CN109678905B - 一种配位驱动的自组装超分子笼、制备方法及其应用 - Google Patents
一种配位驱动的自组装超分子笼、制备方法及其应用 Download PDFInfo
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Abstract
本发明提供了一种配位驱动的自组装超分子笼,所述超分子笼包括四吡啶卟啉衍生物或四吡啶金属卟啉衍生物和Pt(II)受体。采用配位驱动的自组装形成的超分子笼结构,与MOF和纳米颗粒等结构相比,具有非常特殊且独特的结构,且分子量分布单一,更易于控制和使用。该结构中Pt(II)受体将四吡啶卟啉生物分布在其两侧,大大降低了卟啉的自身聚集,避免了卟啉的π‑π堆积和聚集,生产1O2的效率将得到有效提高。分子笼中的四吡啶基卟啉衍生物或四吡啶基金属卟啉衍生物充当PDT光敏剂和给体,Pt(II)受体充当化疗的受体。Pt(II)受体的引入,不但可以增加药物的化学疗法的能力,还可以因为Pt(II)受体进入精确的超分子笼实现与光动力疗法实现更高的协同抗癌效率。
Description
技术领域
本发明属于医药技术领域,涉及一种超分子笼、制备方法及其应用,具体涉及一种配位驱动的自组装超分子笼、制备方法及其应用。
背景技术
在过去的几十年中,光动力疗法(PDT)已被证明是治疗肺癌,膀胱癌,皮肤癌和食道癌的有吸引力和有前途的临床方法。PDT是光敏剂(PS)被适当波长的光激活,产生活性氧(ROS)以诱导癌细胞死亡。与传统治疗手段相比,PDT显示出几个明显的优势,如无创治疗,时间可控,可忽略不计的耐药性和低毒副作用。在许多可能具有PDT功能的光敏剂中,卟啉及其衍生物受到特别关注。因此,科研工作者努力设计并合成了一系列具有改善的PDT效果的新型卟啉光敏剂。例如,Lin(J.Am.Chem.Soc.2014,136,16712)的研究小组开发了几种新型的NMOF,它们将结构的有序性和多孔性与特定的光敏剂结合起来,以实现高PS负载。Tang(Angew.Chem.Int.Ed.,2018,57,4891)的研究小组设计了几种新的MOF,包括Cu(II)和金属卟啉衍生物,以降低细胞内谷胱甘肽浓度或调控基于硫化氢活化的单线态氧。Yan(J.Am.Chem.Soc.,2017,139,1921)的研究小组利用基于简单肽或两亲性氨基酸自组装的纳米粒子传输递送平台来改善药物的EPR效应。Spingler(Angew.Chem.Int.Ed.,2014,53,6938)小组报道了四种卟啉衍生物并证明了卟啉表现出明显的DNA裂解现象以及光照射下的光细胞毒性。然而,大多数报道的卟啉衍生物由于大的平面结构导致严重的π-π堆积,大幅减少1O2的产生,抑制了PDT效率。这种聚集在缺氧条件下产生低单线态氧浓度已经成为限制卟啉衍生物和其他光敏剂在潜在临床应用中实现PDT功能的常见限制之一。
发明内容
为了解决上述问题并同时赋予卟啉衍生物更好的抗癌性能,本发明通过合理地设计,成功的合成了的具有双组分配位驱动的自组装超分子笼。有效降低了卟啉分子之间的距离,增加了单线态氧的产生效率,具有优异的抗癌效果。
具体技术方案如下:
一种配位驱动的自组装超分子笼,所述超分子笼包括四吡啶卟啉衍生物或四吡啶金属卟啉衍生物和Pt(II)受体,其结构为式(I):
本发明采用配位驱动的自组装形成的超分子笼结构,与MOF和纳米颗粒等结构相比,具有非常特殊且独特的结构,且分子量分布单一,更易于控制和使用。分子笼结构的设计组分的相对位置和数量是严格固定的,Pt(II)受体将四吡啶卟啉生物分布在其两侧,大大降低了卟啉的自身聚集,避免了卟啉的π-π堆积和聚集,生产1O2的效率将得到有效提高。分子笼中的四吡啶基卟啉衍生物或四吡啶基金属卟啉衍生物充当PDT光敏剂和给体,Pt(II)受体充当化疗的受体。Pt(II)受体的引入,不但可以增加药物的化学疗法的能力,还可以因为Pt(II)受体进入精确的超分子笼实现与光动力疗法实现更高的协同抗癌效率。
优选的,所述四吡啶卟啉衍生物的结构为式(II):
其中:
R1为H、烷基;
R2为H、F、Cl、Br、I、烷基。
优选的,所述四吡啶金属卟啉衍生物的结构为式(III):
其中:
R1为H、烷基;
R2为H、F、Cl、Br、I、烷基;
M为Zn、Co、Mn、Ce、Fe、Mg、Hg、Ru、Cu、Zr、Rh、Pt、Sn、Tl、Al、Pt、Pd、Ir、Sb、V、Ti、Hf、Au、Cr、Ag、In、Tb、Gd、Er、Yb、Lu、Dy、Nd、Eu、Pr、Ho、Tm、La、Sm;
更优选的,所述四吡啶金属卟啉衍生物的结构为
优选的,所述Pt(II)受体的结构为式(IV)中任意一种:
其中:
R3为H、烷基、氨基、醛基、酰胺基、芳基;
Y为O、S、N、Se或Te;
更优选的,所述Pt(II)受体的结构为
本发明的另一个目的是提供一种自组装超分子笼的制备方法,所述四吡啶卟啉衍生物或四吡啶金属卟啉衍生物与Pt(II)受体的摩尔质量比为1:2,将上述物质溶解于有机溶液中,在60~120℃条件下反应12h,冷却至室温后,进行后处理。
所述反应温度优选为70~100℃,更有选的反应温度为80℃。
所述有机溶剂包括烷烃,例如:戊烷、己烷、庚烷、环己烷,芳香溶剂,例如:甲苯、二甲苯,或者醚类溶剂,例如:乙二醇二甲醚、四氢呋喃、1,4-二氧六环,或者极性溶剂,例如:DMF,DMSO。优选的溶剂为DMSO。
反应的后处理可采用常规的方式处理,包括:沉淀、过滤、淋洗、干燥等。一个典型的后处理方案如下:反应结束后,向反应液中加入一定的有机溶剂,形成沉淀,过滤,用有机溶剂淋洗后,真空干燥。所述的有机溶剂通常用与本发明化合物不溶的或溶解性差的溶剂,例如:正己烷、二乙醚、乙醚等。优选的溶剂为乙醚。
本发明还提供一种注射或者用于口服的组合物,所述组合物包含上述任意一种所述的自组装超分子笼以及药学上可接受的载体。
所述自组装超分子笼在制备利用光动力学治疗法和化学疗法杀死癌细胞的方法中所用药品中的应用。
利用光动力治疗法和化学疗法杀死癌细胞的方法,包括使所述癌细胞与自组装超分子笼接触,并用治疗有效量的光照射自组装超分子笼,诱发所述自组装超分子笼放出单线态氧。
本发明设计的具有新颖结构的自组装超分子笼具有以下优点。首先,与诸如MOF和纳米颗粒的许多结构相比,超分子配位复合物(SCC)具有非常特殊且独特的结构,更易于控制和使用。其次,在SCC中,组分的相对位置和数量是严格固定的,特别是在3D笼结构中,卟啉衍生物可以很好地避免π-π堆积和聚集,生产1O2的效率将得到提高。最后,将Pt(II)引入笼结构中,可在PDT功能上增加化疗能力。因此,组合通过PDT和化学疗法的协同作用,四吡啶卟啉衍生物或四吡啶金属卟啉衍生物和Pt(II)受体进入精确的超分子笼可以实现更高的协同抗癌效率。
附图说明
图1PDP和ZPDP的电喷雾电离质谱(ESI-MS);
图2PDP和ZPDP结构相关的谱图(2D COSY);
图3PDP NPs和ZPDP NPs透射电子显微镜(TEM)和动态激光散射(DLS)研究;
图4单线态氧荧光探针(SOSG)的研究;
图5PDP NPs的体外细胞摄取和协同细胞毒性研究;
图6PDP NPs在患4T1原位乳腺癌小鼠的体内分布及协同抗癌机理研究;
图7对治疗后癌细胞转移情况以及肿瘤体积和在肺表面覆盖率的研究。
具体实施方式
下面通过实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1
PDP的合成
称取5,10,15,20-四(3-吡啶基)卟啉(P)16.2μmol与4,4'-双(反式-双(三乙基膦)(三氟甲烷)合铂)二苯甲酮(DP)32.4μmol,将上述物质溶解于二甲基亚砜中,在80℃条件下反应12h,冷却至室温后,加入过量的二乙醚,形成沉淀,过滤,用乙醚洗涤,然后真空干燥,得到深棕色固体(51.5mg,96.4%)。
1H NMR(δppm):δ9.60(m,8H,Py-Ha),δ9.33(d,8H,Py-Hb),δ8.94(m,24H,Py-Hd,P-He),δ8.28(t,8H,Py-Hc),δ7.63(d,16H,Ph-H2),δ7.20-7.30(m,16H,Ph-H1),δ-3.13(s,4H,P-Hf).
31P{1H}NMR:δ=12.64ppm
ESI-MS(图1(A)):6600Da
2D相关光谱(2D COSY)(图2(A))
实施例2
ZPDP合成
称取锌5,10,15,20-四(4-吡啶基)-21H,23H-卟啉(ZP)14.7μmol与4,4'-双(反式-双(三乙基膦)(三氟甲烷)合铂)二苯甲酮(DP)29.4μmol,将上述物质溶解于二甲基亚砜中,在80℃条件下反应12h,冷却至室温后,加入过量的二乙醚,形成沉淀,过滤,用乙醚洗涤,然后真空干燥,得到紫黑色固体(47.0mg,95.1%)。
1H NMR:δ9.60(s,8H,Py-Ha),δ9.29-9.30(d,8H,Py-Hb),δ8.84-8.87(m,24H,Py-Hd,ZP-He),δ8.22-8.25(t,8H,Py-Hc),δ7.64(d,16H,Ph-H2),δ7.21-7.32(m,16H,Ph-H1)
31P{1H}NMR:12.73ppm
ESI-MS(图1(B)):6732Da
2D相关光谱(2D COSY)(图2(B))
实施例3
超分子笼负载纳米颗粒的制备
超分子笼负载纳米颗粒PDP NPs和ZPDP NPs的制备
将含有6.0mg超分子笼(PNP或ZPNP),mPEG-b-PEBP(25.0mg)和RGD-PEG-b-PEBP(5.0mg)的5mL丙酮溶液滴加到20mL Milli-Q水中并剧烈的搅拌,真空干燥。超声处理5分钟后,获得良好分散的纳米颗粒悬浮液。
纳米颗粒的形态和尺寸通过透射电子显微镜(TEM)和动态激光散射(DLS)进行研究,见图3,可以看出,图3A所示,在干燥状态下观察到直径范围为30~90nm的球形PDP NPs。由于NPs的水合作用,从DLS(图3B)记录了稍大的亲水直径。在将PDP笼加载到NPs中之后观察到直径从35.7nm增加到61.8nm,表明两亲聚合物成功包封笼子。此外,PE封装PDP后,PEBP-b-PEG-RGD形成的NP的zeta电位从-46.9mV增加到-5.4mV(图3C),表明电荷-电荷相互作用是其中的主要驱动力之一。除了疏水相互作用外,自组装的形成。获得的PDP NPs在含有10%胎牛血清的磷酸盐缓冲盐水(PBS)中37℃下培养48小时能稳定存在,证明PDP NPs在生物环境中具有良好的胶体稳定性。
实施例4
单线态氧荧光探针(SOSG)用于量化激光照射(638nm,0.5W/cm2)下纳米材料的活性氧(ROS)产生。如图4A所示,未形成超分子笼结构的P和ZP的荧光强度相近似,其值在2500左右,而形成超分子笼结构后,观察到PDP在532nm处的荧光强度在10000左右,强度增加4倍,这主要由于特殊的超分子笼结构使得卟啉衍生物可以很好地避免π-π堆积和聚集,生产1O2的效率将得到提高。
但P NPs和ZP NPs观察到在532nm处的荧光强度相对与实施例3中的超分子笼负载纳米颗粒来说还是较低,ROS的猝灭主要归因于它们的较差的溶解度和少量π-π堆积相互作用。形成鲜明对比的是,在相同条件下引入笼状结构(PDP NPs)后,SOSG荧光显示出4倍的增强,强度接近40000,证实了它们的高光敏效果(图4a)。PDP NPs产生的ROS产量高,应归功于超分子笼结构,有效防止P分子的聚集,而重原子(Pt)掺入笼中,有利于将分子氧转化为单线态氧。值得说明的是由于ZPDP NPs中Zn离子的引入导致Q-带的移动,因此在此波段的激光照射下产生ROS较低。(图4B)
实施例5
细胞毒性实验
αvβ3整合素受体是肿瘤细胞过度表达的最广泛研究的靶点之一,在本研究中被选择用于抗小鼠三阴性乳腺癌细胞(4T1)。Cyclo(Arg-Gly-Asp-D-Phe-Lys)(cRGD)已被选作特异性靶向部分,因为它可以高亲和力选择性地结合αvβ3整合素,并且在血液循环中具有相对高的稳定性,赋予PDP NPs优异的肿瘤靶向能力。受体介导的细胞摄取通过流式细胞仪和电感耦合等离子体质谱(ICP-MS)定量确认PDP NPs,用更快和更高的细胞摄取PDP NPs证明cRGD由αvβ3整合素过表达4T1细胞而不是没有cRGD的对应物(图5A,图5B)。
将化学疗法和PDT置于单一实验中,PDP NPs在照射时有效引发细胞毒性,其通过使用MTT测定法定量(图5C)。DP和DP+L的半数最大抑制浓度(IC50)测定为7.85±0.8μM和8.15±0.7μM,高于市售顺铂(IC50=4.39±0.7μM,数据未显示)。这可能归因于DP在水性环境中的不稳定性,导致毒性降低。结果还证明激光照射不能增强DP的毒性。在没有光照射的情况下,PDP NPs的IC50值降低至3.56±0.6μM。原因是DP在超分子笼中稳定,并且在细胞摄取后可诱导细胞毒性。光照射(638nm,2分钟,0.2W/cm 2)确定P NPs的IC50值为0.51±0.12μM,而没有激光照射,P NPs没有显示明显的细胞毒性。从PDP NPs+L组观察到最令人兴奋的结果,显示照射后IC50值为87.4±8.7nM,远低于单独的化学疗法和PDT。PDP NPs+L的增强的细胞毒性由化学疗法和PDT的优异协同效应产生,组合指数(CI)远低于1(CI=0.17)。计算出在暗处和暴露于光照射下IC 50值的比率的光毒性指数(PI)高达40.7。PDP NPs的高PI表明它们是优异的光敏剂,因为它们在黑暗中具有低毒性但在光照射时具有高细胞毒性,这对于PDT是非常重要的。值得注意的是,DP和P NPs的摩尔比为2:1的混合物在照射时未显示细胞毒性(IC50=0.49±0.08μM,基于Pt的摩尔量)的显着改善,强调了形成超分子笼在协同光化疗中发挥了显着作用。
Annexin V-FITC/PI测定用于区分活细胞(FITC-/PI-),早期凋亡细胞(FITC+/PI-),晚期凋亡细胞(FITC-/PI+)和坏死细胞(FITC+/PI+)细胞计数分别(图5D)。对于在黑暗中用PDP NPs处理的细胞,早期凋亡细胞,晚期细胞凋亡细胞和坏死细胞的群体分别为0.80%,23.95%和8.43%,表明单独化疗诱导细胞凋亡的能力相对较低。PDT(P NPs+L)处理后,凋亡晚期细胞增加至61.1%,坏死细胞仍为6.81%。令人兴奋的是,接受组合光化疗的坏死期细胞显着增加至42.71%,证实了PDP NPs在癌症协同治疗中的具潜在应用。
荧光素二乙酸酯/碘化丙锭(FDA/PI)共染色用于在荧光图像下区分活细胞和死细胞。如图5E所示,由于极低浓度、光、DP和PDP NPs诱导可忽略不计的细胞死亡。与这些对照组相比,观察到与PDP NPs孵育的细胞随后曝光的细胞死亡显着增加。随着激光照射时间的延长,死细胞的百分比迅速增加,证实PDP NPs具有优异的PDT效果。
实施例6
活体实验
PDP NPs具有适合的循环直径,并且能够在肿瘤部位有效累积,导致更好的治疗效果和更低的副作用。PDP NPs在血流中的长时间循环对于成功的靶向递送和有效治疗是必不可少的,这通过表面移植“保护性”PEG壳来“掩盖”它们来实现,从而防止被网状内皮系统(RES)清除。为了研究它们的药代动力学(pKa),将PDP NPs和游离DP以2mg/kg铂的剂量静脉内(iv)注射到小鼠中。收集血液样本注射后的各个时间点。通过使用ICP-MS定量血液铂浓度,PDP NPs的血液循环半衰期计算为2.39±0.4h,是DP的4.5倍(图6A)。注射剂量(ID)的大约11.4%PDP NPs在24小时时保留在血浆中。虽然DP在注射后8小时几乎完全从血流中消除。PDP NPs的曲线下面积(AUC)显着增加至149μgmL-1h,比DP(7.86μgmL-1h)大18.9倍,表明循环时间大大延长,归因于EPR效果和主动定位。
通过ICP-MS分析不同器官中的铂含量(图6B)来定量评估PDP NPs在生物体的分布情况。生物分布评估表明,PDP NPs在肿瘤中得到有效累积,给药后24小时接近2.24±0.31μg/g组织浓度,显着高于DP(0.39±0.05μg/g组织浓度)。由于RES捕获和代谢后,在肝脏中可以观察到相当高浓度的PDP NPs。与主要由肾脏处理的PDP NPs相比,DP在主要器官中显示出显着不同的分布。这些发现清楚地证明PDP NPs比小分子药物更容易用于肿瘤摄取,并且有利于增加它们的抗肿瘤功效,同时减少对正常组织的不利影响。
体内协同光化学疗法
基于优异的体外组合细胞毒性,PDP NPs的生物体稳定循环和合理的生物分布,对有高度侵袭性的4T1原位乳腺癌荷瘤小鼠进行PDP NPs体内抗肿瘤功效的单次治疗评估。将肿瘤小鼠随机分成六组,当肿瘤体积达到130mm3左右时,分别给予生理盐水,顺铂,DP,PNPs+L,PDP NPs或PDP NPs+L(n=6)。在静脉注射24小时选择具有相对低功率密度(0.5W/cm2)和优化的照射持续时间(6分钟)的激光用于基于光的治疗(单独使用激光,没有明显的皮肤灼伤)。用盐水给药的小鼠肿瘤迅速生长(图6C),与其原始体积相比,在21天内肿瘤体积增加13.0倍。顺铂,DP或PDP NPs使肿瘤的生长略微减少,这是由于单独化学疗法的有限效力,不足以有效抑制肿瘤生长。尽管使用P NPs和激光照射在前6天内PDT显着降低了肿瘤大小,但之后肿瘤生长迅速恢复,因为P NPs的ROS产生相对较低,几乎不能清除所有癌细胞。值得说明的是,PDP NPs+L在这些组中显示出最高的抗肿瘤效率,并且在实验期间几乎完全根除了没有复发的肿瘤(共6只小鼠中有5只)。治疗后21天切除肿瘤,评估肿瘤重量(图6D)。用PDP NPs处理的光照射组的肿瘤生长抑制率为98.4%,而PDP NPs,DP,P NPs+L和顺铂的肿瘤生长抑制率分别为51.5%,37.3%,48.3%,60.5%和31.2%。这些结果清楚地证明了PDP NPs介导的化学疗法和激光照射激活的PDT之间的协同抗肿瘤功效,以完全消融肿瘤而不会在单次治疗后复发。
免疫组织化学分析高度支持上文讨论的关于肿瘤抑制的结果(图6E)。苏木精和伊红(H&E)染色显示接受化疗(DP,顺铂和PDP NPs)或PDT(P NPs+L)的肿瘤与盐水治疗组相比显示出不同程度的肿瘤衰退,表明这些给药具有不同程度的抗肿瘤效果。在用PDP NPs+L进行微量处理后,我们找不到肿瘤细胞,这表明肿瘤被成功破坏。Ki67阳性免疫组织化学染色进一步显示来自光化疗组(PDP NPs+L)的肿瘤区域中的最低增殖。
在处死小鼠后切肺组织并观察(图7A),进一步分析转移性肿瘤结节的数量和肺表面的肿瘤覆盖百分比,以评估这些治疗的抗转移效果。对于分别用盐水,PDP NPs,DP,P NPs+L和顺铂处理的小鼠,平均转移性肿瘤结节穿孔计数为5.67,2.17,3.67,1.17和4.2(图7B)。对于分别用盐水,PDP NPs,DP,P NPs+L和顺铂处理的小鼠,肺表面的肿瘤覆盖百分比计算为9.33,2.23,4.37,0.83和5.51%(图7C),证明了仅通过化学疗法或PDT可以实现有限的抗转移作用。值得说明的是的是,从接受组合治疗的小鼠的六只肺中仅可见一个肿瘤结节,平均肿瘤覆盖肺表面的年龄仅为肺的0.07%,表明光化学疗法具有优异的抗转移功效。
用体重大小和存活率作为适应症仔细评估纳米医学的全身毒性。对于DP和顺铂给药,由于其系统毒性和相关副作用,小鼠的体重在第一周内降低(图6G)。组织学分析提供了对DP或顺铂引起的全身毒性的了解。在顺铂组的DP小鼠中观察到一定程度的肺和肝损伤。然而,从接受其他治疗的小鼠中观察到体重和组织学检查没有明显变化,这意味着PDP NPs在单次注射后对小鼠具有最小的系统毒性。用盐水,PDP NPs,DP,P NPs+L和顺铂治疗的小鼠的中位生存率分别计算为36、49、42、54和42天,而光化疗大大延长了小鼠的存活时间。超过75天只有一次死亡(图6F)。这些结果表明化疗和PDT在肿瘤治疗中的组合有效地延长了它们的寿命而没有明显的副作用。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受实施例的限制,其它任何未背离本发明的精神实质与原理下所做的改变、修饰、组合、替代、简化均应为等效替换方式,都包含在本发明的保护范围之内。
Claims (4)
1.一种配位驱动的自组装超分子笼,其特征在于:所述超分子笼由四吡啶卟啉衍生物或四吡啶金属卟啉衍生物和Pt(II)受体组成,其结构为式(I):
其中:
R1为H、烷基;
R2为H、F、Cl、Br、I、烷基;
其中:
R1为H、烷基;
R2为H、F、Cl、Br、I、烷基;
M为Zn、Co、Mn、Ce、Fe、Mg、Hg、Ru、Cu、Zr、Rh、Pt、Sn、Tl、Al、Pt、Pd、Ir、Sb、V、Ti、Hf、Au、Cr、Ag、In、Tb、Gd、Er、Yb、Lu、Dy、Nd、Eu、Pr、Ho、Tm、La、Sm;
其中:
R3为H、烷基、氨基、醛基、酰胺基、芳基;
Y为O、S、N、Se或Te;
所述OTf基团在超分子笼中将脱去,成为与四吡啶卟啉衍生物或四吡啶金属卟啉衍生物的键合点。
3.一种注射或者用于口服的组合物,其特征在于:所述组合物包含根据权利要求1所述的自组装超分子笼或权利要求2所述制备方法得到的自组装超分子笼以及药学上可接受的载体。
4.权利要求1所述的自组装超分子笼或权利要求2所述制备方法得到的自组装超分子笼在制备利用光动力学治疗法和化学疗法杀死癌细胞的方法中所用药品中的应用。
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