CN107137357B - 用于调节免疫反应的介孔二氧化硅组合物 - Google Patents
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- CN107137357B CN107137357B CN201710148982.2A CN201710148982A CN107137357B CN 107137357 B CN107137357 B CN 107137357B CN 201710148982 A CN201710148982 A CN 201710148982A CN 107137357 B CN107137357 B CN 107137357B
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Abstract
一种组合物包括介孔二氧化硅棒，所述介孔二氧化硅棒包括免疫细胞募集化合物和免疫细胞活化化合物，以及任选的包括抗原，例如肿瘤抗原溶解产物。该组合物用于引发对疫苗抗原的免疫反应。
Description
本申请是2013年04月16日递交的申请号为 201380019880.0，发明名称为“用于调节免疫反应的介孔二氧化硅组合物”的分案申请。
政府支持
本申请具有政府支持，由国家健康研究院授权的第 R01DE019917号权利支持。政府享有本发明的某些权利。
技术领域
本发明涉及生物相容性可注射性组合物。
背景技术
需要体外操作的疫苗，例如大多数基于细胞的治疗，会导致不理想的淋巴结定位以及有限的效力。
发明内容
本发明为现有方法中相关的一些问题和缺陷提供了一种解决方案。因此，本发明的特点在于一种组合物，所述组合物包括介孔二氧化硅(MPS)棒，所述介孔二氧化硅(MPS)棒包括一种免疫细胞募集化合物和一种免疫细胞活化化合物。所述棒包括直径在2-50纳米之间的孔，例如，直径在5-25纳米之间的孔或者直径在5-10纳米之间的孔。在优选的实施方案中，所述棒包括直径大约为8纳米的孔。微棒的长度在5微米到500微米之间。在一个实施例中，所述棒的长度为5-25微米，例如，10-20微米。在其他实施例中，所述棒的长度为50微米-250微米。使用介孔二氧化硅(MPS)微颗粒组合物可以实现细胞的稳固的募集，所述介孔二氧化硅(MPS)微颗粒组合物的特点在于具有较高的宽高比，例如，所述棒的长度为80微米到120微米。
示例性的免疫细胞募集化合物包括粒细胞巨噬细胞-菌落刺激因子(GM-CSF)。其他募集化合物的实施例包括趋化因子，例如，选自由趋化因子(C-C基序)配位体21(CCL-21,基因银行编目号:(aa)CAG29322.1(01:47496599),(na)EF064765.1 (01:117606581),通过引证在此并入本文)，趋化因子(C-C基序)配位体19(CCL-19,基因银行编目号:(aa)CAG33149.1 (01:48145853),(na)NM_006274.2(01:22165424),通过引证在此并入本文)，以及FMS-样酪氨酸激酶3配位体(Flt3)配位体；基因银行编目号:(aa)AAI44040(01:219519004),(na) NM_004119(01:01:121114303)通过引证在此并入本文)所组成的组中。
免疫细胞活化化合物包括Toll样受体激动剂。这种激动剂包括病原相关分子模型(PAMP)，例如，一种感染-模拟组合物，例如，细菌衍生的免疫调节剂(也叫做危险信号)。Toll样受体 (TLR)激动剂包括核酸或者脂类组合物(例如，单磷酸脂A (MPLA))。在一个实施例中，Toll样受体(TLR)激动剂包括TLR9激动剂，例如，一种胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)、一种聚(氮丙啶)(PEI)-浓缩的低聚核苷酸 (ODN)(例如，聚(氮丙啶)(PEI)-胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN))、或者双链脱氧核糖核酸(DNA)。例如，所述装置包括5微克、10微克、25微克、50微克、100微克、 250微克或者500微克的胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)。在另一个实施例中，Toll样受体(TLR)激动剂包括TLR3激动剂，例如，聚肌苷-聚胞苷酸(聚I:C)、一种聚(氮丙啶)(PEI) -聚(I:C)、聚腺尿苷酸(聚(A:U))、聚(氮丙啶)(PEI) -聚(A:U)、或者双链核糖核酸(RNA)。
脂多糖(LPS)同样可以用于实现此目的。
为了产生免疫反应，所述组合物包括此免疫反应所需要的抗原。例如，所述组合物包括肿瘤抗原。在优选的实施方案中，所述抗原包括一种肿瘤细胞溶解产物(例如，从被治疗的主体中收集的肿瘤活组织切片样品中提取的)。所述主体优选是人类患者，但是所述组合物/系统还可以用于兽医用途，例如，用于治疗功能性动物，比如狗、猫以及性能动物，例如，马和家畜，比方说家牛、公牛、羊、山羊，等。
抗原递呈细胞，比如树突状细胞(DC)，通过介孔二氧化硅 (MPS)装置，那就是说，细胞不是永久居住在装置中。向装置中募集免疫细胞，并且使其短时间内居住在装置中，当他们遇到抗原时被活化。然后免疫细胞(比如树突状细胞(DC))定位向淋巴结。他们聚集在淋巴结处，例如，一种引流淋巴结，而不是在介孔二氧化硅(MPS)装置中。在淋巴结处聚集的细胞进一步增加了对疫苗抗原的免疫反应，产生更有力的针对该抗原的细胞反应和体液反应。
因此，一种诱导对疫苗产生全身性抗原特异性免疫反应的方法包括对主体施用如上所述的介孔二氧化硅(MPS)组合物。所述组合物被装入注射器并注入受试者的身体中。例如，少量(例如，50-500微升，例如，150微升)进行皮下注射。一般地，在施用后第2天，使用细胞渗透所述装置(介孔二氧化硅(MPS) 组合物)，并在施用后第5-7天，引流淋巴结中充满从装置中迁移出来的细胞和迁移到淋巴结组织中的细胞，这些细胞在此聚集并进一步的传播抗原-特异性反应。因此，所述组合物可以有效用于诱导免疫细胞向淋巴结的定位。在接种疫苗治疗剂之后，不比去除所述介孔二氧化硅(MPS)组合物。这些组合物可以在施用位点处保存，并在此降解。例如，通过巨噬细胞随着时间来消耗介孔二氧化硅(MPS)颗粒，并直至从身体内清除。
制备疫苗的方法包括，提供一种介孔二氧化硅棒悬浮液，将所述棒与疫苗抗原、免疫细胞募集化合物和免疫细胞活化化合物相接触。所述疫苗抗原一种肿瘤细胞溶解产物，所述募集化合物包括粒性白细胞巨噬细胞集落刺激因子(GM-CSF)，并且所述活化化合物包括胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)。有时候，在将所述棒与一个或一个以上下列化合物相接触之前用羟基乙酸或者乳酸修饰所述棒：疫苗抗原、募集化合物或者活化化合物。选择性的，所述介孔二氧化硅(MPS)组合物/装置是使用介孔二氧化硅(MPS)棒、一种免疫细胞募集化合物和一种免疫细胞活化化合物(选择性地，与羟基乙酸或者乳酸修饰)来制备的，被储存和/或运往应用位点，因此，在施用前，向棒悬浮液中加入病人特异性肿瘤抗原制剂或者溶解产物，例如，在对病人施用前1、2、6、12、24或者48小时之前加入。
所述装入介孔二氧化硅(MPS)组合物中的化合物是被加工或者纯化的。例如、多聚核苷酸、多肽或者其他试剂，可以被纯化和/或分离。具体地说，如这里所使用的，“分离的”或者“纯化的"核苷酸分子、多聚核苷酸、多肽或者蛋白质是指在通过重组技术产生时基本上不含有其他细胞物质或者培养基的物质，或者是指通过化学合成的化学前体物或者其他化学试剂。纯化后的化合物按重量计算(干重)占所关心化合物的至少60％。优选的，所述制剂按重量计算占所关心化合物的至少75％，更优选的占至少90％，并且最优选的占至少99％。例如，纯化后的化合物按重量计算占理想化合物的至少90％，91％，92％，93％，94％，95％， 98％，99％，或者100％(重量/重量)。可以通过任何适当的标准方法来测量纯度，例如，通过柱形色谱法、薄层色层分析法、或者高效液相色谱(HPLC)进行分析。纯化后的或者分离的多聚核苷酸(核糖核酸(RNA)或者脱氧核糖核酸(DNA))不含有那些在其天然存在形式中存在的侧链基因或者序列。纯化的也用于定义一种灭菌程度，这种灭菌程度可以安全的对人类主体给药，例如，不具有传染性或者毒剂。就肿瘤抗原而言，所述抗原可以被纯化或者处理成一种肿瘤细胞溶解产物。
同样，“基本上纯的”是指从其天然伴随的成分中分离出来的核苷酸或者多肽。通常，当核苷酸和多肽按重量计算不含有至少60％、至少70％、至少80％、至少90％、至少95％、或者甚至至少99％的蛋白质和其天然伴随存在的有机分子时，这种核苷酸和多肽是基本上纯的。
小分子是质量小于2000道尔顿的化合物。优选的，所述小分子的分子质量小于1000道尔顿，更优选的，小于600道尔顿，例如，所述化合物的分子质量小于500道尔顿、400道尔顿、300 道尔顿、200道尔顿或者100道尔顿。
过渡术语“包括(comprising)”与“包含(including)”、“含有(containing)”或者“具有...的特征”是同义词，都属于包括性的或者开放式定义，不排除其他未列出的成分或者方法步骤。相反，术语“由。。。组成”不包括任何在权利要求中没有特别指出的成分、步骤或者组分。术语“基本上由…组成"将权利要求的范围限制在指定的材料或者步骤，“以及那些本质上不影响要求保护的发明的本质和新颖特性的材料或者步骤"。
从下面关于本发明优选的实施方案的表述中，以及从权利要求书中，本发明的其他特点和优势将变得显而易见。除非另有定义，这里使用的所有科技用语与本发明所属领域普通技术人员通常的理解具有相同的含义。虽然与这里描述的方法和材料相似的任何方法和材料都可以被用于实施或者检测本发明，但是下面描述的是适当的方法和材料。这里应用的所有公开的外国专利和专利申请在此通过引证全部并入本文。Genbank和NCBI指明的登记号码也通过引证在此全部并入本文。这里引用的其他出版的参考文献、文件、原稿和科学文献通过引证在此全部并入本文。如果出现矛盾，以本发明说明书包括定义为准。此外，这里所述的材料、方法和实施例只起到说明作用，并不作为限制。
附图说明
图1是介孔二氧化硅(MPS)棒的电镜照片。这些棒的随机堆叠和自组装可产生能够进行细胞过滤的3D空间。
图2是一种棒状图，显示了具有不同长度的介孔二氧化硅 (MPS)棒的表面标记物表达作用。将100微克具有不同长度的介孔二氧化硅(MPS)棒与骨髓衍生的树突状细胞一起培养18 小时。作为发炎作用的标记物，通过用细胞表面受体CDllc(树突状细胞标记物)、MHCII(抗原呈递标记物)和CD86(共刺激受体)染色来确定被活化的细胞的百分比。随着长度的增加，所述棒的炎症性质也增加。由于理想的脚手架显示炎症性质(与 PLG脚手架参照相似)，在后续的实验中使用长度为30微米到 100微米或120微米之间的棒。
图3是一系列图，显示了介孔二氧化硅(MPS)棒在小鼠中的作用。图3A是一种图，显示了在用5毫克罗丹明标记的介孔二氧化硅(MPS)棒对C57bl/6j小鼠进行皮下注射5天后切除的脚手架注射位点。皮下小囊显示所述棒被定位并且自组装产生 3D微环境。图3B是切除的脚手架位点的电镜照片，显示了过滤进入脚手架位点的细胞。图3C显示了从介孔二氧化硅(MPS) 脚手架上分离的细胞的活/死成像，说明活细胞被募集。
图4A是线状图，显示了粒细胞巨噬细胞-菌落刺激因子 (GM-CSF)从介孔二氧化硅(MPS)棒中的释放。1微克粒细胞巨噬细胞-菌落刺激因子(GM-CSF)被装载入介孔二氧化硅(MPS)棒中，与0.1BS A/PBS一起培养。定时收集上清液，然后使用ELISA(R&D公司)测定粒细胞巨噬细胞-菌落刺激因子 (GM-CSF)。粒细胞巨噬细胞-菌落刺激因子(GM-CSF)从介孔二氧化硅(MPS)棒中连续释放。图4B是棒状图，显示了在体外骨髓衍生的树突状细胞(BMDC)中与介孔二氧化硅(MPS) 共培养的表面标记物表达。100微克的未修饰的、氨基-、硫醇-、氯-、和膦酸修饰的介孔二氧化硅(MPS)棒与106/毫升骨髓衍生的树突状细胞(BMDC)一起培养18小时。然后对细胞进行分析，确定MHC II类和共刺激性分子CD86的表达。介孔二氧化硅(MPS)刺激骨髓衍生的树突状细胞(BMDC)中MHCII和 CD86的增加的表达作用表示介孔二氧化硅(MPS)棒是炎症性的，并且这一性质可以被表面修饰的介孔二氧化硅(MPS)棒所调节。
图5A是棒状图，显示了通过装载粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的介孔二氧化硅(MPS)棒募集的树突状细胞。皮下注射5毫克/小鼠装载有或者不装载有1微克/小鼠粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的介孔二氧化硅 (MPS)棒。从脚手架位点捕获细胞并进行CD1 lc受体(树突状细胞(DC)标记物)染色。装载有粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的介孔二氧化硅(MPS)脚手架能够比空白介孔二氧化硅(MPS)脚手架募集更多的树突状细胞(DC)。图5b是一种棒状图，描述了树突状细胞(DC)的表面标记物表达。装载粒性白细胞巨噬细胞集落刺激因子(GM-CSF)和胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)的介孔二氧化硅(MPS)脚手架比不装载胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)的脚手架活化更多的树突状细胞(DC)。
图6A-B是棒状图，显示了脚手架位点处的(图6A)B220+ 细胞百分比，或者(图6B)B220+细胞总数。皮下注射5毫克/ 小鼠装载有或者不装载有1微克/小鼠粒性白细胞巨噬细胞集落刺激因子(GM-CSF)、100微克胞嘧啶-鸟嘌呤低聚核苷酸 (CpG-ODN)和130微克卵清蛋白的介孔二氧化硅(MPS)棒。从脚手架位点定时捕获细胞并进行B220受体(B细胞标记物)染色。在第3天，装载有粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)、胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)和卵清蛋白的介孔二氧化硅(MPS)脚手架能够募集更多的B细胞。
图7A-C是流式细胞仪散点图(图7A)和棒状图(图7B-C)，描述了树突状细胞(DC)表面上存在MHC-I-SIINFEKL(SEQ ID NO:l)标记物。装载有粒性白细胞巨噬细胞集落刺激因子(GM-CSF)、胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)和模型抗原卵清蛋白的介孔二氧化硅(MPS)脚手架能够诱导抗原特异性树突状细胞(DC)扩散，定位到引流淋巴结(dLN)。用树突状标记物CD1 lc和标记物标记物MHC-I-SIINFEKL对dLN细胞进行染色显示，在MHC-I复合物中，一部分卵清蛋白(肽序列SIINFEKL)存在于细胞表面上。
图8A-B是棒状图，显示由于介孔二氧化硅(MPS)脚手架形成的次级淋巴小结。在装载有粒性白细胞巨噬细胞集落刺激因子(GM-CSF)、胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)和模型抗原卵清蛋白的介孔二氧化硅(MPS)脚手架能够诱导次级淋巴小结，定位活化的抗原初始化B细胞。用B220(B细胞标记物)和GL7次级淋巴小结标记物)对dLN进行染色，研究次级淋巴小结的形成，所述次级淋巴小结中存在特有的B细胞，这种特有的B细胞被活化并且包括在身体过成熟和同型体转换过程中。
图9A-B是一种棒状图，描述了装载有粒性白细胞巨噬细胞集落刺激因子(GM-CSF)、胞嘧啶-鸟嘌呤低聚核苷酸 (CpG-ODN)和模型抗原卵清蛋白的介孔二氧化硅(MPS)脚手架能够诱导CD8+细胞毒性T细胞(CTLs)的扩散，所述CD8+ 细胞毒性T细胞可以特异性识别模型抗原。用CD8(杀伤T细胞标记物)和MHCI-四聚体-SIINFEKL抗体对脾细胞染色，显示T细胞是否能够识别MHCI复合物上呈递的特异性抗原。
图10A-C是直方图，显示了装载有粒性白细胞巨噬细胞集落刺激因子(GM-CSF)、胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN) 和模型抗原卵清蛋白的介孔二氧化硅(MPS)脚手架能够诱导抗原特异性CD8+CTLs在dLN和脾中的克隆扩散。从OT-I小鼠中注射的脾细胞被追踪染料CFSE染色，追踪染料CFSE的荧光性随着细胞每次分裂减半。完全装载的疫苗组中脾和dLN中 CFSE染色的脾细胞的荧光下降显示ova-特异性CTL增殖。
图11A-C是直方图，显示了装载有粒性白细胞巨噬细胞集落刺激因子(GM-CSF)、胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN) 和模型抗原卵清蛋白的介孔二氧化硅(MPS)脚手架能够诱导抗原特异性CD4+THs在dLN和脾中的克隆扩散。从OT-II小鼠中注射的脾细胞被追踪染料CFSE染色，追踪染料CFSE的荧光性随着细胞每次分裂减半。完全装载的疫苗组中和只装载抗原的介孔二氧化硅(MPS)组的脾和dLN中CFSE染色的脾细胞的荧光下降显示ova-特异性CD4+TH细胞增殖。
图12A-B是直方图，显示了抗原滴定度被定义为抗体-血清溶液被稀释并仍然保持可检测的抗体数量的程度。所述抗卵清蛋白血清抗体被滴定。装载有粒性白细胞巨噬细胞集落刺激因子(GM-CSF)、胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)和卵清蛋白的介孔二氧化硅(MPS)脚手架能够引发有力的和长时间的TH1和TH2抗体反应。单独装载有卵清蛋白的介孔二氧化硅 (MPS)可以引发有效的TH2反应，显示了介孔二氧化硅(MPS) 材料本身的辅助潜力。
图13A-B是线性图，显示了粒性白细胞巨噬细胞集落刺激因子(GM-CSF)以一种控制并持续的方式从介孔二氧化硅(MPS) 微粒中释放。A)1微克粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)被装载入5毫克介孔二氧化硅(MPS)棒中并在0.1 BSA/PBS中培养。定时收集上清液并使用酶联免疫吸附测定 (R&D公司)测定粒性白细胞巨噬细胞集落刺激因子(GM-CSF)。虽然剂量较小，但是粒性白细胞巨噬细胞集落刺激因子(GM-CSF)连续地从介孔二氧化硅(MPS)棒中释放。B) 1微克粒性白细胞巨噬细胞集落刺激因子(GM-CSF)被装载入5毫克的含有OVA和CpG的介孔二氧化硅(MPS)中。然后皮下注射入C57BL/6J小鼠中。在各个时间点，收获包围注射的颗粒脚手架的组织并分析粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)水平。粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)的水平维持一周。
图14A-B是照片，和图14C是棒状图。具有更高宽高比的介孔二氧化硅(MPS)微粒能够募集更多的细胞。图14A显示了长度或者在10微米和20微米之间、或者在80微米和120微米的介孔二氧化硅(MPS)微粒的扫描电镜图像。较长的棒使组合物具有更大面积或者更大的棒间空间。图14B显示了从小鼠中捕获的介孔二氧化硅(MPS)组合物。将5微克介孔二氧化硅(MPS)微粒皮下注射入小鼠中，在注射后第7天收获脚手架位点。图14C是一种棒状图，列举了从脚手架中分离的细胞。具有更高宽高比的介孔二氧化硅(MPS)微粒能够募集更多的细胞。
图15A-B是条形图。作为对粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的反应，树突状细胞(DC)被介孔二氧化硅(MPS) 微粒募集。将粒性白细胞巨噬细胞集落刺激因子(GM-CSF) (0纳克、500纳克、1000纳克、3000纳克)装载入介孔二氧化硅(MPS)微粒中，并将其皮下注射入小鼠中。在注射后第7 天，收获脚手架并用流式细胞仪分析。图15A显示，随着粒性白细胞巨噬细胞集落刺激因子(GM-CSF)剂量的增加，募集的 CDllc+CDllb+树突状细胞(DC)增加。图15B显示，随着粒性白细胞巨噬细胞集落刺激因子(GM-CSF)剂量的增加，募集的成熟CDllc+MHCII+树突状细胞(DC)同样增加。
图16是一种棒状图，显示了粒性白细胞巨噬细胞集落刺激因子(GM-CSF)能够增加募集的树突状细胞(DC)向着引流淋巴结的流通。将装载有Alexa 647标记的卵清蛋白(OVA)、或者Alexa 647标记的OVA和1微克粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的介孔二氧化硅(MPS)微粒皮下注射入小鼠体内。在注射后第7天，收获引流管淋巴结(dLN)并用流式细胞仪分析。在加入了抗原(OVA)的情况下，流向脚手架并吸收OVA的Alexa 647+CD11C+树突状细胞(DC)有适度增加。然而，粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的加入使从脚手架流向dLN的树突状细胞显著增加。
图17A-C是散点图，图17D是棒状图。胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)从介孔二氧化硅(MPS)微粒脚手架中的局部运输能够增加活化的树突状细胞的循环。介孔二氧化硅 (MPS)微粒装载有1微克粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)、300微克OVA和100微克胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)。然后将其皮下注射入小鼠中。在注射后 7天收获dLNs并分析。用CDllc和CD86染色淋巴结细胞。胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)能够从介孔二氧化硅(MPS) 脚手架中局部释放，因此它的加入能够进一步增加dLN中活化的、成熟树突状细胞(DC)的百分比和数目。
图18A-C是照片，图18D是棒状图。蛋白质以控制且持续的方式从介孔二氧化硅(MPS)微粒脚手架中释放。将Alexa 647 标记的卵清蛋白(或者处于缓冲溶液中，或者装载在介孔二氧化硅(MPS)微粒上)皮下注射到老鼠侧面。使用IVIS测定各个时间点的相对荧光。如果在缓冲溶液中注射，所述蛋白质在小于1天的时间里从注射部位扩散。但是，如果装载在介孔二氧化硅(MPS)微粒上，所述蛋白质以一种持续的方式从局部脚手架位点释放，例如，超过一周的时间(2、3、4、5、7或者更多天)。
图19A-B是线性图，显示了抗体滴定度。抗体滴定度被定义为抗体-血清溶液被稀释但始终包含可检测数量抗体的程度。使用30微克OVA、10微克胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)和1微克粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)，或着以可溶形式、或者装载在5毫克介孔二氧化硅(MPS)微粒中，对小鼠接种。滴定抗卵白蛋白血清抗体。装载有粒性白细胞巨噬细胞集落刺激因子(GM-CSF)、胞嘧啶- 鸟嘌呤低聚核苷酸(CpG-ODN)和ova的介孔二氧化硅(MPS) 可以引发有力的、长时间的TH1和TH2抗体反应，分别如IgG2a 和IgGl抗体的高滴定度所示。更令人难忘的是，这些反应在单次注射接种超过200天后仍然明显。该反应可以与使用氢氧化铝传递的OVA相比，这是美国唯一获批的助剂。虽然介孔二氧化硅(MPS)疫苗能够诱导TH1和TH2抗体反应，由于其能够装载小的细胞因子、蛋白质和DNA，通过硫酸铝诱导的反应是完全TH2偏移的。介孔二氧化硅(MPS)疫苗用途非常广泛，并且容易精确的转变和控制，诱导特异性免疫反应。
图20A-D是一种散点图，显示了使用介孔二氧化硅(MPS) 疫苗接种能够诱导T卵泡辅助细胞的扩增。用CFSE染色OT-II 脾细胞并适应性传递进入Thy 1.1+受体小鼠中。然后用介孔二氧化硅(MPS)和溶菌酶、介孔二氧化硅(MPS)和OVA，和包括粒性白细胞巨噬细胞集落刺激因子(GM-CSF)和CpG的全形式疫苗接种受体小鼠。在疫苗接种三天后，收获dLN并分析适应性传递的细胞。这里显示，接种介孔二氧化硅(MPS)和 ova的小鼠，接种全形式疫苗的小鼠能够产生强壮的卵泡T辅助细胞群，这是直接负责“辅助”B细胞分化并成熟为完全功能性抗原特异性抗体分泌的浆细胞。
图21A-D是一种线状图，显示了使用介孔二氧化硅(MPS) 疫苗接种能够诱导CD4+T辅助细胞的克隆扩增。用CFSE染色 OT-II脾细胞并适应性传递进入Thy 1.1+受体小鼠中。然后用介孔二氧化硅(MPS)和溶菌酶、介孔二氧化硅(MPS)和OVA，和包括粒性白细胞巨噬细胞集落刺激因子(GM-CSF)和CpG的全形式疫苗接种受体小鼠。在疫苗接种三天后，收获dLN并分析适应性传递的细胞。据这里所显示，介孔二氧化硅(MPS) 和OVA，以及全型疫苗都能够诱导CD4+T辅助细胞有效的颗粒扩增，显示全身性抗原特异性反应。
图22A-B是一种线性图，显示了介孔二氧化硅(MPS)微粒羟基乙酸和乳酸修饰作用帮助生物活性粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的释放。^1微克的粒性白细胞巨噬细胞集落刺激因子(GM-CSF)被装载入5毫克的羟基乙酸或者乳酸修饰的介孔二氧化硅(MPS)棒中，并在0.1BSA/PBS中培养。周期性收集上清液并使用酶联免疫吸附测定(R&D公司)粒性白细胞巨噬细胞集落刺激因子(GM-CSF)。与从未修饰的介孔二氧化硅(MPS)微粒中释放的粒性白细胞巨噬细胞集落刺激因子(GM-CSF)相比，羟基乙酸和乳酸修饰作用能够使生物活性粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的累积释放增加超过20倍。
图23A-D是散点图，显示了羟基乙酸修饰的介孔二氧化硅 (MPS)能够增加募集的树突状细胞(DC)和成熟树突状细胞 (DC)的百分比。在37度下，5毫克未修饰的或者羟基乙酸修饰的介孔二氧化硅(MPS)微粒装载有1微克粒性白细胞巨噬细胞集落刺激因子(GM-CSF)1小时，然后皮下注射入小鼠中。在第7天收获脚手架并分析。这里证实，修饰的介孔二氧化硅 (MPS)几乎使募集的CDllc+CDl lb+树突状细胞(DC)的百分比加倍，并且，CDllc+CD86+成熟树突状细胞(DC)百分比显著增加。这些结果显示，介孔二氧化硅(MPS)微粒良好的表面修饰能力允许进行进一步募集细胞的表型操作，从而诱导更有效的免疫反应。
具体实施方式
可注射的介孔二氧化硅(MPS)-基的微棒在体内随机自组装形成3D脚手架。设计该系统从而使该系统释放细胞因子，募集并短时间内收容免疫细胞，用抗原呈递他们并用危险信号活化他们。在募集并短时间收容所述细胞或者结构中含有所述细胞之后，这些免疫细胞从装置结构中迁移出来并定位到淋巴结中。因此，所述组合物是一种细胞在其中来回交流/循环的组合物，他们的免疫活化状态通过装置运输的结果而改变/调节。
在淋巴结中发现抗原特异性树突状细胞群落的显著扩增以及次级淋巴小结的形成，这是通过使用本发明的装置，在淋巴结中引入卵泡T辅助细胞来实现的。在脾中，抗原识别性CD8+CTL 群落也被发现显著增加了。该系统同样诱导抗原特异性CD4和 CD8T细胞的克隆扩增。除了细胞免疫反应显著扩增之外，还检测到产生大量耐受性抗体和平衡性TH1/TH2反应。
用于调节免疫细胞流通和重新编码的可注射性介孔二氧化硅微棒-基脚手架系统的基本元素包括：
·介孔二氧化硅(MPS)微棒的宽高比(10纳米横截面积除以100微米长度)防止其被吸收，并因此允许局部形成三维结构。
·8纳米孔径，允许吸附那些能够通过控制的并且连续的方式扩散而传递的小分子。
·高表面面积与体积比，允许控制各种细胞因子、危险信号和抗原的装载。
·介孔二氧化硅(MPS)微棒的炎症性质能够促进免疫细胞募集，并且不需要其他炎症性细胞因子。
·介孔二氧化硅(MPS)棒表面化学修饰能力的多功能性，可以调节所述棒的性质以及蛋白质与棒的结合方式。
·粒性白细胞巨噬细胞集落刺激因子(GM-CSF)的控制释放可以调节免疫细胞流向脚手架位点。
·胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)的控制释放能够活化募集的树突状细胞。
·募集免疫细胞在脚手架位点可以吸收锚定蛋白质抗原。
据发现，孔径为大约5-10纳米，例如8纳米时，对于小分子以及蛋白质的装载效率达到最佳，例如，粒性白细胞巨噬细胞集落刺激因子(GM-CSF)(其分子直径为大约3纳米)。
将悬浮在缓冲液中的微棒进行皮下注射，所述棒随机堆叠成一种三维结构，所述棒的末端相互之间形成物理接触，并且在此接触之间形成一种微空隙。
MPS
通过将四乙基原硅酸酯与一种由胶束棒制成的模板发生反应来合成介孔二氧化硅纳米颗粒。所得结果是一系列纳米尺寸的球或者棒，其中充满规则排列的小孔。通过溶剂洗涤调节合适的 pH值，并因此除去模板。在另一个技术中，所述介孔颗粒可以使用简单的溶胶-凝胶法或者喷雾干燥法合成。四乙基原硅酸酯还可以与其他的聚合物单体(作为模板)一起使用。其他方法包括美国专利公开号20120264599和20120256336中所描述的那些方法，通过引证在此并入本文。
粒性白细胞巨噬细胞集落刺激因子(GM-CSF)
粒性白细胞巨噬细胞集落刺激因子(GM-CSF)是一种蛋白质，由巨噬细胞、T细胞、肥大细胞、内皮细胞和成纤维细胞所分泌。具体地说，粒性白细胞巨噬细胞集落刺激因子(GM-CSF) 是一种细胞因子，可以起到白细胞生长因子的功能。粒性白细胞巨噬细胞集落刺激因子(GM-CSF)刺激干细胞产生粒性白细胞和单核细胞。单核细胞从血流中出来，移入组织，并随后成熟进入巨噬细胞。
这里描述的脚手架装置包括并且释放粒性白细胞巨噬细胞集落刺激因子(GM-CSF)多肽，用于将宿主树突状细胞(DC) 吸引到所述装置中。预计的粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)多肽是从体内分离的，或者是体内或者体外合成的。内生的粒性白细胞巨噬细胞集落刺激因子(GM-CSF)是从健康的人类组织中分离出来的。在将模板DNA转染或者转化进入宿主有机体或者细胞(例如，哺乳动物或者培养的人细胞系)中之后，体内合成性粒性白细胞巨噬细胞集落刺激因子(GM-CSF) 多肽。做为选择，合成性粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)多肽是使用聚合酶链式反应(PCR)或者其他本领域内已知的方法体外合成的Sambrook,J.,Fritsch,E.F.,和 Maniatis,T.,Molecular Cloning:ALaboratory Manual(分子克隆：一种实验操作手册).Cold Spring Harbor LaboratoryPress(冷泉港冷泉出版社),NY,第1,2,3卷(1989),通过引证在此并入本文)。
粒性白细胞巨噬细胞集落刺激因子(GM-CSF)多肽被修饰以增加体内蛋白质的稳定性。做为选择，对粒性白细胞巨噬细胞集落刺激因子(GM-CSF)多肽进行设计使其具有更多或者更少的免疫原性。内原性的成熟人粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)多肽是糖基化的，据报道，在氨基酸残基23(白氨酸)、27(天门冬酰胺)于是39(谷氨酸)处糖基化(参见美国专利第5,073,627号)。相对于糖基化状态，在一个或者一个以上的氨基酸残基上修饰本发明的粒性白细胞巨噬细胞集落刺激因子(GM-CSF)多肽。
粒性白细胞巨噬细胞集落刺激因子(GM-CSF)多肽是重组的。做为选择，粒性白细胞巨噬细胞集落刺激因子(GM-CSF) 多肽是哺乳动物粒性白细胞巨噬细胞集落刺激因子(GM-CSF) 多肽的人源化衍生物。可以衍生粒性白细胞巨噬细胞集落刺激因子(GM-CSF)多肽的示范性的哺乳动物种类包括，但是不局限于，小鼠、大鼠、仓鼠、荷兰猪、白鼬、猫、狗、猴子或者灵长类动物。在一种优选的实施方案中，粒性白细胞巨噬细胞集落刺激因子(GM-CSF)是一种重组人蛋白质(PeproTech公司，编目号300-03)。做为选择，粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)是一种重组鼠科(小鼠)蛋白质(PeproTech公司，编目号＃_315-03)。最后，粒性白细胞巨噬细胞集落刺激因子 (GM-CSF)是重组体小鼠蛋白质人源化的衍生物。
人重组粒性白细胞巨噬细胞集落刺激因子(GM-CSF) (PeproTech公司，编目＃_300-03)(由下列多肽序列编码(SEQ ID NO：2))：
MAPARSPSPS TQPWEHVNAI QEARRLLNLS RDTAAEMNETVEVISEMFDL QEPTCLQTRLELYKQGLRGS LTKLKGPLTM MASHYKQHCPPTPETSCATQ IITFESFKEN LKDFLLVIPF DCWEPVQE
鼠重组粒性白细胞巨噬细胞集落刺激因子(GM-CSF) (PeproTech公司，编目＃_315-03)(由下列多肽序列编码(SEQ ID NO：3))：
MAPTRSPITV TRPWKHVEAI KEALNLLDDM PVTLNEEVEV VSNEFSFKKL TCVQTRLKIFEQGLRGNFTK LKGALNMTASYYQTYCPPTP ETDCETQVTT YADFIDSLKT HLTDIPFECK KPVQK
人内原性的粒性白细胞巨噬细胞集落刺激因子(GM-CSF) (由下列mRNA序列(NCBI登记号NM_000758和SEQ ID NO： 4)编码)：
人内原性的粒性白细胞巨噬细胞集落刺激因子(GM-CSF)(由下列氨基酸序列(NCBI登记号NP_000749.2和SEQ ID NO：5) 编码)：
MWLQSLLLLGTVACSISAPARSPSPSTQPWEHVNAIQEARRLLNLSRDTAAEM NETVEVISEMFDLQEPTCLQTRLELYKQGLRGSLTKLKGPLTMMASHYKQHC PPTPETSCATQIITFESFKENLKDFLLVIPFDCWEPVQE
胞嘧啶-鸟嘌呤(CpG)低聚核苷酸(CpG-ODN)序列
CpG位点是脱氧核糖核酸(DNA)区域，在此区域中，基质线性序列沿着其长度方向胞嘧啶核苷紧挨着鸟苷酸(″p″表示他们之间存在的磷酸键，并将他们与胞嘧啶-鸟嘌呤互补碱基对相区别)。CpG位点在DNA甲基化过程中发挥关键作用，这是细胞用来静止基因表达的一些内源性机制中的一个。启动子元素内 CpG位点的甲基化能够使基因静止。在癌症的情况下，已知肿瘤抑制基因通常是静止的，而致癌基因或者癌症诱导基因被表达。重要地，已经证实肿瘤抑制基因(预防癌症形成的基因)启动子区域中的CpG位点是被甲基化的，而在某些癌症中致癌基因启动子区域中的CpG位点是低甲基化的或者未甲基化的。Toll样受体(TLR)-9受体结合DNA中未甲基化的CpG位点。
这里描述的疫苗组合物包括CpG低聚核苷酸。CpG低聚核苷酸是从体内分离的，或者是体内或者体外合成的。示范性的内源性CpG低聚核苷酸来源包括，但是不局限于，微生物、细菌、真菌、原生虫、病毒、霉菌或者寄生虫。或者，内源性的CpG 低聚核苷酸是从哺乳动物良性或者恶性赘生性肿瘤中分离出来的。合成的CpG低聚核苷酸是在将模板DNA转染或者转化入宿主有机体内之后，在体内合成的。做为选择，合成性CpG低聚核苷酸是使用聚合酶链式反应(PCR)或者其他本领域内已知的方法体外合成的(Sambrook,J.,Fritsch,E.F.,和Maniatis,T., Molecular Cloning:A Laboratory Manual(分子克隆：一种实验操作手册).Cold Spring Harbor Laboratory Press(冷泉港冷泉出版社),NY,第1,2,3卷(1989),通过引证在此并入本文))。
呈递CpG低聚核苷酸用于树突状细胞的胞内吸收。例如，使用无保护的CpG低聚核苷酸。术语“无保护的”用于描述一种分离的内源性或者合成的多聚核苷酸(或者低聚核苷酸)，其上不含有额外的取代基。在另一个实施方案中，CpG低聚核苷酸与一种或者一种以上化合物相结合，增加细胞吸收的效率。做为选择或者另外，CpG低聚核苷酸与一种或者一种以上的化合物结合，增加脚手架和/或树突状细胞内低聚核苷酸的稳定性。在细胞吸收之前，选择性地浓缩CpG低聚核苷酸。例如，使用聚(氮丙啶)(PEI)浓缩CpG低聚核苷酸，所述聚(氮丙啶)(PEI) 是一种阳离子聚合物，能够增加树突状细胞的细胞吸收的效率。
CpG低聚核苷酸可以被分成多个种类。例如，本发明组合物、方法和装置中包括的示范性的CpG-ODNs是刺激性的、中性的或者抑制性的。这里的术语“刺激性的”用于描述一类能够活化TLR9的胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)序列。这里的术语“中性的”用于描述一类不能活化TLR9的胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)序列。这里的术语“抑制的”用于描述一类能够抑制TLR9的胞嘧啶-鸟嘌呤低聚核苷酸 (CpG-ODN)序列。术语“活化的TLR9”描述了一种方法，使用此方法TLR9能够引起细胞内的信号传导。
刺激性胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)可以进一步被分成三种类型，A、B和C，这些类型在免疫刺激活性方面有所不同。A类刺激性CpG低聚核苷酸(ODNs)的特点在于包括磷酸二酯中心性CpG的回文结构部分和一种硫代磷酸3'聚-G 线。在TLR9活化之后，这些胞嘧啶-鸟嘌呤低聚核苷酸 (CpG-ODN)诱导浆样树突状细胞(pDC)中产生高产量的IFN- α。A类胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)微弱地刺激TLR9 -依赖性的NF-κB信号传导。
B型刺激性胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)包括一种全硫代磷酸主链，具有一种或者一种以上CpG二核苷酸。在 TLR9活化后，这些CpG-ODNs有力的刺激B细胞。与A类胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)不同，B类胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)微弱地刺激IFN-α分泌。
C类刺激性胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)包括A 和B类的特征。C类胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)包括一种全硫代磷酸主链和一种包括CpG的回文结构部分。与A 类胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)相似，C类胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)诱导pDC产生大量的IFN-α。与 B类胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)相似，C类胞嘧啶-鸟嘌呤低聚核苷酸(CpG-ODN)诱导强烈的B细胞刺激。
示范性的刺激性CpG ODNs包括，但是不局限于，ODN 1585、 ODN 1668、ODN 1826、ODN 2006、ODN 2006-G5、ODN 2216、 ODN 2336、ODN 2395、ODN M362(都来自InvivoGen)。本发明还包括前述CpG低聚核苷酸(ODNs)任何人源化的版本。在一个优选的实施方案中，本发明的组合物、方法和装置包括 ODN 1826(其序列从5'到3'是tccatgacgttcctgacgtt，其中CpG元素用黑体表示，SEQ ID NO:10)。
不刺激TLR9的中性或者参照CpG ODNs被包括在本发明中。这些低聚核苷酸(ODNs)包括与其刺激性对应物相同的序列，但是不含有CpG二核苷酸，而是含有GpC二核苷酸。
本发明所包括的示范性的中性或者参照CpG ODNs包括，但是不局限于，ODN 1585参照物、ODN 1668参照物、ODN 1826 参照物、ODN 2006参照物、ODN 2016参照物、ODN 2336参照物、ODN 2395参照物、ODN M362参照物(都来自InvivoGen)。本发明还包括前述CpG低聚核苷酸(ODNs)任何人源化的版本。
抗原
这里所描述的组合物、方法和装置中包括肿瘤抗原或者其他抗原。在施用这种装置的患者体内，抗原引发保护性免疫或者产生治疗免疫反应。优选的肿瘤抗原是肿瘤细胞溶解产物(参见，例如，Ali et.AL,2009,Nature Materials 8,151-158；通过引证在此并入本文)。例如，从人类患者(或者非人动物)中提取全肿瘤样品或者肿瘤活组织切片样品，并使用胶原酶消化，降解胞外基质。然后，所述肿瘤细胞经历三次冷冻融化过程循环，其中，细胞在液氮中冷冻，然后在水浴中解冻。该过程产生肿瘤抗原，然后将肿瘤抗原与粒性白细胞巨噬细胞集落刺激因子(GM-CSF)和CpG ODN一起装载在介孔二氧化硅(MPS) 颗粒上。例如，肿瘤细胞溶解产物抗原的疫苗剂量是获得1x106个肿瘤细胞。在制备MPS颗粒之后，将此颗粒悬浮在生理学可接受性缓冲液(例如，PBS)中，然后向棒的悬浮液中加入募集化合物(例如，粒性白细胞巨噬细胞集落刺激因子(GM-CSF))、活化化合物(例如，CpG)和抗原。在室温下摇动混合物整夜，然后冷冻干燥大约4小时。在给药之前，将棒在此悬浮在缓冲液中，然后将悬浮液装载进入1毫升注射器(18号针)中。通常，每次注射的混合物疫苗剂量是150微升。
本发明的组合物、方法和装置中包括的示范性的癌症抗原包括，但是不局限于，从活体检查中提取的肿瘤溶解产物、照射的肿瘤细胞、抗原的MAGE系列(例如MAGE-1)、MART-1/梅拉纳、酪氨酸酶、神经节苷脂、gp100、GD-2、O-乙酰化GD-3、 GM-2、MUC-1、Sos1、蛋白激酶C-结合蛋白、反转录酶蛋白质、 AKAP蛋白质、VRK1、KIAA1735、T7-1、T11-3、T11-9、现代人端粒酶发酵产物(hTRT)、细胞角蛋白-19(CYFRA21-1)、鳞状细胞癌抗原1(SCCA-1)、(蛋白质T4-A)、鳞状细胞癌抗原2(SCCA-2)、卵巢癌抗原CA125(1A1-3B)(KIAA0049)、粘蛋白1(肿瘤相关的粘蛋白)、癌-相关的粘蛋白)、(多形态上皮细胞粘蛋白)、(PEM)、(PEMT)、(EPISIALIN)、 (肿瘤相关的上皮细胞膜抗原)、(EMA)、(H23AG)、(花生反应性的尿粘蛋白)、(PUM)、(乳腺癌相关的抗原DF3)、 CTCL肿瘤抗原se1-1、CTCL肿瘤抗原se14-3、CTCL肿瘤抗原 se20-4、CTCL肿瘤抗原se20-9、CTCL肿瘤抗原se33-1、CTCL 肿瘤抗原se37-2、CTCL肿瘤抗原se57-1、CTCL肿瘤抗原se89-1、前列腺特异性膜抗原、5T4癌坯滋养层糖蛋白、Orf73皮肤多发性出血性肉瘤相关的疱疹病毒、MAGE-C1(癌症/睾丸抗原 CT7)、MAGE-B1抗原(MAGE-XP抗原)(DAM10)、MAGE-B2 抗原(DAM6)、MAGE-2抗原、MAGE-4a抗原、MAGE-4b抗原、结肠癌抗原NY-CO-45、肺癌抗原NY-LU-12变体A、癌症相关的表面抗原、腺癌抗原ART1、伴生肿瘤相关的脑-睾丸-癌症抗原(旁瘤抗原MA2；伴生肿瘤神经元抗原)、神经肿瘤腹部抗原2(NOVA2)、肝细胞癌抗原基因520、肿瘤相关的抗原 CO-029、肿瘤相关的抗原MAGE-X2、滑膜肉瘤、X断点2、T 细胞识别的鳞状细胞癌抗原、血清学检测的结肠癌抗原1、血清学检测的乳癌抗原NY-BR-15、血清学检测的乳癌抗原 NY-BR-16、嗜铬粒蛋白A；甲状旁腺分泌的蛋白质1、DUPAN-2、 CA19-9、CA72-4、CA195、癌胚抗原(CEA)。纯化的肿瘤抗原可以单独被是用或者彼此结合使用。
所述系统还可以有效用于产生针对其他抗原(例如，微生物病原体，比如细菌、病毒、真菌)的免疫反应。
下列材料和方法用于产生这里描述的数据。
介孔二氧化硅(MPS)脚手架的制备
在室温下，将Pluronic P-123(Sigma-Aldrich公司)表面活性剂溶解在1.6M HCl中，然后加热至40℃。加入42毫摩尔正硅酸乙酯(TEOS)(Sigma-Aldrich公司)，在40℃下加热20分钟，同时搅拌(600rpm)。然后将组合物加热到100℃，24小时。通过过滤收集棒状颗粒，在室温条件下空气干燥。80℃下，将颗粒在乙醇/盐酸(5部分HCl比500部分乙醇)中提取过夜。或者，在100％乙醇中，在550℃下煅烧颗粒4小时。所述MPS组合物可以在加入募集化合物和/或活化化合物之前或之后，并且在加入抗原之前或者之后被储存并运输使用。例如，如果抗原是有来自病人的活组织检查样品制备的肿瘤细胞溶解产物，他可以被处理并在对病人施用前很短时间加入到MPS颗粒中。
对于全型疫苗组合物，1微克/鼠GM-CSF、100微克/鼠 CpG-ODN和130微克/鼠的卵清蛋白与5毫克/鼠MPS一起在 dH2O中培养12小时，冷冻干燥12小时，重新悬浮在150微升/鼠PBS中，用18G针头皮下注射。
为了确定GM-CSF和CpG-ODN从MPS棒中释放的动力学，放射活化的I-标记的重组人GM-CSF被用作示踪剂，然后进行标准释放研究。相似的，通过使用Nanodrop仪(ND1000,Nanodrop Technologies公司)的吸光读数确定释放进入PBS的CpG-ODN的量。
MPS微颗粒的修饰作用
使用1-乙基-3-(3-二甲基氨基丙基)二亚胺碳(EDC)标准化学品来活化羟基乙酸和乳酸上的羧酸。使用胺丙基硅烷对MPS 颗粒进行氨基修饰。然后室温下将两种组分混合在一起，过夜反应。然后允许颗粒风干。将所得的羟基乙酸和/或乳酸修饰的颗粒与GM-CSF或其他上面描述的化合物相接触。
体外树突状细胞(DC)活化试验
使用20纳克/毫升的GM-CSF将鼠树突状细胞(DC)从骨髓细胞中分化出来。分化的树突状细胞以106/毫升的浓度与100微克/毫升MPS颗粒一起培养18小时，然后使用流式细胞仪分析 CD1 1c(ebiosciences公司，圣地亚哥，加利福尼亚州)、 CD86(ebiosciences公司，圣地亚哥，加利福尼亚州)和MHC类 -II(ebiosciences公司，圣地亚哥，加利福尼亚州)的表达。
分析MPS脚手架募集的树突状细胞及其向淋巴结的迁移
从动物体内取回MPS脚手架然后通过机械分离的方式消化棒中细胞。APC共轭的CD11c(树突状细胞标记物)、FITC共轭的MHC类-II和PE共轭的CD86(B7，共刺激分子)染色被用于树突状细胞和白细胞募集分析。根据阳性异硫氰酸荧光素 (FITC)，异藻蓝蛋白(APC)和藻红蛋白(PE)，使用同型参照对细胞进行分类，记录对每种表面抗原染色呈阳性的细胞百分比。
为了确定淋巴结中是否存在抗原特异性树突状细胞，收获引流淋巴结(dLN)并用APC共轭的CD11c和PE共轭的 SIINFEKL-MHC类-I(ebiosciences公司，圣地亚哥，加利福尼亚州)进行分析。
抗原特异性CD8+脾T细胞的分析
收获并消化脾。在裂解血红细胞之后，使用PE-CY7共轭的 CD3(ebiosciences公司，圣地亚哥，加利福尼亚州)、APC共轭的CD8(ebiosciences公司，圣地亚哥，加利福尼亚州)、PE 共轭的SIINFEKL(SEQ ID NO:)MHC类-I四聚体(Beckman Coulter公司)分析脾细胞。SIINFEKL是一种卵清蛋白衍生的肽 [OVA(257-264)]。
CD4+或者CD8+T细胞克隆扩增的分析
收获来自OT-II(对于CD4)或者OT-I(对于CD8)转基因 C57bl/6鼠(Jackson实验室)的脾，消化、汇集并用细胞示踪剂羧基荧光素琥珀酰亚胺酯(CFSE)染色。在免疫2天之后，20xl06个染色的脾细胞/小鼠被静脉注射入C57bl/6鼠(Jackson实验室) 中。静脉注射4天之后，回收dLN和脾，然受使用PE共轭的 CD8或者CD4标记物分析。
抗-OVA体液免疫反应的特点
使用卵清蛋白包覆的平板ELISA分析血清中的IgG1和 IgG2a抗体。抗体滴定度定义为ELISA的OD读数>0.3(空白) 的最低血清稀释程度。
其他实施方案
尽管本发明已经结合具体实施方式进行了描述，但之前的描述只起到解释作用并不能限制本发明的范围，本发明的范围由所附权利要求书定义。其他的方面、优势和修饰也被包括在所附权利要求书记载的范围内。
这里所涉及的所有专利和科技文献构成了本领域普通技术人员能够获得的知识。这里引用的所有美国专利和公开的或者未公开的美国专利申请通过引证在此并入本文。这里引用的所有公开的外国专利和专利申请在此通过引证全部并入本文。 Genbank和NCBI指明的登记号码也通过引证在此并入本文。这里引用的其他出版的参考文献、文件、原稿和科学文献通过引证在此并入本文。
尽管本发明已经参照其优选的实施方案进行了具体的显示和表述，但是本领域普通技术人员应该理解，在不脱离本发明范围的情况下，在形式和细节上可以存在各种各样的变化，本发明的范围由所附的权利要求书概括。
Claims (18)
1.一种用于注射和具有微空隙的3D结构的体外自组装的组合物,所述组合物包括介孔二氧化硅棒、免疫细胞募集化合物和免疫细胞活化化合物，其中所述棒的长度为20-500微米，且所述棒包括孔，其孔径为2-50纳米。
2.根据权利要求1所述的组合物，其中所述组合物包括10纳米横截面积除以100微米长度的所述棒的宽高比。
3.根据权利要求1所述的组合物，其中所述免疫细胞募集化合物包括趋化因子。
4.根据权利要求1所述的组合物，其中，所述棒包括孔，所述孔的孔径在5-25纳米之间。
5.根据权利要求1所述的组合物，其中，所述棒包括孔，所述孔的孔径在5-10纳米之间。
6.根据权利要求1所述的组合物，其中，所述棒包括孔，所述孔的孔径为8纳米。
7.根据权利要求1所述的组合物，其中，所述棒的长度为30微米到120微米。
8.根据权利要求1所述的组合物，其中，所述棒的长度为80微米到120微米。
9.根据权利要求1所述的组合物，其中，所述组合物进一步包括一种抗原。
10.根据权利要求9所述的组合物，其中，所述抗原包括肿瘤抗原。
11.根据权利要求9所述的组合物，其中，所述抗原包括肿瘤细胞溶解产物。
12.根据权利要求9所述的组合物，其中，所述抗原包括微生物病原体。
13.根据权利要求1-12任一权利要求所述的组合物，其中所述棒为化学修饰的。
14.根据权利要求13所述的组合物，其中所述的化学修饰是由选自氨基、硫醇基、氯基、磷酸基、乙醇基和乳酸的化学基团或化合物进行的修饰。
15.权利要求1-12任一权利要求所述的组合物在制备用于诱导对抗原产生全身抗原特异性免疫反应的药物组合物中的应用。
16.包括介孔二氧化硅棒的组合物在制备诱导对抗原产生全身抗原特异性免疫反应或者诱导抗原特异性免疫细胞定位到淋巴结方面的药物组合物的应用，其中，所述包括介孔二氧化硅棒的组合物包括免疫细胞募集化合物和免疫细胞活化化合物和一种抗原，以及其中，当向受试者注射所述药物组合物时，所述棒自组装形成具有微空隙的3D结构，其中所述棒的长度为20-500微米，且所述棒包括孔，其孔径为2-50纳米。
17.根据权利要求16所述的应用，其中，在将所述棒与所述抗原、免疫细胞募集化合物或者免疫细胞活化化合物相接触之前，所述棒被羟基乙酸或者乳酸修饰。
18.权利要求1-12任一权利要求所述的组合物在制备用于诱导免疫反应的药物组合物中的应用，其中所述药物组合物适于注射。
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