PLGA纳米囊,以实施例2中所述方法制备各组分比例与实施例2不同的携氧PFOB纳米乳,将二者按3:1体积混合为溶液A,其中,PFOB其体积百分数为10%,DSPE-MPEG2000的浓度为50mg/mL,PLGA11K -MPEG5K的浓度为300mg/mL,Glucose用量为5mg/mL。实施例3中所得PEI修饰的8nm四氧化三铁纳米颗粒(mPEI:mFe=3:1)与α-环糊精(α-CD)、葡萄糖氧化酶(GOD)和甘露醇(D-Mannitol)混合为溶液B,其中α-CD浓度为300mg/mL,GOD浓度为5mg/mL,D-Mannitol浓度为2mg/mL,铁元素含量6mg/ml。溶液A和溶液B混合,其混合的体积比例为0.5:1,搅拌均匀后,室温静置时间范围10s,得到磁热触发级联酶反应超分子凝胶。
图2d为凝胶合成过程样品展示图,将溶液A与溶液B混匀,静置之后即得到可注射器注射的磁性超分子凝胶。图2e中,磁性超分子凝胶被冷冻干燥,然后用扫描电子显微镜观察其结构,发现其结构为经典的网络多孔凝胶状。EDX元素分析发现,铁元素均匀分布在凝胶之中。图3a XRD检测发现凝胶的2θ值在19.7°,证明其凝胶结点为α-CD和PEG链结合形成凝胶。图3b MHZ的粘度随温度变化曲线发现42℃时粘度出现最低拐点,图3c模量随温度变化曲线发现42度时储存模量G"大于弹性模量G',表示42℃为相变点。图3d升温曲线显示出凝胶的环境并未对磁性纳米颗粒升温产生明显影响。图4a为不同温度下,磁性凝胶催化过氧化氢氧化TMB变色吸光度比较,升温对于酶催化增强效果显著,图4b为42°C,PH=4.8的条件下,磁性凝胶中GOD氧化PLGA纳米囊中葡萄糖,产生过氧化氢,进而被氧化铁催化去氧化TMB变蓝的吸光度随时间变化图,上述检测均为为实施例6制备的凝胶。
实施例7
磁热触发级联酶反应超分子凝胶多功能协同治疗肿瘤
选取肿瘤体积约为50立方毫米的4T1荷瘤小鼠,用5%(w/v,g/mL)水合氯醛将其麻醉,将实施例6制备的凝胶(MHZ)通过注射器注射至肿瘤组织内,然后将小鼠置于交变磁场线圈之中,尽量确保肿瘤部位在线圈中央,施加条件为410kHz,1.8kA/m的交变磁场15min,磁性纳米颗粒升温至凝胶相变温度42℃,此时凝胶液化,促进纳米颗粒和凝胶中负载的GOD在肿瘤细胞间隙扩散,凝胶中负载的甘露醇通过使细胞脱水扩大细胞间隙,增加纳米颗粒在肿瘤细胞间隙的渗透性;此时,GOD和肿瘤组织中富含及PLGA中缓慢释放的葡萄糖反应生成H2O2,与肿瘤组织本身较高浓度的H2O2叠加,Fe3O4颗粒在肿瘤微酸性环境中发挥类过氧化物酶功效,通过亚铁离子和铁离子参与的芬顿反应催化H2O2产生·OH。同时,热疗升温促进Fe3O4纳米酶酶活性增强而产生更多·OH,·OH进一步损伤热疗中高表达的热休克蛋白HSP70等。治疗结束后,每天监测治疗后小鼠的生命体征,体重,肿瘤复发情况,并记录生存期,观察治疗效果及愈后情况。基于磁性纳米颗粒的磁感应热疗和促氧化协同治疗使得肿瘤治疗效果显著,42°C温热疗即可消退小鼠乳腺癌皮下瘤。
图5为不同实验组实验过程图,MHZ组(实施例6制备)磁热疗和促氧化治疗同时进行;对照组1为单纯促氧化治疗,其操作过程为注射实施例6制备的凝胶,不施加交变磁场,单纯依赖氧化铁纳米颗粒的纳米酶效应来提升肿瘤组织氧化还原水平;对照组2为单纯磁热疗,其所用凝胶为实施例6制备,其中,凝胶不加葡萄糖氧化酶,使得过氧化氢水平不足以触发氧化铁的纳米酶反应,导致实验组中级联酶反应难以启动,只显示磁热的效果;对照组3空白对照组,只注射生理盐水。施加交变磁场,MHZ组和对照组2的肿瘤升温至42℃,此过程中升温5分钟,维持十分钟。
图6为用实施例6制备的凝胶对小鼠治疗后肿瘤情况观察及病理组织分析。通过观察发现,治疗后三十天,实验组小鼠肿瘤已经消退,三个对照组出现不同情况的复发,HE染色从病理学角度印证了治疗效果;同时对单纯热疗组和实验组及对照组进行了热休克蛋白HSP70表达检测,经过分析发现,单纯热疗组表达量最高,实验组次之,空白对照组最少,这也证明了实验组中ROS的产生对热休克蛋白的表达产生了抑制作用,使得热疗效果更加明显,加上磁热促进纳米酶催化过氧化氢产生ROS,实验组表现出磁热疗和纳米酶促氧化治疗的协同作用。图5和图6说明了磁热触发级联酶反应超分子凝胶可以消退肿瘤,而单纯的42℃热疗只能维持肿瘤体积不过快增长。
Claims (10)
1.一种磁热触发级联酶反应超分子凝胶的制备方法,其特征在于,包括如下步骤:
(1)用二硬脂酰磷脂酰乙醇胺-甲氧基聚乙二醇制备富含氧气的全氟溴辛烷纳米乳,聚乳酸-羟基乙酸共聚物-甲氧基聚乙二醇制备包载葡萄糖的聚乳酸-羟基乙酸共聚物纳米囊,两者混合形成溶液A;
(2)用聚乙烯亚胺(PEI)修饰四氧化三铁(Fe3O4)纳米颗粒得到Fe3O4@PEI溶液,并将α-环糊精、葡萄糖氧化酶和甘露醇加入其中,混匀溶解,得到溶液B;
(3)将溶液A和溶液B混合,搅拌均匀,室温静置,得到磁热触发级联酶反应超分子凝胶。
2.根据权利要求1所述磁热触发级联酶反应超分子凝胶的制备方法,其特征在于,步骤(1)所述二硬脂酰磷脂酰乙醇胺-甲氧基聚乙二醇在溶液A中的终浓度为50~100mg/mL,PFOB在溶液A中的终体积百分数为10%~30%。
3.根据权利要求1所述磁热触发级联酶反应超分子凝胶的制备方法,其特征在于,步骤(1)所述的聚乳酸-羟基乙酸共聚物-甲氧基聚乙二醇在溶液A中的终浓度为100~300mg/mL,葡萄糖在溶液A中的终浓度为1~5mg/mL。
4.根据权利要求1所述磁热触发级联酶反应超分子凝胶的制备方法,其特征在于,步骤(1)所述的全氟溴辛烷纳米乳和聚乳酸-羟基乙酸共聚物纳米囊按体积比1:1~3:1混合形成溶液A。
5.根据权利要求1所述磁热触发级联酶反应超分子凝胶的制备方法,其特征在于,步骤(2)所述的四氧化三铁纳米颗粒尺寸在5~50纳米之间,B溶液中铁元素含量1~8mg/mL。
6.根据权利要求1所述磁热触发级联酶反应超分子凝胶的制备方法,其特征在于,步骤(2)所述的聚乙烯亚胺与四氧化三铁纳米颗粒质量比为1:1~5:1。
7.根据权利要求1所述磁热触发级联酶反应超分子凝胶的制备方法,其特征在于,步骤(2)所述溶液B中α-环糊精浓度为100~300mg/mL、葡萄糖氧化酶浓度为1~5mg/mL,甘露醇浓度为1~3mg/mL。
8.根据权利要求1所述磁热触发级联酶反应超分子凝胶的制备方法,其特征在于,步骤(3)所述的溶液A和溶液B混合,其混合的体积比例为3:1~0.5:1,搅拌均匀后,室温静置时间为10s~30min。
9.一种权利要求1-8任一所述磁热触发级联酶反应超分子凝胶的制备方法所制备的磁热触发级联酶反应超分子凝胶。
10.一种权利要求1-8任一所述磁热触发级联酶反应超分子凝胶的制备方法所制备的磁热触发级联酶反应超分子凝胶在制备抗肿瘤药物中的应用。
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