CN109512798B - 一种用于抗肿瘤免疫治疗的药物组合物纳米体系 - Google Patents
一种用于抗肿瘤免疫治疗的药物组合物纳米体系 Download PDFInfo
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Abstract
本发明设计一种用于抗肿瘤免疫治疗的药物组合物纳米体系，具体为将治疗有效量的一种或多种全氟化碳化合物以及一种或多种免疫检查点抑制剂作为有效成份包载于白蛋白外壳中。实验验证，该药物组合物可通过打开肿瘤血管屏障，增加血管渗透性，促进免疫T细胞肿瘤内浸润，同时增强肿瘤相关T细胞的杀伤活性，升高IFN‑γ、TNF‑α和IL‑6等毒性杀伤因子表达水平，发挥协同抗肿瘤免疫疗效，为临床上免疫检查点抑制剂单药使用过程中患者响应率低的问题提供了解决方法。
Description
技术领域
本发明属于医药领域，涉及一种用于抗肿瘤免疫治疗的药物组合物纳米体系，具体涉及该药物组合物纳米体系通过打开肿瘤血管屏障，增加血管渗透性，促进免疫细胞肿瘤浸润，诱导抗肿瘤免疫反应，协同增敏抗肿瘤疗效。
背景技术
当前肿瘤仍是威胁人类健康的最大的难题之一，每年全球罹患癌症的人数超过1400万，而死于癌症的人数超过800万，随着恶性肿瘤发病率和死亡率逐年增加，恶性肿瘤治疗需求越来越大。手术、放疗、化疗以及靶向治疗是目前肿瘤的主要治疗手段，但这些方法或多或少存在副作用大、易产生耐药性等问题，并未给晚期实体瘤患者带来长期的生存获益。肿瘤免疫治疗在现有的癌症治疗中具有独特优势，受到越来越多研究机构和制药企业的青睐，近年来呈现蓬勃发展的趋势。
程序化死亡分子(programmed death-1，PD-1)是免疫细胞T细胞表面的一种受体蛋白，它会与肿瘤细胞表面表达的程序性死亡配体(Programmed death-ligand 1，PD-L1)发生作用，两者一旦结合便会向T细胞传递一种负向调控信号，诱导T细胞进入静息状态，抑制其免疫识别功能，同时介导T细胞自身增殖减少或凋亡，有效解除机体的免疫反应。而PD-1/PD-L1抑制剂可以阻断PD-1与PD-L1的结合，使T细胞恢复活性，从而增强免疫应答。免疫检查点抑制剂是目前肿瘤免疫疗法的热点，目前上市的免疫检查点抗体主要有：PD-1单抗Nivolumab和Pembrolizumab、PD-L1单抗Atezolizumab、CLTA-4单抗Ipilimumab。虽然免疫检查点抑制剂可以一定程度上提高患者的生存率，在临床应用中带来比较持久的抗肿瘤作用，然而仅有10％-30％的实体瘤患者可以从单药治疗中获益。患者在长期单用免疫检查点过程中，还会发生“响应低”、“无响应”或“耐药”的现象。
大量研究表明，临床患者对免疫检查点阻断治疗的响应很大程度上决定于肿瘤微环境中浸润的免疫T细胞数量及其免疫杀伤活性。因此增加效应毒性T细胞的瘤内浸润是目前迫切需要突破的科学问题。为了达到理想的免疫增效效果，亟需一种安全有效的辅助抗肿瘤药物以联合增效现有免疫治疗。
全氟化碳类化合物是碳氢化合物中的氢原子被氟原子取代后形成的一类化合物，常温下PFC为无色无味，具有强疏水性的透明液体，其化学性质稳定和呈生物惰性，生物相容性良好。全氟化碳具有良好的气体溶解度，使其成为良好的呼吸气体运载介质，最早被用于血液代用品(PFC乳剂)广泛用于医学领域，但是现在的主要医疗用途还是限制在供氧范畴之内。
到目前为止，基于全氟化碳化合物和免疫检查点抑制剂的药物组合物纳米体系在增敏抗肿瘤免疫治疗方面的文献专利未见记载及报道。
发明内容
本发明的目的，在于针对临床免疫疗法的现状和存在问题，提供一种用于抗肿瘤免疫治疗的药物组合物纳米体系，该药物组合物具体包括：治疗有效量的一种或多种全氟化碳化合物、治疗有效量的一种或多种免疫检查点抑制剂和白蛋白外壳。
其中，所述的药物组合物纳米体系既能增加瘤内浸润的免疫细胞数量，且能有效激活免疫细胞的抗肿瘤杀伤活性，同时具有优良的肿瘤靶向性和生物安全性。
进一步地，所述的药物组合物纳米体系，其特征在于所述纳米粒的平均粒径为25nm-400nm，优选100nm-250nm。
进一步地，所述的药物组合物纳米体系，其特征在于所述的全氟化碳化合物为链状、环状、杂环以及卤代或含氮全氟化物中的一种或它们的组合物，其中优选全氟三丁胺、全氟三戊胺和全氟碘代丁烷。
进一步地，所述的药物组合物纳米体系，其特征在于所述白蛋白包括但不限于血清白蛋白、卵白蛋白、乳白蛋白、肌白蛋白、麦白蛋白和豆白蛋白及其他种类白蛋白，或者它们的组合，优选为人血清白蛋白。
进一步地，其中所述免疫检查点抑制剂包含但不限于PD-1、PD-L1、CLTA-4、LAG3、B7-H3、B7-H4、KIR、TIM3的抑制剂及其组合物。
进一步地，其中所述免疫检查点抑制剂为抗体，包含可溶性融合蛋白受体、肽、小分子及其组合物。
进一步地，所述的药物组合物纳米体系在应用时，可被制作成静脉注射制剂或冻干粉针剂。
进一步地，所述的组合物还包含一种或多种药学可接受的赋形剂。
进一步地，所述药物组合物纳米体系中，全氟化碳化合物占总体系比重为0.1mL/mL至0.5mL/mL，其中优选0.2mL/mL。
进一步地，所述药物组合物纳米体系中，免疫检查点抑制剂占总体系比重为0.5mg/mL至3mg/mL，其中优选1mg/mL。
进一步地，所述的药物组合物纳米体系可用于治疗多种癌症包括但不限于结肠癌、三阴性乳腺癌、恶性黑色素瘤、非小细胞肺癌、肝癌、肾细胞癌、前列腺癌、卵巢癌或胃癌。
相较于现有技术，本发明提供的药物组合物纳米体系具有以下优点：
药物组合物纳米体系在使用时，能显著增加肿瘤组织中浸润的CD4+T淋巴细胞和CD8+T淋巴细胞数量，并有效促进抗肿瘤相关免疫细胞分泌毒性杀伤因子IFN-γ、TNF-α和IL-6的水平，从而更好发挥杀伤肿瘤细胞的作用。
本发明药物组合物纳米体系具有良好的肿瘤靶向性，可以特异性蓄积至肿瘤部位，减少对其他正常组织的毒副作用。
本发明药物组合物纳米体系存在协同作用使其抗肿瘤免疫药效优于单一组分形成的纳米体系。
本发明药物组合物纳米体系可以激活肿瘤免疫系统，对肿瘤免疫治疗具有较好的协同增效作用，对于现有缺乏有效治疗药物的恶性肿瘤具有重大的临床研究意义，特别是囿于肿瘤较差的免疫微环境导致的免疫治疗响应低的病例，为增敏临床现有的免疫治疗提供了新的思路和平台。
附图说明
图1是药物组合物纳米体系的制剂外观图
图2是药物组合物纳米体系的体内生物分布图
图3是药物组合物纳米体系作用前后肿瘤血管SEM表征图
图4是给药前后血液中淋巴细胞数量统计结果图
图5是肿瘤部位浸润淋巴细胞的免疫组化荧光图
图6是实施例7中各组小鼠的肿瘤体积和瘤重
图7是实施例8中各组小鼠的肿瘤CD3+、CD4+和CD8+T淋巴细胞相对百分比统计结果图
图8是实施例9中各组小鼠的肿瘤内IFN-γ、TNF-α和IL-6水平统计结果图
图9是实施例10中器官组织切片H&E染色图
图10是药物组合物纳米体系的细胞毒性评价
具体实施方式
下面结合实例对本发明加以进一步说明，以下实施方式只以举例的方式描述本发明。但不意味对本发明加以任何限制，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可做出种种等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。需要了解的是，本发明意欲涵盖在所附权利要求书中包括的变通和修改。
实施例1：包载全氟化碳和PD-L1检查点抑制剂的药物组合物纳米体系(PFC@PD-L1@Albumin)制备方案
量取适量的白蛋白原液，用蒸馏水配置白蛋白溶液(10g/200mL)并置于超声小瓶中，用1mL移液枪预混，再加入1mL全氟碘代丁烷和500μL乙醇(分析纯)，最后加入3mg anti-PD-L1抗体，充分吹打混匀。将上述所得纳米乳体系置于冰水浴中，使用细胞超声破碎仪超声3个循环(超声功率300W)，每个循环2分钟。每次超声结束将制剂静置于4℃水浴中冷却1-2分钟。最后将样品3500rpm离心3min，取上清即为制备的药物组合物纳米体系(PFC@PD-L1@Albumin)，制剂外观见图1。
实施例2：单独全氟化碳白蛋白制剂(PFC@Albumin)制备方案
量取适量的白蛋白原液，用蒸馏水配置白蛋白溶液(10g/200mL)并置于超声小瓶中，用1mL移液枪预混，再加入1mL全氟碘代丁烷和500μL乙醇(分析纯)，充分吹打混匀。将上述所得纳米乳体系置于冰水浴中，使用细胞超声破碎仪超声3个循环(超声功率300W)，每个循环2分钟。每次超声结束将制剂静置于4℃水浴中冷却1-2分钟。最后将样品3500rpm离心3min，取上清即为制备的单独全氟化碳白蛋白制剂(PFC@Albumin)。
实施例3：药物组合物纳米体系在荷瘤小鼠体内的生物分布情况
选取体重在18-22g左右的雄性Balb/c小鼠建立结肠癌(CT26)皮下移植模型，将IR775包载入药物组合物纳米体系来追踪纳米粒在荷瘤小鼠体内的分布情况。小鼠肿瘤接种一周之后，尾静脉注射包载IR775的药物组合物纳米体系(0.1mL/10g)，给药后取1h、10h、24h、48h和72h时间点，用2％戊巴比妥钠溶液对小鼠进行麻醉，通过小动物活体成像对各组小鼠进行生物荧光成像追踪药物组合物纳米体系体内生物分布情况，见图2。结果显示，药物组合物纳米体系可以有效靶向蓄积在肿瘤部位。
实施例4：药物组合物纳米体系对肿瘤血管屏障的影响
取体重在18-22g左右的雄性Balb/c小鼠建立结肠癌(CT26)皮下移植模型。待肿瘤体积长至～200mm3时，将小鼠随机分成两组。实验组小鼠尾静脉注射实施例1制备的PFC@PD-L1@Albumin(10mL/kg)，另外一组注射等量生理盐水作为对照。给药10h后，将小鼠处死并解剖取其肿瘤组织，通过冻干机将肿瘤组织冻干，借助扫描电子显微镜(SEM)观察肿瘤血管表面的孔洞情况，见图3。结果表明，药物组合物纳米体系可以明显增大肿瘤血管表面的孔洞，即该药物组合物纳米体系可以有效打开肿瘤血管屏障，增加肿瘤血管渗透性。
实施例5：药物组合物纳米体系给药前后血液中淋巴细胞变化
选取正常的Balb/c雄性小鼠随机分成2组：①对照组：10mL/kg生理盐水(i.v.)；②10mL/kg实施例1制备的PFC@PD-L1@Albumin(i.v.)。给药10h之后，对各组小鼠进行眼眶取血，将血样进行血常规检测，分析各组小鼠血液中淋巴细胞数目的变化。结果如图4所示，表明药物组合物纳米体系可以显著增加外周血中淋巴细胞数量。
实施例6：药物组合物纳米体系给药前后肿瘤部位淋巴细胞浸润情况
选取正常的Balb/c小鼠解剖取其脾脏，用手术剪剪碎脾脏，再将组织块置于细胞筛网上研磨成细胞匀浆后转移至离心管中，3000rpm离心5min。舍弃上清，取下层细胞并加入红细胞裂解液(ACK)对其中的红细胞进行裂解，再次3000rpm离心5min，用PBS清洗3次，分离可得淋巴细胞。用荧光染料CFSE对分离所得的淋巴细胞进行荧光预标记。另取雄性Balb/c荷瘤小鼠(CT26结肠癌模型)随机分成2组：①对照组：10mL/kg生理盐水(i.v.)；②10mL/kg实施例1制备的PFC@PD-L1@Albumin(i.v.)。给药10h之后，再尾静脉分别注射等量CFSE标记的淋巴细胞。24h之后解剖各组小鼠，取其肿瘤组织制成冰冻切片。用DAPI对肿瘤细胞核进行标记。结果如图5所示，可见药物组合物纳米体系组的小鼠肿瘤组织内浸润的淋巴细胞数量明显增多。
实施例7：采用CT26荷瘤小鼠模型评价药物组合物纳米体系的抗肿瘤药效
选取6-7周龄的雄性Balb/c小鼠，体重在18-22g之间，建立小鼠结肠癌(CT26)皮下移植模型来评估实施例1制备的药物组合物纳米体系(PFC@PD-L1@Albumin)的免疫增敏作用。
肿瘤接种一周后(肿瘤大小约为80mm3)，将小鼠进行随机分成4组(每组8-10只)：①对照组：10mL/kg生理盐水(i.v.)；②10mL/kg全氟化碳白蛋白纳米粒(i.v.)；③10mg/kganti-PD-L1抗体(i.p.)；④10mL/kg药物组合物纳米体系，分别在第0、2、4、6、8天给药，实验持续两周。实验过程中，每天测量一次肿瘤大小并记录数据，各组小鼠肿瘤体积见图6。
结果显示，与anti-PD-L1抗体单独治疗组比，药物组合物纳米体系组小鼠的肿瘤体积均显著降低，表明药物组合物纳米体系能协同增敏免疫药效。
实施例8：药物组合物纳米体系治疗对肿瘤内T细胞浸润的影响
将实施例7中的对照组、单独PFC纳米粒组、单独anti-PD-L1组和药物组合物纳米体系组的小鼠肿瘤组织制作成8μm的切片样本，用anti-mouse CD3-Alexa Fluor抗体(Biolegend)、anti-CD8a-Alexa Fluor 594抗体(Biolegend)和anti-CD4-Alexa Fluor488抗体(Biolegend)荧光染色相应的CD3+、CD8+和CD4+T细胞，通过免疫荧光定量各组小鼠肿瘤组织内浸润各类T细胞相对百分比，结果见图7。结果表明，联合治疗组小鼠肿瘤组织内浸润的CD3+、CD8+和CD4+T细胞的百分比显著升高，该结果与其抑瘤效果具有一致性。
实施例9：药物组合物纳米体系治疗对肿瘤内的免疫杀伤因子水平的影响
将实施例7中的对照组、单独PFC纳米粒组、单独anti-PD-L1组和药物组合物纳米体系组的小鼠肿瘤组织酶解成细胞匀浆，300g离心10min去除下层细胞沉淀，取上清溶液分别进行IFN-γ、TNF-α和IL-6因子水平的酶联免疫吸附检测(ELISA)，检测结果见图8。结果表明，联合治疗组小鼠瘤内IFN-γ、TNF-α和IL-6的水平明显高于anti-PD-L1抗体单独给药组，说明药物组合物纳米体系可以有效激活肿瘤免疫系统，使得效应T细胞的毒性杀伤因子水平显著上升，增敏抗肿瘤免疫效果。
实施例10：药物组合物纳米体系的细胞毒性研究
良好的生物安全性是药物制剂应用的前提，本实验采用的是人脐静脉内皮细胞(HUVEC)模型，考察实施例1制备的PFC@PD-L1@Albumin细胞毒性。将HUVEC以1*104/mL的密度接种于96孔板。培养24h后，加入梯度稀释的实施例1药物组合物纳米体系溶液。加药共培养24h，每孔加入10μL的CCK-8于培养基中，在37℃条件下孵育3h，在450nm波长下测定吸光度值，以未处理细胞为参照，计算细胞存活率，见图9。实验结果表明，药物组合物纳米体系在体外对正常细胞不具有毒副作用。
实施例11：药物组合物纳米体系体内安全性评价
取正常Balb/c小鼠随机分成两组，实验组小鼠尾静脉注射实施例1制备的PFC@PD-L1@Albumin溶液(10mL/kg)，另外一组注射等量生理盐水作为对照。给药7天后，取两组小鼠的正常组织制作H&E病理切片并拍照，见图10。结果表明，药物组合物纳米体系对正常组织没有毒副作用，具有良好的体内生物安全性。
Claims (5)
1.一种用于抗肿瘤免疫治疗的药物组合物纳米体系，其特征在于，该药物组合物由以下成分组成：治疗有效量的一种或者多种全氟化碳化合物、治疗有效量的一种或者多种免疫检查点抑制剂和白蛋白外壳；该药物组合物可以打开肿瘤血管屏障，增加肿瘤血管渗透性，促进具有抗肿瘤活性的CD3+、CD4+和CD8+T淋巴细胞中一种或几种淋巴细胞的肿瘤浸润；
所述免疫检查点抑制剂为可溶性融合蛋白受体、肽、小分子或其组合物，所述免疫检查点抑制剂为PD-1、PD-L1、CLTA-4、LAG3、B7-H3、B7-H4、KIR、TIM3的抑制剂或其组合物；
所述的全氟化碳化合物占总体系比重为0.1mL/mL至0.5mL/mL，所述全氟化碳化合物为含氮全氟化物，所述含氮全氟化物为全氟三丁胺、全氟三戊胺或者全氟碘代丁烷；
所述的免疫检查点抑制剂占总体系比重为0.5mg/mL至3mg/mL；
所述纳米体系的平均粒径为25nm-400nm。
2.根据权利要求1所述的药物组合物纳米体系，其特征在于，所述白蛋白为血清白蛋白、卵白蛋白、乳白蛋白、肌白蛋白、麦白蛋白和豆白蛋白或者它们的组合。
3.根据权利要求2所述的药物组合物纳米体系，其特征在于，所述血清白蛋白为人血清白蛋白。
4.根据权利要求1所述的药物组合物纳米体系，其特征在于，所述的药物组合物纳米体系可增强肿瘤相关T细胞的杀伤活性，升高IFN-γ、TNF-α和IL-6。
5.根据权利要求1所述的药物组合物纳米体系，其特征在于，治疗多种癌症包括结肠癌、三阴性乳腺癌、恶性黑色素瘤、非小细胞肺癌、肝癌、肾细胞癌、前列腺癌、卵巢癌或胃癌。
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| WO2018119313A1 (en) * | 2016-12-23 | 2018-06-28 | The Johns Hopkins University | Tumor and immune cell imaging based on pd-l1 expression |
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