WO2022206451A1 - 靶向-共装载亲/疏水药物的铁蛋白笼纳米载体及其应用 - Google Patents
靶向-共装载亲/疏水药物的铁蛋白笼纳米载体及其应用 Download PDFInfo
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Abstract
本发明通过基因工程技术,将含有疏水肽的功能性基序展示在铁蛋白笼的外表面或内表面,通过铁蛋白纳米笼中的亲水性离子通道和蛋白笼表面上展示的疏水性肽的静电吸附作用,分别将亲疏水药物装载到蛋白笼纳米载体的内腔或外表面,构建新型靶向和亲疏水协同双药共装载的蛋白笼纳米载体。发现该载体不仅可延长小分子药物的半衰期,降低副作用,还通过靶向促进药物对肿瘤细胞的亲和力和渗透性,并可穿越血脑屏障在脑肿瘤中有效聚集。载药后的铁蛋白笼纳米材料可通过协同作用的级联释药策略提高对肿瘤尤其是恶性、耐药性肿瘤的治疗效果,可作为一种新型铁蛋白笼纳米载体平台用于协同性亲疏水药共装载和靶向联合化疗。
Description
本发明属于铁蛋白装载药物技术领域,具体涉及靶向-共装载亲/疏水药物的铁蛋白笼纳米载体及其应用。
铁蛋白是一种铁储存蛋白,在细胞的铁稳态和抗氧化过程中起重要作用。近年来,人类H-铁蛋白(HFn)作为药物载体的应用有了极大的发展。作为天然笼状蛋白,HFn具有空心球形结构,内外直径分别为8nm和12nm,由24个亚基自组装形成独特的24聚体蛋白笼结构。HFn纳米笼具有以下特点:(1)HFn具有很好的生物相容性,即无毒无免疫原性,并且可生物降解成人体所需要的营养物质——氨基酸;(2)HFn可在高温(80℃)下保持稳定和生物活性;(3)HFn具有CD71(也称为转铁蛋白受体,TfR1,在多数肿瘤和血脑屏障(BBB)内皮细胞高表达)靶向性,即无需任何靶向修饰,HFn可通过与受体相互作用主动靶向定位到包括肺癌和乳腺癌在内的不同类型的肿瘤细胞(ZL201110122433.0,PCT/CN2012/075291),而且可以穿越BBB,目前已有几种靶向CD71的纳米药物进入脑肿瘤治疗的临床试验阶段,表明了HFn在肿瘤靶向应用中的潜在用途;(4)在酸性环境和高浓度脲环境中可解组装,而在中性环境中可重新组装成笼状结构,可应用于药物装载和pH响应性的肿瘤药物递送;(5)此外,HFn纳米笼可以由生物系统(例如大肠杆菌系统)稳定和大批量生产,产物HFn蛋白具有均一的尺寸和独特的笼状结构,并可以通过基因工程技术引入其它刺激响应性功能(如酶响应性等)以及靶向功能,从而使得修饰后的HFn具有多重功能,更具智能性,使其成为靶向递送抗肿瘤药物有潜力的纳米载药 系统。因此,由于其具有分子量单一可控、pH响应性释放、半衰期长,良好的生物识别性、生物相容性和生物可降解性等优点,当前研究中多被用于组织工程或作为小分子药物、生物制剂、核酸等的递送载体。2014年,阿霉素分子被首次应用梯度脲方法装载到人HFn内腔,并已证明HFn-Dox针对人乳腺癌,结直肠癌,肝癌三种不同的小鼠移植瘤模型都有很好的抗肿瘤效果。2018年,HFn-Dox被证明可以有效穿透BBB并靶向治疗脑神经胶质瘤。利用HFn蛋白笼在pH控制和脲等变性剂浓度调控的情况下发生蛋白笼解聚和重新聚合的特点,抗肿瘤化疗药物(如铂类药物,阿霉素,姜黄色素,阿托品,5-氟尿嘧啶等),小干扰RNA,光动力/光热治疗药物(如IR820)等都被报道成功装载到HFn蛋白笼内腔中,并且表现出了良好的抗肿瘤活性。综上所述,目前将HFn用于化疗药物体内递送取得了良好的治疗效果。这些初步的研究表明,HFn作为新一代天然蛋白纳米载体在小分子药物高效递送中具有广阔的应用前景,有望成为生物材料学科发展的一个新生长点与应用出口。
目前HFn的载药方法主要包括直接将药物化学偶联到HFn表面,以及pH或脲介导的HFn解聚/复聚法(ZL201410230829.0,PCT/CN2014/140159)。然而这些方法会影响HFn理化性质,同时造成潜在毒性,难以实现产业化转化,且药物装载效率有限,不能满足临床需求。近期研究发现HFn纳米笼上存在亲水性离子通道,可以允许亲水性小分子药物在铁蛋白天然状态下实现装载,升温可进一步打开通道,促进亲水性药物装载(CN202011496039.9),为HFn提供了温和、稳定、便捷的载药方法。然而,受可溶性蛋白质的亲水性限制,目前基于铁蛋白的纳米药物载体依然难以有效装载疏水性药物,而疏水性药物通常会由于迅速从体内清除,生物利用度极低而限制其临床应用。同时在一个HFn蛋白纳米载体上装载亲水性和疏水性药物更是巨大挑战。而由于联合化疗优越的协同治疗效果,亲疏水药物 共装载和可控递送也是联合化疗在临床中的应用需求。因此,需要进一步考虑将HFn作为纳米载体的药物装载新策略。
发明内容
为实现上述目的,本发明制备了生物工程化铁蛋白笼纳米载体(amphiphilic multi-drug loading protein nanocage,Am-PNCage,下文统一用Am-PNCage指代铁蛋白笼纳米载体),并应用了一种非变性条件下,保持Am-PNCage结构完整的前提下,方便、快捷、高效、足量的亲疏水药物共装载的方法。利用本发明的Am-PNCage亲疏水双药共装载体系,可大幅度提高铁蛋白的药物装载量,进而在达到同样治疗前提下,临床给药剂量将会大大减少。
第一方面,本发明提供了一种靶向-共装载亲/疏水药物的铁蛋白笼纳米载体,所述铁蛋白笼纳米载体中的至少一个铁蛋白亚基经过含有疏水性多肽的功能性氨基酸基序修饰。
在某些实施例中,所述修饰为所述含有疏水性多肽的功能性氨基酸基序替换所述铁蛋白亚基的第五α螺旋。
在某些实施例中,所述含有疏水性多肽的功能性氨基酸基序直接连接至所述铁蛋白亚基的C末端。
在某些实施例中,所述含有疏水性多肽的功能性氨基酸基序由5-200个氨基酸组成,优选由5-15个氨基酸组成。
在某些实施例中,所述疏水性多肽包括但不限于疏水性氨基酸A、F、I、L、M、P、V、W、Y中任意一种或至少两种的组合。
在某些实施例中,所述疏水性多肽为AAVVVFAFAFAFA(SEQ ID NO:1),AAIMV(SEQ ID NO:2),LLLVVVAAA(SEQ ID NO:3),PPWWYYYLVVAA(SEQ ID NO:4),基质金属蛋白酶MMP-2响应肽 PLGLWA(SEQ ID NO:5)任一或至少两种的组合。
在某些实施例中,所述含有疏水性多肽的功能性氨基酸基序还包括与疏水性多肽连接的任意多肽,所述任意多肽为亲水肽和/或靶向肽。
在某些实施例中,所述亲水肽为任意亲水性氨基酸序列组合,包括但不限于亲水性氨基酸D、E、H、K、Q、R、S、T中任意一种或至少两种的组合,优选为HHHHHHKK(SEQ ID NO:6),DDDDEDDDDE(SEQ ID NO:7),RRQQHHHHHH(SEQ ID NO:8),DDDSSTT(SEQ ID NO:9),DDEEKKQS(SEQ ID NO:10),HHEQSSTTT(SEQ ID NO:11);
在某些实施例中,所述靶向肽优选为肿瘤靶向肽GRGDS(SEQ ID NO:12),肿瘤靶向肽QHWSYGLRPG(SEQ ID NO:13),纤维蛋白靶向肽CREKA(SEQ ID NO:14),脑毛细血管内皮细胞靶向肽HAIYPRH(SEQ ID NO:15),巨噬细胞靶向肽YEQDPWGVKWWY(SEQ ID NO:16),神经细胞靶向肽CLEVSRKNC(SEQ ID NO:17),心肌细胞靶向肽CSTSMLKAC(SEQ ID NO:18)中任一种或至少两种的组合。
第二方面,本发明提供了第一方面所述的铁蛋白笼纳米载体在亲水性和/或疏水性小分子药物装载及递送中的应用,所述装载是在铁蛋白笼纳米载体在非变性条件下进行药物装载。
在某些实施例中,所述小分子药物包括但不限于化学小分子药物、核酸药物、放射性药物。
在某些实施例中,所述铁蛋白笼纳米载体与所述亲水性小分子药物装载摩尔质量比为1:100~1:180,优选地,1:130~1:150。
在某些实施例中,所述亲水性小分子药物为蒽环类,铂类,嘧啶类,生物碱类;蒽环类优选为表阿霉素、柔红霉素;铂类优选为顺铂、卡铂、奥沙利铂;嘧啶类优选为吉西他滨、卡培他滨、阿糖胞苷;生物碱类优选为伊利替康。
在某些实施例中,所述铁蛋白笼纳米载体与所述疏水性小分子药物装载摩尔质量比为1:20~1:70,优选地,1:30~1:50。
在某些实施例中,所述疏水性小分子药物为嘧啶类,紫杉醇类,亚硝脲类;所述嘧啶类为5-氟尿嘧啶、吉美嘧啶,所述紫杉醇类为紫杉醇、多西他赛,所述亚硝脲类为替莫唑胺、尼莫斯汀。
在某些实施例中,所述药物装载的反应体系中缓冲液为任意pH为6~8的缓冲液,优选地,Tris-HCl缓冲液;和/或,优选地,溶液浓度为10~300mM。
在某些实施例中,所述小分子核酸药物优选为siRNA,lncRNA。
与现有技术相比,本发明具有以下优势:
1、通过基因工程修饰,用疏水肽-亲水肽-RGD肽(靶向肿瘤细胞表面高表达的整合素ɑvβ3)组成的功能性基序P
out替换人HFn亚基的第五螺旋,将多肽功能基序展示在铁蛋白笼的外表面;或将疏水肽基序Pin直接连接在人HFn的C末端,将多肽功能基序展示在铁蛋白笼的内表面,构建出2种Am-PNCage重组质粒,并用大肠杆菌表达纯化出相应蛋白。因此其结构与功能完全精准可控。
2、本发明在保证Am-PNCage结构不变,非变性条件下,通过简便易行的两步法,将亲水性药物EPI和疏水性药物CPT分别空间立体地装载到Am-PNCage纳米载体的内腔和外壳上,制备出EPI@Am-PNCage-P
out/CPT纳米颗粒。或通过更加简单的一步法,将亲水性EPI和疏水性CPT药物分子同时装载到Am-PNCage纳米载体的内腔,制备出EPI/CPT@Am-PNCage-P
in纳米颗粒。对于EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in,一个纳米载体上的EPI和CPT载药量摩尔比分别为1:132:50和1:150:39,是目前基于HFn的纳米载体得到的最大载药量。
3、本发明在体外探索了EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in由于两亲性结构引起的药物在不同空间位点共装载及其引发的级联药物释放动力学特性。体外表征EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的抗细胞增殖生物活性、协同作用系数、靶向肿瘤细胞亲和力、肿瘤渗透能力及体外抗耐药肿瘤治疗功效。体内表征EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的药物代谢动力学、生物分布、最大耐受剂量、肿瘤靶向性、对不同肿瘤模型的治疗效果及生物安全性。系统研究Am-PNCage的结构与功能对装载药物的释放动力学、活性、稳定性、体内药代、生物分布、药效和生物安全性的影响规律并阐明协同作用机制。
4、利用本发明所提出的生物工程化修饰方法,可以方便、快捷、高效、足量的利用Am-PNCage装载临床一线常用的不同亲水/疏水抗癌药物组合,并表现出优秀的抗肿瘤增殖活性和抗耐药功能。作为一种广谱性多药载药平台可广泛应用于靶向联合化疗。。
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式描述中所需要使用的附图作简单地介绍。
图1为Am-PNCage的合成和表征。(A)纯化后HFn和Am-PNCage蛋白的SDS-PAGE表征;(B)HFn和Am-PNCage的分子排阻分析;(C)TEM图像分析;(D)通过DLS测量的纳米载体的流体动力学尺寸。
图2为EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的合成和表征。(A)HFn和Am-PNCage载药后的分子排阻分析;(B)TEM图像分析;(D)DLS粒径分析。
图3为EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的体外药物释放动力学。(A)在37℃下PBS和小鼠血清中72小时的稳定性;(B)在不同pH值(5.0和7.4)条件下,PBS中的EPI和CPT释放;(C)CLSM分析U87细胞对双药共装载的Am-PNCage纳米颗粒的内吞以及EPI和CPT在不同时间的顺序释放行为。紫色,溶酶体;红色,细胞核;绿色,EPI;蓝色,CPT。
图4为EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的细胞毒性作用。(A)装载双药或单一药物的Am-PNCage纳米载体处理48小时后的U87,HepG2和MCF7/MDR细胞活力;(B)EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in在不同细胞系中的CI值;(C-D)EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in对细胞集落抑制效果。
图5为双重靶向的EPI@Am-PNCage-P
out/CPT特异性靶向肿瘤细胞并促进药物渗透。(A)EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
i
n与肿瘤细胞结合;(B)流式细胞仪检测U87细胞亲和能力;(C)EPI@Am-PNCage-P
out/CPT在MCF7/MDR 3D细胞球中的渗透率;(D)70μm处截面断层扫描的EPI荧光强度分布图;(E)EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in对MCF7/MDR耐药细胞球的生长抑制作用;(F)MCF7/MDR细胞球6天内的体积变化。
图6为EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in血药浓度随时间的变化。
图7为EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的体内 生物分布。注射后1、4和24小时(n=3)在肿瘤和主要组织中的近红外荧光图像(A,B)和定量(C,D)。
图8为EPI@Am-PNCage-P
out/CPT(A)和EPI/CPT@Am-PNCage-P
in(B)的最大耐受剂量。
图9为EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in对U87脑胶质瘤(A),HepG2肝癌肺转移瘤(B),MCF7/MDR(C)耐药性乳腺癌的抗肿瘤功效。
图10为EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的体内生物安全性。(A)最大耐受剂量注射后小鼠主要组织器官的H&E染色;(B)血液学和生化分析。
图11为Am-PNCage共装载亲疏水药物的广谱性。(A)各种小分子抗癌药物的吸收光谱;(B-K)Am-PNCage-P
out和Am-PNCage-P
in装载不同的协同亲水和疏水药物组合后的吸收光谱。280nm处的虚线表示Am-PNCage蛋白的吸收峰。
图12为Am-PNCage-P
out(A)和Am-PNCage-P
in(B)共装载不同亲疏水药物组合后的细胞毒性测定。
图13为Am-PNCage纳米载体装载双药或单一药物后的IC50值。
下面将结合附图对本发明技术方案的实施例进行详细的描述。以下实施例仅用于更加清楚地说明本发明的技术方案,因此只是作为示例,而不能以此来限制本发明的保护范围。需要注意的是,除非另有说明,本申请使用的技术术语或者科学术语应当为本发明所属领域技术人员所理解的通 常意义。实施例中所用试剂除非特殊说明,均为市售常规产品。
定义
本发明的铁蛋白是指可以形成笼状结构的任何铁蛋白,其可以是天然来源的铁蛋白,也可以是重组表达的铁蛋白,或其突变体,其可以来源于原核生物、原生生物、真菌、植物或动物,例如来源于细菌、真菌、昆虫、爬行动物、禽类、两栖动物、鱼类、哺乳动物,例如来源于啮齿类动物、反刍动物、非人灵长类动物或人类,例如小鼠、大鼠、豚鼠、犬类、猫、牛、马、羊、猴、大猩猩、人。从细菌到人类,尽管不同生物的铁蛋白氨基酸序列具有极大的差别,但其结构相似,均可以形成蛋白壳结构。在一些实施方案中,本发明的铁蛋白是人铁蛋白,在一些实施方案中,本发明的铁蛋白是基因工程全人重链铁蛋白,其亚基核苷酸序列如SEQ ID NO:3所示。
本发明的疏水性多肽是指含有疏水性的氨基酸序列,包括但不限于疏水性氨基酸A(丙氨酸)、F(苯丙氨酸)、I(异亮氨酸)、L(亮氨酸)、M(甲硫氨酸)、P(脯氨酸)、V(缬氨酸)、W(色氨酸)、Y(酪氨酸)的任一或至少两种的组合,以及有生物功能的疏水性多肽。本发明的亲水性多肽是指除疏水性氨基酸之外的任意亲水性氨基酸序列组合,包括但不限于亲水性氨基酸D(天冬氨酸)、E(谷氨酸)、H(组氨酸)、K(赖氨酸)、Q(谷氨酰胺)、R(精氨酸)、S(丝氨酸)、T(苏氨酸)。
本发明的药物或包载药物是指可以包载在铁蛋白中的任何药物,只要所述药物的分子尺寸小于8纳米。在一些实施方案中,本发明的药物或包载药物选自抗生素类肿瘤药物、天然来源类抗肿瘤药、金属化合物、放射性同位素、烷化剂、抗代谢类抗肿瘤药,激素类抗肿瘤药物。其中抗生素类抗肿瘤药选自阿霉素(盐酸多柔比星),盐酸佐柔比星,戊柔比星,硫酸博莱霉素,丝裂霉素,盐酸表柔比星,盐酸依达比星,放线菌素D,光辉霉 素,柔红霉素,吡柔比星,表阿霉素,依达比星,阿克拉霉素,博来霉素A5,色霉素A3,盐酸博来霉素,棕霉素,盐酸平阳霉素,柔红霉素,盐酸阿柔比星,含氮霉素,匹来霉素,盐酸吡柔比星,放线菌素C;天然来源类抗肿瘤药选自盐酸拓扑替康,10-羟基喜树碱,7-乙基-10-羟基喜树碱,10-羟基喜树碱,鲁比特康,白藜芦醇,喜树碱,紫杉醇,秋水仙素,依托泊甙,多西他赛,硫酸长春碱,斑蝥素,伊立替康,舒尼替尼,鬼臼毒素,拓扑替康,克唑替尼,高三尖杉酯碱,埃博霉素,替尼泊甙,帕博西尼,野百合碱,长春新碱,长春瑞宾,硫酸长春地辛,靛玉红,硫酸长春新碱,去甲斑蝥素,去甲斑蝥素,鬼臼毒素,多西他赛,秋水仙碱,三尖杉碱,埃博霉素C,埃博霉素E,华蟾素,硫酸长春地辛,去甲斑蝥酸钠,美登素,肿节风,足叶草脂,重酒石酸长春瑞宾,马蔺子素,鸦胆子油,米托肼,三尖杉酯碱,秋裂胺,羟喜树碱,甲基斑蝥胺;金属化合物选自卡铂,顺铂,奈达铂,奥沙利铂等;放射性同位素选自钋,氡,钫,镭,锕,钍,镤,铀,镎,钚,锝,钷,镅,锔,锫,锎,锿,镄,钔,锘,铹,104,105,106,107,108和109号元素;烷化剂选自盐酸苯达莫司汀,咪唑司汀,苯磺酸贝托司汀,白消安,恩比兴,达卡巴嗪,洛莫司汀,苯丁酸氮,芥卡莫司汀,三亚乙基硫代磷酰胺,盐酸尼莫司汀,美法仑尼莫司汀,苯达莫司汀,雌莫司汀,磷酸钠2,3-二溴-1,4-丁烯二醇,雌莫司汀,六甲蜜胺,福莫司汀,尼莫司汀,加莫司汀,泼尼莫司汀,雌莫司汀,磷酸依考莫司汀,他莫司汀,氨莫司汀,雌莫司汀,盐酸苯达莫司汀杂质A,奈莫司汀,波呋莫司汀,盐酸依匹司汀,盐酸苯达莫司汀杂质C,洛莫司汀胶囊,盐酸倍他司汀,盐酸倍它司汀,二硫莫司汀,牛磺莫司汀,依莫司汀,螺莫司汀,盐酸苯达莫司汀杂质B,泼尼莫司汀,司莫司汀,雷莫司汀,卡波醌,甲尿嘧啶氮芥,氮芥,依匹司汀,碱乌拉莫司汀,二溴甘露醇,盐酸氧氮芥,氧氮芥,依匹哌啶,邻脂苯芥,去水卫矛醇,亚胺醌,甲氧芳芥, 恩普氨酯,甘磷酰芥,硝卡芥,异芳芥,氮甲,三亚胺醌,甘露醇氮芥,2,4,6-三亚乙基亚胺-1,3,5-三嗪;抗代谢类抗肿瘤药选自甲氨蝶呤,5-氟-2'-脱氧脲核苷,吉西他滨,去氧氟尿苷,阿糖胞苷,6-硫鸟嘌呤,盐酸吉西他滨,磷酸氟达拉滨,酒石酸长春瑞滨,氟达拉宾,替莫唑胺,己酮可可碱,克罗拉滨,奈拉滨,盐酸环胞苷,替加氟,盐酸阿糖胞苷,6-巯基嘌呤,4-羟基-5-氟嘧啶,5-氟尿嘧啶,氨基蝶呤,米替福新,雷替曲塞,脱氧助间型霉素,卡莫氟,安吖啶,乙嘧替氟,替加氟,环胞啶,甲异靛,氟尿嘧啶,肌苷二醛,1-乙烯基-1-甲基-2,4-二(丙-1-烯-2-基)环己烷,磺巯嘌呤钠;激素类抗肿瘤药选自依西美坦,雷洛昔芬,氟维司群,来曲唑,阿那曲唑,氟他胺,枸橼酸他莫昔芬,屈洛昔芬,艾多昔芬,尼鲁米特,氨鲁米特,福美司坦,他莫昔芬,托瑞米芬,氨鲁米特。
本发明的亲水性小分子药物为蒽环类,铂类,嘧啶类,生物碱类。蒽环类,更优选为表阿霉素、柔红霉素;铂类,更优选为顺铂、卡铂、奥沙利铂;嘧啶类,更优选为吉西他滨、卡培他滨、阿糖胞苷;生物碱类,更优选为伊利替康。
本发明的疏水性小分子药物为嘧啶类,紫杉醇类,亚硝脲类。嘧啶类,更优选为5-氟尿嘧啶、吉美嘧啶;紫杉醇类,更优选为紫杉醇、多西他赛;亚硝脲类,更优选为替莫唑胺、尼莫斯汀。
不受限于任何理论,本发明的包载药物的铁蛋白可以靶向肿瘤,与肿瘤结合后释放包载的药物,药物从而作用于肿瘤,实现对肿瘤的预防和/或治疗。例如,人铁蛋白可能通过结合其受体转铁蛋白受体(Transferr
in Recept or 1,TfR1)特异性靶向人体实体肿瘤和血液恶性癌变细胞,如肺癌、乳腺癌、前列腺癌、宫颈癌、结直肠癌、卵巢癌、食管癌、胃癌、胸腺癌、T淋巴细胞白血病、红细胞白血病等。
在一些实施方案中,本发明的药物或包载药物选自抗肿瘤药物之外的 药物,即,非抗肿瘤药物。例如,这样的药物可以是不需要靶向性的药物,例如全身性施用的药物,例如难溶的、不稳定的和/或易发生相互作用而失效的药物。在一些实施方案中,这样的药物选自两性霉素B、醋酸格拉替雷、复合葡萄糖酸钠铁、雷帕霉素、盐酸司维拉姆硫酸根结合剂、注射用维替泊芬、蔗糖铁、聚乙二醇干扰素α-2a/2b、非诺贝特、培非格司亭、利培非格司亭、阿米卡星、芬太尼、环孢霉素、西替利嗪、辣椒素、神经酰胺等。在一些实施方案中,本发明的非抗肿瘤药物选自放射性药物、神经递质类药物、多巴胺受体激动剂、神经中枢抗胆碱药、胆碱受体激动剂类药物、γ分泌酶抑制剂、抗氧剂或麻醉剂,更优选地,放射性药物选自
64Cu、
235U,神经递质类药物选自碳酰胆碱、阿托品、东莨菪碱、多巴胺及其衍生物,多巴胺受体激动剂选自溴隐亭、培高利特、阿扑吗啡等麦角碱类衍生物及非麦角碱类衍生物,神经中枢抗胆碱药选自苯海索、苯扎托品及丙环定,胆碱受体激动剂类药物选自毒蕈碱、毛果芸香碱,γ分泌酶抑制剂选自双氟酮类,抗氧剂选自褪黑激素,麻醉剂选自蒽胺。
在一些实施方案中,在将药物包载到铁蛋白中时需要在孵育溶液中加入添加剂,以促进药物的溶解和/或铁蛋白的聚集,从而实现和/或改善药物包载效果。例如,在一些实施方案中,涉及包载铂类药物,此时需要在孵育溶液中加入DMA、DMF、DMSO或其混合物。根据待包载药物的不同,需要添加的添加剂也可能相应不同。
在一些实施方案中,孵育溶液的缓冲体系为Tris-HCl缓冲液、磷酸盐缓冲液(PBS)、碳酸盐缓冲液、甘氨酸缓冲液或柠檬酸盐缓冲液,缓冲液的pH介于6-8,例如6.5、7、7.5,缓冲液的浓度介于20~500mM,更优选地,25~100mM,更优选地,25~50mM。根据使用的缓冲液的不同,其缓冲能力、pH范围、所需浓度等可能需要进行调整。
实施例一生物工程化铁蛋白笼纳米载体Am-PNCage的构建
1、应用基因工程技术,用疏水肽-亲水肽-RGD肽组成的功能性氨基酸基序P
out(AAVVVFAFAFAFAHHHHHHKKGRGDS(SEQ ID NO:19))替换人HFn亚基的第五螺旋,将多肽功能基序展示在铁蛋白笼的外表面,构建Am-PNCage-P
out(SEQ ID NO:20)。用疏水肽组成的功能性氨基酸基序P
in(AAVVVFAFAFAFA(SEQ ID NO:1))直接连接到HFn的C末端,将多肽功能基序展示在铁蛋白笼的内表面,构建Am-PNCage-P
in(SEQ ID NO:21)。两种Am-PNCage重组质粒序列和HFn亚基的DNA序列(SEQ ID NO:22)经全基因合成(Generay,Shanghai)后,使用NdeI和BamH1限制性内切酶酶切,将其克隆到具有NdeI和BamHI限制酶切位点的大肠杆菌(E.coli)表达载体pET22b(+)质粒(Novagen)中,经DNA测序鉴定序列正确。
2、Am-PNCage的表达和纯化
蛋白表达:将上述获得的质粒转入E.coli BL21(TransGen)表达菌株,转化后的大肠杆菌在含100mg/L氨苄的LB培养基中生长过夜,然后用0.5mM的IPTG(Sigma-Aldrich),30℃培养8h来诱导蛋白表达。
蛋白纯化:4000g离心15min收集菌体,并在Tris缓冲液(20mM Tris,pH 8.0)中重悬。重悬的大肠杆菌菌体高压匀浆破碎后,12000g离心30min收集上清。上清液80℃热处理20min,使大部分大肠杆菌杂蛋白变性沉淀下来,再次12000g离心30min收集上清。随后用阴离子交换柱Q-Sepharose Fast Flow(GE Healthcare)纯化分离HFn及Am-PNCage蛋白,最后用superdex200(10/300GL,GE Healthcare)分子筛纯化分离。以牛血清白蛋白为标准,采用BCA蛋白检测试剂盒(Pierce)测定HFn及其突变体蛋白的浓度,三次重复。
通过十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)验证蛋白纯度,通过体积排阻色谱(SEC)验证Am-PNCage的成功自组装。通过透射电子 显微镜(TEM)和动态光散射(DLS)进一步表征Am-PNCage的形态。
结果如图1所示,SDS-PAGE分析表明,多肽修饰后的Am-PNCage在21kDa左右的分子量处出现与HFn相似的单一条带,与理论值吻合。Am-PNCage在SEC柱上的洗脱体积与24聚体HFn蛋白笼相似,证明Am-PNCage成功自组装成笼状结构。并且在TEM下显示出与HFn相似的球状形貌,表明多肽修饰不会影响蛋白质的整体纳米笼结构。DLS结果显示Am-PNCage平均粒径在14-16nm,与TEM结果一致。
实施例二生物工程化的铁蛋白纳米笼(Am-PNCage)协同性亲疏水药共装载的方法
1、对于多肽功能基序P
out展示在铁蛋白笼外表面的Am-PNCage-P
out,将Am-PNCage-P
out纳米载体与亲水药EPI在60℃环境下避光孵育4小时,使用透析袋(MWCO 3500Da,Thermofisher Scientific)除去游离的EPI药物分子,获得产物EPI@Am-PNCage-P
out,然后避光于室温下与疏水药CPT混合搅拌过夜,透析除去游离的CPT药物分子,获得终产物EPI@Am-PNCage-P
out/CPT。通过简便易行的两步法,将亲水性药物EPI和疏水性药物CPT分别空间立体地装载到Am-PNCage-P
out纳米载体的内腔和外壳上。分别按上述方法制备EPI@Am-PNCage-P
out和Am-PNCage-P
out/CPT作为对照。
2、对于多肽功能基序P
in展示在铁蛋白笼内表面的Am-PNCage-P
in,将Am-PNCage-P
in纳米载体与亲水药EPI和疏水药CPT混合均匀后在60℃环境下避光孵育4小时,使用透析袋除去游离的药物分子,即可获得产物EPI/CPT@Am-PNCage-P
in。分别按上述方法制备EPI@Am-PNCage-P
in和CPT@Am-PNCage-P
in作为对照。
3、通过SEC验证两种药物EPI和CPT的成功装载并计算药物装载量,通过TEM表征Am-PNCage载药前后的形貌,通过DLS测定水合粒径。
结果如图2所示:
对于P
out展示在铁蛋白笼外表面的Am-PNCage-P
out,通过简单的两步反应,首先将亲水性EPI通过HFn的亲水性离子通道经热处理封装到Am-PNCage-P
out的内腔中,然后将复合物与CPT孵育,后者通过疏水相互作用与蛋白笼外表面上展示的疏水P
out肽结合。即可制备将亲疏水药物分别空间立体地装载到Am-PNCage-P
out纳米载体的内腔和外壳上的EPI@Am-PNCage-P
out/CPT。结果表明,1个Am-PNCage-P
out纳米载体能够稳定装载132个左右EPI分子和50个左右CPT分子。
对于P
in展示在铁蛋白笼内表面的Am-PNCage-P
in,通过更加简单的一步反应,即可将亲水药EPI和疏水药CPT共同封装到Am-PNCage-P
in纳米载体的内腔中,获得产物EPI/CPT@Am-PNCage-P
in。其中CPT通过疏水相互作用与蛋白笼内表面上展示的疏水P
in肽结合。结果表明,1个Am-PNCage-P
in纳米载体能够稳定装载150个左右EPI分子和39个左右CPT分子。
经比较,此方法的载药量是已有报道的基于HFn的纳米载体的最高载药量。SEC结果表明,HFn只能装载亲水药EPI而无法装载疏水药CPT,疏水性多肽的修饰克服了HFn亲水性的局限,从而达到了将亲水和疏水性药物有效装载在一种蛋白质纳米载体上的目的。Am-PNCage蛋白纳米笼的洗脱液在480nm和365nm处有两个特定的吸收峰,分别对应于EPI和CPT,证明了EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的形成。通过TEM和DLS进一步表征了EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的形态,药物的共同装载未能影响HFn纳米笼的单分散状态和自组装笼状性质,平均粒径为14-16nm。
实施例三将EPI和CPT分别装载到Am-PNCage纳米载体的不同空间结构位点引起不同药物释放机制,表现出药物级联释放的动力学特性
1、体外稳定性和药物级联释放动力学
用透析法在37℃下体外表征EPI@Am-PNCage/CPT在血清和PBS中的稳定性和不同pH条件下的药物释放性能。为了研究EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的药物释放特性,将10mg样品溶于2mL PBS溶液,放入透析管中,将其分别浸入pH值为7.4和5.0的30mL缓冲溶液中并在37℃透析。通过检测EPI和CPT的荧光强度来计算释放的药物浓度(EPI的λex=480nm,CPT的λex=365nm)。通过将双药共装载的Am-PNCage纳米载体与PBS(pH=7.4)或正常小鼠血清共孵育,以相同的方法进行稳定性评估。
2、细胞内药物递送过程
在37℃下将U87脑胶质瘤细胞与EPI@Am-PNCage-P
out/CPT或EPI/CPT@Am-PNCage-P
in孵育不同时间(0.5、2、6、24和48小时),然后用冷的PBS洗涤细胞,并在室温下用4%甲醛固定20分钟。进一步对溶酶体用溶酶体相关膜蛋白1(LAMP1)染色,细胞核用碘化丙啶(PI)染色。在共聚焦激光扫描显微镜(CLSM,Carl Zeiss LSM 700)下观察EPI@Am-PNCage-P
out/CPT或EPI/CPT@Am-PNCage-P
in内吞进入肿瘤细胞的过程和细胞内定位,以及药物在细胞内的释放速度和顺序。
结果如图3所示:
用透析法研究药物释放性能,EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in在小鼠血清和PBS(pH=7.4)中稳定,在72小时内没有明显的药物释放。但在pH 5.0孵育时却观察到了更快的释放:仅在6小时后,将近68%-69%的EPI和47%的CPT被释放,而48小时后90%的EPI和CPT被释放,表明低pH值引起了HFn纳米笼的分解,并表现出了EPI和CPT的先后释放顺序。
使用CLSM进一步研究了药物在细胞内的释放过程。EPI@Am-PNCage-P
out/CPT或EPI/CPT@Am-PNCage-P
in孵育U87细胞2小时后,纳米载体 主要位于溶酶体中,6小时后,虽然EPI(绿色荧光)主要定位在细胞核中,但CPT(蓝色荧光)仍大部分保留在溶酶体中。孵育后24小时,从Am-PNCage纳米载体释放的EPI和CPT都积聚在细胞核中,作用于DNA并激活凋亡途径,导致细胞核溶解并在48小时内死亡。因此,EPI和CPT依次从溶酶体中的纳米载体中释放出来,并最终进入细胞核以发挥抗癌作用。这可能是由于EPI和CPT的载药途径和释放机制不同。EPI@Am-PNCage-P
out/CPT或EPI/CPT@Am-PNCage-P
in靶向结合受体内吞进入细胞后被溶酶体途径吸收,在溶酶体酸性环境下随着纳米笼的缓慢崩解释放EPI,随着表面上的疏水作用逐渐减弱,进一步缓慢释放CPT。时空程序化的级联药物释放动力学延长了药物在细胞中的滞留时间,有助于增强抗肿瘤活性。
实施例四Am-PNCage装载的亲疏水双药通过协同作用提高细胞毒性和抗耐药功效
1、CCK8细胞毒性检测
选用U87脑胶质瘤细胞、HepG2肝癌细胞和MCF7/MDR耐药乳腺癌细胞,应用细胞增殖试剂盒8(CCK8),通过细胞增殖试验研究双药共装载的EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in对肿瘤细胞的毒性,并与装载其中一种药物的Am-PNCage纳米载体和游离小分子药物进行比较。使用Origin 8.0(OriginLab,Northampton,MA)计算半致死剂量(IC50)。
2、药物相互作用研究
通过药物互作方程CIx=Da/Dxa+Db/Dxb计算出Am-PNCage共装载的两种药物EPI和CPT的相互作用性质和协同作用参数。抑制浓度(ICx)值使用Origin 8.0(OriginLab,Northampton,MA)确定。其中Da和Db是共同发挥作用的药物a和药物b的浓度。Dxa和Dxb是达到相同效果的单个药物对应的浓度。CI>1表示拮抗作用,CI=1表示加性反应,CI< 1表示协同作用。
3、肿瘤细胞集落形成实验
将2×10
3个U87细胞接种到6孔板中,并与载药的Am-PNCage纳米载体在37℃下孵育24小时。然后将药物溶液替换为新鲜的培养基继续培养,培养10天后待其形成宏观细胞集落,用结晶紫染色,进行细胞集落计数,研究EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in在较长时间内的抗肿瘤细胞功效。
结果如图4及表1所示:
双药共装载的EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in对U87脑胶质瘤细胞,HepG2肝癌细胞,以及MCF7/MDR耐药乳腺癌细胞的抑制作用明显大于单药载体(EPI@Am-PNCage-P
out、Am-PNCage-P
out/CPT、EPI@Am-PNCage-P
in和CPT@Am-PNCage-P
in)。依据IC50值的结果可知,EPI@Am-PNCage-P
out/CPT对肿瘤细胞的毒性高于EPI/CPT@Am-PNCage-P
in,并且可以更有效地克服肿瘤细胞的耐药性,这可能是由于P
out肽包含靶向肿瘤细胞表面整合素ɑvβ3的RGD序列,因此EPI@Am-PNCage-P
out/CPT通过CD71和ɑvβ3双重靶向介导的入胞作用增强以及细胞内药物浓度升高克服了转运蛋白对药物的外排作用。
为了证明Am-PNCage纳米载体上装载的EPI和CPT的协同作用,根据方程式CIx=Da/Dxa+Db/Dxb计算出了药物相互作用性质的组合指数(CI)。结果表明,EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的CI值在有效药物水平范围内都小于1,表明EPI和CPT之间存在显著的协同作用。
细胞集落形成实验结果表明,在EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in处理的肿瘤细胞中,菌落的形成受到了明显的抑制。进一步证明了Am-PNCage装载的EPI和CPT具有优异的协同作用,能够在 较长时间内抑制肿瘤细胞增殖。
表1:Am-PNCage纳米载体装载双药或单一药物后的IC50值
实施例五双重靶向促进特异性结合,肿瘤渗透和体外治疗效果
1、CLSM研究靶向特异性
为了研究EPI@Am-PNCage-P
out/CPT与CD71和αvβ3的相互作用,将EPI@Am-PNCage-P
out/CPT(10μM)处理的U87肿瘤细胞与抗CD71和抗αvβ3单克隆抗体或其中之一共孵育。然后将细胞用4%预冷甲醛固定,并用PI进一步染色细胞核,通过CLSM观察肿瘤细胞膜上结合的EPI@Am-PNCage-P
out/CPT含量,研究双重靶向的特异性。为了研究与CD71受体相互作用的EPI/CPT@Am-PNCage-P
in受体介导的靶向作用,将EPI/CPT@Am-PNCage-P
in(10μM)处理的U87肿瘤细胞与抗CD71单克隆抗体孵育,按上述方法通过CLSM研究CD71靶向特异性。
2、流式细胞术研究亲和能力
为了进行结合能力分析,用Cy5标记的Am-PNCage和HFn装载药物,将100μL分散的U87细胞悬液(2.5×10
6细胞/mL)分别与10μM的EPI@Am-PNCage-P
out/CPT,EPI@Am-PNCage-P
out,Am-PNCage-P
out/CPT,Am-PNCage-P
out或EPI/CPT@Am-PNCage-P
in,EPI@Am-PNCage-P
in,Am-PNCage-P
in/CPT,Am-PNCage-P
in,以及HFn和PBS在4℃下孵育45分钟。将 处理后的肿瘤细胞用流式细胞仪系统分析药物荧光强度,比较具有双靶向功能的Am-PNCage-P
out载体和单一靶向CD71的Am-PNCage-P
in的肿瘤细胞亲和力,并与HFn进行对比。
3、3D细胞球实验
(1)双靶向促进药物肿瘤渗透的能力
将2×10
3个MCF7/MDR耐药乳腺癌细胞接种到超低附着力的圆底96孔板(Corning,美国)培养形成3D细胞球。将EPI@Am-PNCage-P
out/CPT,EPI@Am-PNCage-P
out,Am-PNCage-P
out/CPT,EPI@HFn,游离EPI、游离CPT加入培养8小时后,使用激光共聚焦断层扫描获得荧光图像,用尼康NIS-Elements分析双靶向的Am-PNCage-P
out纳米载体的肿瘤渗透能力,并与单一靶向的HFn进行对比研究。
对耐药性肿瘤的体外疗效
为了研究EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in的体外治疗效果,按上述方法培养形成MCF7/MDR耐药细胞的3D细胞球,在第0天加入EPI@Am-PNCage-P
out/CPT,EPI@Am-PNCage-P
out,Am-PNCage-P
out/CPT,EPI@HFn,或EPI/CPT@Am-PNCage-P
in,EPI@Am-PNCage-P
in,Am-PNCage-P
in/CPT,以及游离EPI和CPT,记录MCF7/MDR的3D细胞球6天内的体积变化。评价亲疏水双药共装载的Am-PNCage对耐药肿瘤的治疗功效。
结果如图5所示:
CLSM结果证明了EPI@Am-PNCage-P
out/CPT可通过结合CD71和αvβ3与U87神经胶质瘤细胞膜结合。而EPI/CPT@Am-PNCage-P
in仅通过结合CD71与U87细胞膜结合。流式细胞术(FACS)结果显示,靶向CD71的HFn与细胞的结合荧光强度约为50,Am-PNCage-P
in的荧光曲线与HFn重合,表明多肽修饰未改变铁蛋白笼与细胞的亲和力,而双重靶向的Am-PN Cage-P
out纳米载体的荧光强度约为100,这表明与单靶向相比,双重靶向的Am-PNCage-P
out纳米载体与肿瘤细胞的结合能力增强。
在此基础上,进一步通过MCF7/MDR耐药乳腺癌3D细胞球评估双重靶向的EPI@Am-PNCage-P
out/CPT渗透到肿瘤组织中的能力,发现游离EPI和CPT孵育后的细胞球相对暗淡,且荧光大部分出现在边缘区域。而EPI@Am-PNCage-P
out/CPT孵育后,球体边缘和核心区域都有EPI和CPT荧光。表明双重靶向纳米载体进一步增强了药物渗透能力。70μm处截面断层扫描的EPI荧光强度图谱显示,与未经含有靶向肽的P
out多肽修饰,只具有铁蛋白笼CD71单一靶向的EPI@HFn相比,双重靶向的EPI@Am-PNCage-P
out向3D细胞球中聚集的药物明显更多。
与EPI/CPT@Am-PNCage-P
in相比,EPI@Am-PNCage-P
out/CPT对MCF7/MDR体外耐药细胞球生长的抑制更为有效。结果表明,双靶向Am-PNCage-P
out纳米载体对肿瘤细胞的亲和力优于单靶向的Am-PNCage-P
in,并显著增强了肿瘤穿透能力,有效克服了3D肿瘤细胞球的耐药性。其原因可能是CD71和ɑvβ3受体介导的有效的内吞作用,细胞内溶酶体中的高药物浓度以及EPI和CPT的级联释放和协同效应介导的对药物的敏感性提高。
实施例六药代动力学性质
将EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in 10mg/mL与等效剂量的EPI@Am-PNCage-P
out,Am-PNCage-P
out/CPT,EPI@Am-PNCage-P
in,CPT@Am-PNCage-P
in,EPI和CPT静脉注射到BALB/c裸鼠体内,在注射后的不同时间点,从尾静脉收集血液,分离血浆。将获得的血浆样品(10μL)与490μL酸化的异丙醇避光于-20℃孵育过夜,以提取游离药物。然后将混合物以15,000×g离心20分钟,并将上清液加载到96孔板(Corning)上。使用Varioskan Flash光谱扫描多模式读板机(ThermoFisher Scientific)在480nm或365nm下测量荧光来确定EPI或CPT浓度。以未处理 小鼠的血液样品荧光作为背景。扣除非特异性背景荧光后,通过与荧光标准曲线进行比较,对血液样品的药物浓度进行定量并分析血液中药物浓度随时间变化情况。
结果如图6及表2所示:
我们研究了EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in纳米载体以及游离药物EPI和CPT的药代动力学性质。结果表明,用EPI@Am-PNCage-P
out/CPT给药的小鼠血浆中的药物半衰期(6.79±0.07h)比游离EPI和CPT的半衰期分别长8.5倍(0.80±0.12h)和12.6倍(0.54±0.26h)。EPI@Am-PNCage-P
out/CPT的曲线下面积(AUC)(160.24±27.99%ID/mL*h)比游离EPI和CPT大76倍(2.10±0.42%ID/mL*h)和111倍(1.44±0.35%ID/mL*h)。EPI/CPT@Am-PNCage-P
in的药代动力学性质与之相似,且双药共装载和单药装载的Am-PNCage的小鼠药代动力学没有显著差异,表明将药物装载于Am-PNCage纳米载体是延长药物循环时间的原因。
表2:Am-PNCage纳米载体装载双药或单一药物后的药代动力学参数(n=3)
实施例七Am-PNCage纳米载体可促进所装载药物在肿瘤中的靶向富 集,延长药物在肿瘤中的滞留时间
为了进行药物的生物分布研究,建立U87-luc脑胶质瘤小鼠模型,通过尾静脉注射剂量为3mg/kg EPI当量的EPI@Am-PNCage-P
out/CPT,EPI@Am-PNCage-P
out,EPI/CPT@Am-PNCage-P
in,EPI@Am-PNCage-P
in和游离EPI。注射后1、4和24小时后,收集小鼠的肿瘤以及主要器官(心、肝、脾、肺、肾),应用IVIS光谱成像系统(Xenogen)进行离体组织近红外成像。并通过Living Image软件分析各组织器官中的EPI药物荧光强度。
结果如图7所示,将EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in静脉注射U87胶质瘤荷瘤小鼠1、4和24小时后,收集组织器官和脑组织用于离体成像。结果表明,EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in在24小时内在肿瘤中的富集量大大优于游离药物。与游离EPI相比,给药1小时和4小时后,EPI@Am-PNCage-P
out/CPT,EPI@Am-PNCage-P
out,EPI/CPT@Am-PNCage-P
in,EPI@Am-PNCage-P
in在肿瘤部位都表现出显著增强的EPI信号。EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in组小鼠在注射后1h的肿瘤荧光强度分别是游离EPI处理的小鼠的15.2倍和10.4倍。在注射后4小时和24小时,在肿瘤中检测到强荧光信号,但由于血液的快速清除,在给予游离EPI的小鼠肿瘤中几乎没有发现信号。
实施例八Am-PNCage纳米载体大大提高机体对所装载药物的最大耐受剂量
使用6周龄健康雌性SPF BALB/c小鼠研究Am-PNCage共装载亲疏水药物后的最大耐受剂量变化。以25、30、35mg/kg体重剂量的EPI@Am-PNCage-P
out/CPT,30、35、40mg/kg体重剂量的EPI/CPT@Am-PNCage-P
i
n和5、10、15mg/kg的游离EPI或CPT对小鼠进行尾静脉注射(n=3)。每天监测小鼠体重和存活率的变化,持续两周。对失去了超过15%治疗前 体重的小鼠实施安乐死。没有动物死亡且体重减轻不超过15%的最高剂量定义为最大耐受剂量。
结果如图8所示,为了评估其最大耐受剂量,给小鼠注射不同剂量的EPI@Am-PNCage-P
out/CPT或EPI/CPT@Am-PNCage-P
in。对于EPI@Am-PNCage-P
out/CPT组,给药剂量为25和30mg/kg时,小鼠几乎没有可见的功能障碍,并且体重没有明显变化,但是给予35mg/kg EPI@Am-PNCage-P
o
ut/CPT的小鼠体重逐渐减少,在6天内降至初始体重的85%以下,因此,EPI@Am-PNCage-P
out/CPT的最大耐受剂量约为30mg/kg。同理得到EPI/CPT@Am-PNCage-P
in的最大耐受剂量约为35mg/kg。相比之下,单次注射游离EPI和CPT的最大耐受剂量仅为10mg/kg。因此,亲疏水双药共装载的Am-PNCage纳米载体可显著改善EPI和CPT的最大耐受剂量,从而可以应用更高剂量的EPI和CPT进行癌症治疗。
实施例九双靶向的Am-PNCage纳米笼共装载亲疏水药物后表现出高效杀伤肿瘤的能力
本研究中的所有小鼠及其相应研究均经中国科学院动物保护与使用委员会批准(批准号:SYXK2019021)。
U87脑胶质瘤的治疗效果评估
通过脑内原位注射1×10
6个表达荧光素酶的U87MG(U87-luc)细胞建立小鼠脑胶质瘤模型,将小鼠称重,随机分为6组,分别静脉注射剂量为3mg/kg的EPI@Am-PNCage-P
out/CPT,EPI/CPT@Am-PNCage-P
in与等效EPI剂量的EPI@Am-PNCage-P
out,EPI@Am-PNCage-P
in,EPI和等效CPT剂量的Am-PNCage-P
out/CPT,CPT@Am-PNCage-P
in,CPT。每3天给药一次,共给药3次。每3天应用IVIS光谱成像系统(Xenogen)进行活体成像比较肿瘤体积变化。在实验期间测量小鼠的存活率和体重。使用TUNEL细胞死亡检测试剂盒(罗氏)对固定的肿瘤切片进行染色。用荧光显微镜(IX7 1,Olympus)观察肿瘤组织切片。
HepG2肝癌肺转移瘤的治疗效果评估
通过尾静脉注射2×10
6个表达荧光素酶的HepG2(HepG2-luc)细胞建立肝癌肺转移的小鼠模型,将小鼠称重,随机分为6组,分别静脉注射最大耐受剂量的EPI@Am-PNCage-P
out/CPT(30mg/kg),EPI/CPT@Am-PNCage-P
in(35mg/kg)与等效EPI剂量的EPI@Am-PNCage-P
out,EPI@Am-PNCage-P
in,EPI和等效CPT剂量的Am-PNCage-P
out/CPT,CPT@Am-PNCage-P
in,CPT。每3天应用IVIS光谱成像系统(Xenogen)进行活体成像比较肿瘤体积变化。在实验期间测量小鼠的存活率和体重。在第30天处死小鼠后取肺,用PBS洗涤三次,10%中性福尔马林固定,用苏木精和伊红(H&E)染色,并通过光学显微镜(DM5500B,徕卡)进行成像观察。
MCF7/MDR耐药性乳腺癌治疗效果评估
乳房脂肪垫原位注射1×10
7个耐药的MCF7/MDR细胞建立耐药性乳腺癌小鼠模型。当肿瘤体积达到50mm
3时,将小鼠称重,随机分为6组,分别静脉注射最大耐受剂量的EPI@Am-PNCage-P
out/CPT(30mg/kg),EPI/CPT@Am-PNCage-P
in(35mg/kg)与等效EPI剂量的EPI@Am-PNCage-P
o
ut,EPI@Am-PNCage-P
in,EPI和等效CPT剂量的Am-PNCage-P
out/CPT,CPT@Am-PNCage-P
in,CPT。在实验期间,每3天测量小鼠的肿瘤大小和体重。并以V=L×W
2/2计算肿瘤体积,其中L代表肿瘤的最大直径,W代表肿瘤的最小直径。
结果如图9所示:
小鼠脑内注射U87-luc肿瘤细胞后,第7、10、13天静脉给药治疗。结果表明,PBS组小鼠肿瘤持续生长,而EPI@Am-PNCage-P
out/CPT治疗导致肿瘤明显消退,且由于双靶向提高了Am-PNCage与肿瘤细胞亲和能力和渗透性,其治疗效果优于单靶向的EPI/CPT@Am-PNCage-P
in,进一步通过 TUNEL法表征瘤内细胞凋亡情况。亲疏水双药共装载的EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in治疗组比单药装载的EPI@Am-PNCage,EPI@Am-PNCage-P
in和游离的EPI诱导了更多的肿瘤细胞凋亡。结果证明了EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in在体内杀死胶质瘤的优越能力,这可能是由于其BBB穿透能力,选择性靶向肿瘤细胞,以及药物的协同作用实现的。
通过在第15天单次注射最大耐受剂量来评估各种药物对HepG2-Luc肿瘤的治疗效果。在用EPI@Am-PNCage-P
out/CPT(30mg/kg)和EPI/CPT@Am-PNCage-P
in(35mg/kg)治疗的小鼠中,肺中的HepG2-Luc肿瘤被显著抑制。相反,注射了EPI,CPT或PBS的小鼠肿瘤大小均增加,并在第33天之前死亡。
以最大耐受剂量一次给药后,EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in有效阻止了MCF7/MDR耐药肿瘤的生长,而单药装载的Am-PNCage仅部分抑制了肿瘤的增长。直到第120天EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in组小鼠依然全部存活,显著延长了生存时间(单药装载的Am-PNCage组少于60天,而EPI、CPT或PBS组小鼠的平均存活时间少于36天)。这些数据表明EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in对小鼠耐药MCF7/MDR细胞具有有效的靶向和杀伤作用。
实施例十共装载亲疏水药物的Am-PNCage纳米笼表现出极好的生物安全性
1、组织学检查
以最大耐受剂量注射EPI@Am-PNCage-P
out/CPT或EPI/CPT@Am-PNCage-P
in后,将主要组织器官用福尔马林固定。制作石蜡切片并通过H&E染色,用Nikon Eclipse 90i显微镜对肿瘤组织切片进行组织学检测和形态观 察。
2、血液学检查
为了进行血液学检查,通过眼眶后采集血样,并通过自动生化分析仪进行分析,以获取临床血液学参数,主要包括:肝功能的标志物丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST),肾功能的标志物肌酐(CREA)和血尿素氮(UREA),心脏功能的标志物肌酸激酶同工酶(CK-MB)和乳酸脱氢酶(LDH)。
结果如图10所示,为了评估最大耐受剂量注射后的生物安全性,对组织切片,血细胞和生化参数进行了组织学检查。收集小鼠的主要器官,包括心脏,肝脏,肺,脾脏和肾脏,以进行组织学检查。EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in治疗组的H&E染色切片未显示明显的器官损伤。小鼠的血液生化指标表明其心脏,肝脏和肾脏的功能正常,与游离药物或PBS处理组无明显差别。因此,EPI@Am-PNCage-P
out/CPT和EPI/CPT@Am-PNCage-P
in没有明显的器官和组织毒性,并且具有生物相容性。
实施例十一Am-PNCage纳米笼表现出共装载亲疏水药物的广谱性
按照与实施例二相同的两步或一步反应方法,用Am-PNCage纳米笼共装载临床上有协同作用的其他亲疏水药物组合,制备双药共装载的Oxaliplatin@Am-PNCage/5-Fluorouracil,Gemcitabine@Am-PNCage/5-Fluorouracil,Gemcitabine@Am-PNCage/Docetaxel,Epirubicin@Am-PNCage/Docetaxel,和Irinotecan@Am-PNCage/Temozolomide,通过SEC验证两种药物的成功装载。
结果如图11所示,通过两步或一步孵育方法在Am-PNCage纳米载体上装载其他亲水/疏水抗癌药物组合。SEC结果证明了Oxaliplatin@Am-PNCage/5-Fluorouracil,Gemcitabine@Am-PNCage/5-Fluorouracil,Gemcitabine@Am-PNCage/Docetaxel,Epirubicin@Am-PNCage/Docetaxel,和Irinotecan @Am-PNCage/Temozolomide除了280nm的蛋白吸收峰外,吸收光谱均与相应的游离药物光谱匹配,表明两种药物的成功装载。因此,除EPI/CPT外,Am-PNCage还具有有效装载临床中使用的多种协同性亲水/疏水抗肿瘤药物的能力,并且在将来可能具有广泛的临床应用。
实施例十二Am-PNCage纳米笼共装载亲疏水药物组合后具有广谱性的协同作用抗肿瘤增殖能力
针对药物临床应用方向分别选用U87脑胶质瘤细胞、HepG2肝癌细胞和MCF7/MDR耐药乳腺癌细胞,应用细胞增殖试剂盒8(CCK8),通过细胞增殖试验研究双药共装载的Oxaliplatin@Am-PNCage/5-Fluorouracil,Gemcitabine@Am-PNCage/5-Fluorouracil,Gemcitabine@Am-PNCage/Docetaxel,Epirubicin@Am-PNCage/Docetaxel,和Irinotecan@Am-PNCage/Temozolomide对肿瘤细胞的毒性,并与装载其中一种药物的Am-PNCage纳米载体和游离小分子药物进行比较。使用Orig
in 8.0(Orig
inLab,Northampton,MA)计算半致死剂量(IC50)。
结果如图12-13所示,在有效装载多种协同性亲水/疏水抗肿瘤药物的基础上,进一步通过细胞毒性实验评估双重靶向的Am-PNCage共装载多种亲疏水药物组合后的抗肿瘤细胞增殖能力,发现共装载有成对的亲水和疏水协同抗癌药物的Am-PNCage显示出比单独装载亲水药物和疏水药物时显著增强的细胞毒性作用,表明Am-PNCage共装载亲疏水药物组合后具有广谱性的协同作用抗肿瘤细胞增殖的能力,具有广阔的临床应用前景。
除非另外具体说明,否则在这些实施例中阐述的数值并不限制本发明的范围。在这里示出和描述的所有示例中,除非另有规定,任何具体值应被解释为仅仅是示例性的,而不是作为限制,因此,示例性实施例的其他示例可以具有不同的值。
Claims (10)
- 一种靶向-共装载亲/疏水药物的铁蛋白笼纳米载体,其特征在于,所述铁蛋白笼纳米载体中的至少一个铁蛋白亚基经过含有疏水性多肽的功能性氨基酸基序修饰。
- 根据权利要求1所述的铁蛋白笼纳米载体,其特征在于,所述修饰为所述含有疏水性多肽的功能性氨基酸基序替换所述铁蛋白亚基的第五α螺旋或所述含有疏水性多肽的功能性氨基酸基序直接连接至所述铁蛋白亚基的C末端。
- 根据权利要求1所述的铁蛋白笼纳米载体,其特征在于,所述含有疏水性多肽的功能性氨基酸基序由5-200个氨基酸组成,优选由5-15个氨基酸组成。
- 根据权利要求3所述的铁蛋白笼纳米载体,其特征在于,所述疏水性多肽包括但不限于疏水性氨基酸A、F、I、L、M、P、V、W、Y中任意一种或至少两种的组合。
- 根据权利要求4所述的铁蛋白笼纳米载体,其特征在于,所述疏水性多肽为AAVVVFAFAFAFA(SEQ ID NO:1),AAIMV(SEQ ID NO:2),LLLVVVAAA(SEQ ID NO:3),PPWWYYYLVVAA(SEQ ID NO:4),基质金属蛋白酶MMP-2响应肽PLGLWA(SEQ ID NO:5)任一或至少两种的组合。
- 根据权利要求1所述的铁蛋白笼纳米载体,其特征在于,所述含有疏水性多肽的功能性氨基酸基序还包括与疏水性多肽连接的任意多肽,优选地,所述任意多肽为亲水肽和/或靶向肽;所述亲水肽为任意亲水性氨基酸序列组合,包括但不限于亲水性氨基酸D、E、H、K、Q、R、S、T中任意一种或至少两种的组合,优选为HHHHHHKK(SEQ ID NO:6),DDDDEDDDDE(SEQ ID NO:7),RRQQHHHHHH(SEQ ID NO:8),DDDSSTT(SEQ ID NO:9),DDEEKKQS(SEQ ID NO:10),HHEQSSTTT (SEQ ID NO:11);所述靶向肽优选为肿瘤靶向肽GRGDS(SEQ ID NO:12),肿瘤靶向肽QHWSYGLRPG(SEQ ID NO:13),纤维蛋白靶向肽CREKA(SEQ ID NO:14),脑毛细血管内皮细胞靶向肽HAIYPRH(SEQ ID NO:15),巨噬细胞靶向肽YEQDPWGVKWWY(SEQ ID NO:16),神经细胞靶向肽CLEVSRKNC(SEQ ID NO:17),心肌细胞靶向肽CSTSMLKAC(SEQ ID NO:18)中任一种或至少两种的组合。
- 权利要求1-6任一所述的铁蛋白笼纳米载体在亲水性和/或疏水性小分子药物装载及递送中的应用,其特征在于,所述装载是在铁蛋白笼纳米载体在非变性条件下进行药物装载。
- 根据权利要求7所述的应用,其特征在于,所述小分子药物包括但不限于化学小分子药物、核酸药物、放射性药物。
- 根据权利要求8所述的应用,其特征在于,所述铁蛋白笼纳米载体与所述亲水性小分子药物装载摩尔质量比为1:100~1:180,优选地,1:130~1:150;其中,亲水性小分子药物为蒽环类,铂类,嘧啶类,生物碱类,蒽环类优选为表阿霉素、柔红霉素,铂类优选为顺铂、卡铂、奥沙利铂,嘧啶类优选为吉西他滨、卡培他滨、阿糖胞苷,生物碱类优选为伊利替康。
- 根据权利要求8所述的应用,其特征在于,所述铁蛋白笼纳米载体与所述疏水性小分子药物装载摩尔质量比为1:20~1:70,优选地,1:30~1:50;其中所述疏水性小分子药物为嘧啶类,紫杉醇类,亚硝脲类,所述嘧啶类为5-氟尿嘧啶、吉美嘧啶,所述紫杉醇类为紫杉醇、多西他赛,所述亚硝脲类为替莫唑胺、尼莫斯汀。
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