CN108191714B - 化合物、纳米超分子药物载体及包含所述纳米超分子药物载体的药物 - Google Patents
化合物、纳米超分子药物载体及包含所述纳米超分子药物载体的药物 Download PDFInfo
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- CN108191714B CN108191714B CN201810057869.8A CN201810057869A CN108191714B CN 108191714 B CN108191714 B CN 108191714B CN 201810057869 A CN201810057869 A CN 201810057869A CN 108191714 B CN108191714 B CN 108191714B
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- polyethylene glycol
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
- A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
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- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0054—Macromolecular compounds, i.e. oligomers, polymers, dendrimers
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
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Abstract
本发明提供了化合物、纳米超分子药物载体及包含所述纳米超分子药物载体的药物,属于纳米超分子材料技术领域,所述化合物可以与修饰的聚乙二醇共组装成纳米超分子药物载体,实现对阴离子型光敏剂的负载,并且能够在肿瘤部位特异性释放光敏剂,达到对实体肿瘤的靶向成像和治疗。所述化合物为特定结构的5,11,17,23,29‑五胍基‑31,32,33,34,35‑五烷氧基杯[5]芳烃。所述纳米超分子药物载体以结构式如(I)所示的化合物和修饰后的聚乙二醇作为构筑单元。所述药物包含所述纳米超分子药物载体和负载在所述纳米超分子药物载体上的阴离子光敏剂。
Description
技术领域
本发明涉及一种化合物、纳米超分子药物载体及包含所述纳米超分子药物载体的药物,属于纳米超分子材料技术领域。
背景技术
光动力治疗(Photodynamic therapy,简称PDT)是一种新兴的疾病治疗方式,因其具有良好的安全性和非侵入性的特质受到医疗领域和广大科研工作者的关注。光动力治疗主要涉及光敏剂、光和氧分子。首先,光敏剂聚集在病变组织周围,然后通过合适的光源照射病变组织,光敏剂吸收能量后从基态跃迁至激发态,激发态的光敏剂将能量传递给细胞周围的氧分子,进而发生一系列的光化学反应,产生大量具有强氧化性的活性氧物质,这些活性物质可以与周围细胞发生反应,引起细胞坏死和凋亡。光动力治疗已被证明可以杀死肿瘤细胞以及微生物,并且被广泛应用于皮肤癌、寻常疣、肺癌等疾病治疗中,被认为是侵入性及毒性最小的治疗方式。传统商用光敏剂中最具代表性的是呫吨类(例如曙红Y,玫瑰红),卟啉类(例如四磺酸苯基卟啉)和酞菁类(例如四磺酸基酞菁氯化铝)染料。它们作为商用光敏剂,拥有较高的单线态氧量子产率、成熟的生产工艺和较高的化学纯度。但是作为小分子药物,它们缺乏对肿瘤的选择性,易于被肾快速消除,并且其光动力活性不能够根据实际需要进行调控,容易在光治疗过程中伤害到正常组织。为了改善传统光敏剂的性能,科研工作者们通过化学合成的方法对光敏剂进行共价修饰,以达到靶向成像和治疗的效果。但是这种方式需要复杂的分子设计和大量的人力物力,并且对最终修饰后的化合物的光动力性能无法预知。在光动力治疗具有广阔应用的前景下,如何摆脱无止尽的化学修饰,高效的调控光敏剂的荧光及其光活性,建立一个基于特定疾病环境响应的纳米药物载体变得极为重要。
发明内容
发明目的
本发明的一个目的是提供一种化合物,可以与修饰的聚乙二醇(以下简称PEG)共组装成纳米超分子药物载体,实现对阴离子型光敏剂的负载,并且能够在肿瘤部位特异性释放光敏剂,达到对实体肿瘤的靶向成像和治疗。
本发明的另一个目的是提供一种以上述化合物作为构筑单元的纳米超分子药物载体,实现对阴离子型光敏剂的负载,并且能够在肿瘤部位特异性释放光敏剂,达到对实体肿瘤的靶向成像和治疗。
本发明的另一个目的是提供一种包含上述纳米超分子药物载体的药物,能够在肿瘤部位特异性释放光敏剂,达到对实体肿瘤的靶向成像和治疗。
发明概述
根据本发明的第一方面,本发明提供了一种化合物,结构式如(I)所示:
其中,M=Cl、Br或I;n为1-9的整数。
上述化合物的名称为:5,11,17,23,29-五胍基-31,32,33,34,35-五烷氧基杯[5]芳烃。
优选的,n为7-9的整数,最优选的,n=9;进一步优选的,M=Cl,此时所述化合物结构式如(III)所示:
上述具体化合物名称为:5,11,17,23,29-五胍基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃(以下简称为GC5A-12C)。其制备方法为:以5,11,17,23,29-五叔丁基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃为原料,经过硝化、还原、叔丁氧羰基保护胍基修饰,脱保护得到目标化合物。具体合成路线如下:
上述具体制备方法中每一步骤的具体反应条件及产物分离方法均为现有技术,在此不再赘述。本发明所述化合物的制备方法均采用上述合成路线。
根据本发明的第二方面,本发明提供了一种纳米超分子药物载体,所述纳米超分子药物载体以结构式如(I)所示的化合物和修饰后的聚乙二醇作为构筑单元。
所述修饰后的聚乙二醇和结构式如(I)所示的杯芳烃共组装,得到纳米超分子药物载体,其中修饰后的聚乙二醇为现有技术中与杯芳烃共组装的惯常选择,其具体结构和用量可以由本领域技术人员根据杯芳烃的结构确定。通常通过端氨基聚乙二醇的酰胺化得到修饰后的聚乙二醇。
优选的,所述修饰后的聚乙二醇的结构式如(II)所示,其中未经修饰的聚乙二醇NH2(CH2OCH2O)nH的数均分子量为1000-100000(如1000-4000,具体如2000、3000等):
优选的,所述结构式如(I)所示的化合物与修饰后的聚乙二醇的物质量的比为1∶0.1~1∶1。
优选的,所述纳米超分子药物载体的水合粒径为110~130nm,多分散系数小于0.3。
通过共组装制备上述纳米超分子药物载体的方法为本领域现有技术,具体的,所述纳米超分子药物载体的制备方法可以是:将GC5A-12C的甲醇溶液与修饰的聚乙二醇2000的氯仿溶液混合均匀(为了便于操作,GC5A-12C的甲醇溶液与修饰的聚乙二醇2000的氯仿溶液浓度通常相同,例如,均为1mmol/L),然后真空去掉溶剂,加入水加热超声,最终得到GC5A-12C的纳米超分子药物载体水溶液,浓度通常为1mmol/L。一般可继续采用真空干燥或冷冻干燥的方法得到纳米超分子药物载体的固体产品。
根据本发明的第三方面,本发明还提供了一种药物,所述药物包含所述纳米超分子药物载体和负载在所述纳米超分子药物载体上的阴离子光敏剂。
优选的,所述阴离子光敏剂为四磺酸基酞菁氯化铝(以下简称为AlPcS4)。
所述负载的AlPcS4光敏剂与纳米超分子药物载体中所含的结构式如(I)所示的化合物的物质量的比不超过1∶1。具体负载量可以根据实际情况进行调节。
将所述阴离子光敏剂负载在所述纳米超分子药物载体上的方法为本领域现有技术,通常将阴离子光敏剂的溶液与所述纳米超分子药物载体的溶液混合均匀即可成功实现负载。
本发明通过试验发现,在上述纳米超分子药物载体中加入近红外光敏剂AlPcS4,即结构式如(I)所示的化合物与AlPcS4的用量物质量的比为1∶1,由于AlPcS4被包结进杯芳烃的空腔中,其荧光和光活性被完全淬灭;当加入10nmol/L ATP(正常组织的ATP浓度)后,AlPcS4的荧光和单线态氧能力并没有恢复,而加入100μmol/L ATP(肿瘤组织的ATP浓度)后,AlPcS4的荧光和单线态氧能力几乎完全恢复。在小鼠活体成像和治疗中,在小鼠上肢处接种小鼠4T1乳腺肿瘤,将上述负载AlPcS4的纳米超分子药物载体通过尾静脉注射给药,利用小动物成像系统对肿瘤部位实时成像。由于纳米超分子药物载体的粒径为110~130nm,此范围已被诸多文献证明具有优良的高渗透长滞留(EPR)效应,因此药物最终可以被靶向富集在肿瘤部位,同时由于肿瘤组织和正常组织ATP浓度极大的差异,使AlPcS4可以特异性地在肿瘤部位释放,极大地提高了活体荧光成像的信噪比,同时也避免了在治疗时对于正常组织的光毒。
本发明以两亲杯芳烃(即结构式如(I)所示的化合物)与修饰后的聚乙二醇经共组装得到的纳米超分子组装体作为药物载体,负载阴离子光敏剂,淬灭光敏剂的荧光和光活性,使其在药物运输过程中即使受到光照也不会产生细胞毒性。所得药物最终通过EPR效应富集在肿瘤部位,由于肿瘤部位ATP含量远高于正常组织,因此高浓度的ATP将光敏剂从GC5A-12C的空腔中竞争出来,使光敏剂的荧光和光活性恢复,达到了肿瘤的成像和治疗的效果。同时,上述药物载体具有广谱性,结构式如(I)所示的化合物由于五个胍基的存在,使其可以与多种阴离子型光敏剂通过氢键和正负电荷吸引产生强力键合,使所述纳米超分子药物载体可以根据实际需要更换不同的光敏剂,不必再去繁琐的去修饰现有成熟的光敏剂。基于所述纳米超分子药物载体由于上述优良的表现,使其在活体成像、靶向药物、以及光动力治疗应用上拥有广阔的前景。
附图说明
图1:5,11,17,23,29-五硝基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃的核磁共振氢谱;
图2:5,11,17,23,29-五氨基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃的核磁共振氢谱;
图3:5,11,17,23,29-五[(N,N-叔丁氧羰基)胍基]-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃的核磁共振氢谱;
图4:5,11,17,23,29-五胍基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃(GC5A-12C)的核磁共振氢谱;
图5:5,11,17,23,29-五胍基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃(GC5A-12C)的核磁共振碳谱;
图6:5,11,17,23,29-五胍基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃(GC5A-12C)的高分辨质谱图;
图7:动态光散射(DLS)图。
图8:纳米超分子药物载体透射电镜(TEM)图。
图9:纳米超分子药物载体扫描电镜(SEM)图。
图10:AIPcS4自身的荧光、纳米超分子药物载体负载AIPcS4后以及加入不同浓度ATP后的荧光变化图,图中浓度单位M表示mol/L,所示浓度均为加入ATP的终浓度。
图11:AlPcS4自身的单线态氧产生情况、纳米超分子药物载体负载AlPcS4后以及加入不同浓度ATP后的产生单线态氧的变化图,图中浓度单位M表示mol/L,所示浓度均为加入ATP的终浓度。
图12:纳米超分子药物载体负载AlPcS4的药物在肿瘤小鼠活体上的实时成像荧光图。
具体实施方式
下面用实施例进一步描述本发明,但所述实施例仅用于本发明而不是限制本发明。
以下实施例中所涉及制剂来源如下:
二氯甲烷、甲醇、乙醇、乙酸乙酯、乙醚为色谱纯级别,来源于天津市康科德科技有限公司;
醋酸、硝酸、三乙胺为分析纯级别,来源于天津市化学试剂供销公司;
氨基聚乙二醇2000(NH2(CH2OCH2O)nH,数均分子量为2000,简称为NH2-PEG2000)、氘代氯仿、氘代二甲基亚砜和氘代甲醇来源于北京百灵威科技有限公司;
碳酸钠、氯化钠、硫酸钠、二水合二氯亚锡、氢氧化钠、硝酸银、四氯化锡、1,3-二(叔-丁氧羰基)-2-甲基-2-异硫脲,、4-羟乙基哌嗪乙磺酸为分析纯级别,来源于上海阿拉丁生化科技股份有限公司;
四磺酸基酞菁氯化铝纯度为97%,来源于美国Frontier Scientific公司。
以下实施例中所涉及主要设备如下:
Bruker AV400核磁共振波谱仪;
Varian 7.0T FTMS傅立叶变换高分辨质谱仪;
岛津紫外可见分光光度计;
安捷伦Cary Eclipse荧光分光光度计;
Brookhaven ZetaPals/BI-200SM动态光散射仪(659nm激光光源,散射角度90°);
JSM-7500F扫描电子显微镜;
Tecnai G2F20高分辨透射电镜;
CRI Maestro动物成像系统。
制备实施例1
1、5,11,17,23,29-五硝基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃的合成过程:
将3.97g的5,11,17,23,29-五叔丁基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃(合成过程参见Arnaud-Neu,F.,Fuangswasdi,S.,Notti,A.,Pappalardo,S.& Parisi,Angew.Chem.,Int.Ed.1998,37,112-114和Garozzo,D.,et al.Angew.Chem.,Int.Ed.2005,44,4892-4896)溶解于119mL干燥的二氯甲烷和34.28mL的醋酸溶液中,后逐渐滴加10.28mL硝酸,室温搅拌1至4小时。溶液的颜色从深紫色变为橙色。然后向反应溶液中加入250mL水搅拌30分钟,将混合溶液用饱和碳酸钠溶液,饱和食盐水溶液,水萃取分液,收集有机相,浓缩,无水硫酸钠干燥,用二氯甲烷和甲醇重结晶,得到1.74g 5,11,17,23,29-五硝基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃淡黄色固体,其核磁共振氢谱(图1)结果如下:
1H NMR(400MHz,氘代氯仿(CDCl3),δ):7.85(s,10H,ArH),4.59(d,J=14.74Hz,5H,Ar-CH2-Ar),3.87(t,J=7.52Hz,10H,CH2-O-Ar),3.55(d,J=14.74Hz,5H,Ar-CH2-Ar),1.89(m,10H,-CH2-CH2-O-Ar),1.31(m,90H,alkyl CH2),0.91(t,J=6.60Hz,15H,-CH3)。
2、5,11,17,23,29-五氨基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃的合成过程:
将0.38g的5,11,17,23,29-五硝基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃溶解于50mL乙醇和乙酸乙酯溶液中(体积比1∶1),加入0.15g二水合二氯亚锡,反应回流48小时。将反应产物倒入冰水中,冰融化后,加入氢氧化钠调pH值为8.0。将二氯甲烷加入反应溶液中,在室温下搅拌过夜。有机相水洗,干燥,旋干,得到0.13g 5,11,17,23,29-五氨基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃白色固体,其核磁共振氢谱(图2)结果如下:
1H NMR(400MHz,氘代氯仿(CDCl3),δ):6.30(s,10H,ArH),4.36(d,J=14.08Hz,5H,Ar-CH2-Ar),3.67(t,J=7.51Hz,10H,CH2-O-Ar),3.11(d,J=14.08Hz,5H,Ar-CH2-Ar),1.81(m,10H,-CH2-CH2-O-Ar),1.28(m,90H,alkyl CH2),0.88(t,J=6.21Hz,15H,-CH3)。
3、5,11,17,23,29-五[(N,N-叔丁氧羰基)胍基]-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃的合成过程:
将0.32g 5,11,17,23,29-五氨基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃,0.33g 1,3-二(叔-丁氧羰基)-2-甲基-2-异硫脲,0.2g硝酸银和0.17mL三乙胺加入到25mL二氯甲烷中,室温搅拌48小时,反应液旋干,柱色谱分离得到0.17g5,11,17,23,29-五[(N,N-叔丁氧羰基)胍基]-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃白色固体,其核磁共振氢谱(图3)结果如下:
1H NMR(400MHz,氘代氯仿(CDCl3),δ):11.63(s,5H,NH),9.87(s,5H,NH),7.15(s,10H,ArH),4.52(d,J=13.56Hz,5H,Ar-CH2-Ar),3.73(t,J=7.58Hz,10H,CH2-O-Ar),3.30(d,J=13.62Hz,5H,Ar-CH2-Ar),1.94(m,10H,-CH2-CH2-O-Ar),1.46(s,90H,But),1.28(m,90H,alkyl CH2),0.88(t,J=6.18Hz,15H,-CH3)。
4、5,11,17,23,29-五胍基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃(GC5A-12C)的合成过程:
将0.08g 5,11,17,23,29-五[N,N-叔丁氧羰基]-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃加入到0.2mL四氯化锡和20mL乙酸乙酯中。反应液在室温搅拌3小时。然后将反应液旋干,溶于甲醇,后加入大量乙醚,沉淀出0.04g5,11,17,23,29-五胍基-31,32,33,34,35-五(正十二烷氧基)杯[5]芳烃(GC5A-12C)白色固体,其核磁共振氢谱(图4)、碳谱(图5)及高分辨质谱(图6)结果如下:
1H NMR(400MHz,氘代甲醇(CD3OD),δ):6.91(s,10H,ArH),4.51(d,J=13.86Hz,5H,Ar-CH2-Ar),3.81(t,J=7.48Hz,10H,CH2-O-Ar),3.38(d,J=13.63Hz,5H,Ar-CH2-Ar),1.93(m,10H,-CH2-CH2-O-Ar),1.22(m,90H,alkyl CH2),0.81(t,J=6.07Hz,15H,-CH3).
13C NMR(100MHz,氘代甲醇(CD3OD),δ):156.65,154.70,135.57,129.45,126.46,74.51,31.86,30.38,30.22,30.01,29.88,29.74,29.35,26.41,22.46,13.13.
ESI-FTMS:m/z:[M+H-5HCl]+calcd.for C100H166N15O5 +1658.3224,found1658.3188.
5、修饰的聚乙二醇(4-正十二烷氧基苯甲酰胺聚乙二醇2000)(结构式见下图)的合成过程:
将244mg正十二烷氧基苯甲酸,200mg氨基聚乙二醇2000,108mg 1-羟基苯并三唑和303mg苯并三氮唑-N,N,N′,N′-四甲基脲六氟磷酸酯一并加入到10mL N,N-二甲基甲酰胺中,上述溶液在氩气氛围下常温搅拌30分钟,然后加入0.26mL N,N-二异丙基乙胺,常温搅拌4小时,随后加入400mL乙醚,溶液冷冻过夜。离心得到固体,加水溶解后透析并冷冻干燥最终得到蜡状固体,即为以下实施例所用的修饰的聚乙二醇:4-正十二烷氧基苯甲酰胺聚乙二醇2000。
制备实施例2
纳米超分子药物载体的制备过程:
将浓度为1mmol/L的GC5A-12C的甲醇溶液与浓度为1mmol/L的修饰的聚乙二醇的氯仿溶液按物质量的比1∶1混合均匀,然后真空去掉溶剂,加入水后加热超声,最终得到浓度为1mmol/L的GC5A-12C的纳米超分子药物载体。动态光散射测得超分子纳米药物载体的水合粒径为113nm,多分散系数为0.17(图7);TEM样品的制备,将分散好的纳米载体溶液取适量滴在碳支撑的铜网上,常温晾干,然后真空干燥24h,TEM拍照(图8);SEM样品的制备,将分散好的纳米载体溶液取适量滴在硅片上,常温晾干,然后真空干燥24h,SEM拍照(图9)。TEM与SEM的成像结果表明纳米载体的形貌为近球形,大小约为100nm。
制备实施例3
药物的制备过程:
称取2.383g N-(2-羟乙基)哌嗪-N′-2-乙烷磺酸(以下简称HEPES),用超纯水配制成1L 10mmol/LpH 7.4的缓冲溶液(以下简称HEPES缓冲溶液)。称取A1PcS4,用10mmol/LHEPES缓冲溶液配制成1mmol/L的AlPcS4储备液,在25℃温度下,用10mmol/L pH 7.4的HEPES缓冲溶液将AlPcS4储备液稀释,加入制备实施例2所得的纳米超分子药物载体,AlPcS4和纳米超分子药物载体的终浓度均为2μmol/L,混合均匀后得到浓度为2μmol/L的药物。
应用实施例
称取2.383g HEPES,用超纯水配制成1L 10mmol/L pH 7.4的缓冲溶液(以下简称HEPES缓冲溶液)。称取适量四磺酸基酞菁氯化铝(AlPcS4,近红外光敏剂),用10mmol/LHEPES缓冲溶液配制成1mmol/L的AlPcS4储备液。在25℃温度下,用10mmol/L pH 7.4的HEPES缓冲溶液将AlPcS4储备液稀释到2μmol/L,激发波长选择606nm,发射波长选择625~800nm可以看到本体明显的荧光信号(图10);相同条件下,当AlPcS4溶液中加入制备实施例2所得纳米超分子药物载体,使AlPcS4和纳米超分子药物载体的终浓度均为2μmol/L(图中简称AlPcS4/GC5A-12C+ATP0μM)时,AlPcS4的荧光被完全淬灭(图10)。这时所述纳米超分子药物载体不仅能够负载而且可以淬灭AlPcS4的荧光。
同样的,当结构式(I)中n=1-8时,所述化合物与GC5A-12C一样具有两亲性质,当它们在水里的浓度达到其自身的临界聚集浓度时,便会与所述修饰的聚乙二醇共组装成纳米载体,由于胍基的识别位点依旧保持,所以依旧可以实现如GC5A-12C的上述过程。
模拟肿瘤组织和正常组织的ATP浓度对于纳米超分子药物载体释放AlPcS4的过程:称取5.51mg ATP溶于10mL 10mmol/L HEPES中,所得ATP溶液零下20℃保存。按制备实施例3所得方法制备药物,其中一份加入ATP溶液,使AlPcS4和纳米超分子药物载体的终浓度均为2μmol/L、ATP浓度为10nmol/L(正常组织的ATP浓度)(所得溶液简称AlPcS4/GC5A-12C+ATP 10nM溶液)后,AlPcS4的荧光没有恢复,而另一份加入ATP溶液,使AlPcS4和纳米超分子药物载体的终浓度均为2μmol/L、ATP浓度为100μmol/L(肿瘤组织的ATP浓度)(所得溶液简称AlPcS4/GC5A-12C+ATP 100μM溶液)后,AlPcS4的荧光几乎完全恢复(图10)。
模拟肿瘤组织和正常组织的ATP浓度对于纳米载体释放AlPcS4后的单线态氧测定:选用对亚硝基-N,N-二甲基苯胺和咪唑作为单线态氧的探针,通用单线态氧测定方法描述如下,将对亚硝基-N,N-二甲基苯胺(50μmol/L)和咪唑(10mol/L)以及样品充分混合后置于石英比色皿中,混合溶液在氙灯下照射(添加滤光片,滤除波长小于440nm部分),每隔一定时间用紫外可见分光光度计测量440nm处的吸光度值。操作如上,采用亚硝基-N,N-二甲基苯胺和咪唑作为单线态氧探针,分别测定2μmol/L AlPcS4溶液、制备实施例3所得药物(图中简称AlPcS4/GC5A-12C+ATP0μM)、含10nmol/LATP(正常组织的ATP浓度)的AlPcS4/GC5A-12C+ATP 10nM溶液和含100μmol/L ATP(肿瘤组织的ATP浓度)的AlPcS4/GC5A-12C+ATP 100μM溶液的单线态氧的产生,结果见图11。荧光实验(图10)和单线态氧的产生实验(图11)表明,所述纳米超分子药物载体负载AlPcS4后不仅可以淬灭其荧光和光动力活性,而且能够在肿瘤ATP浓度下特异性释放AlPcS4,而正常组织ATP浓度下几乎没有作用。
小鼠活体肿瘤特异性实时成像的具体操作如下:
1、选用雌性BALB/c裸鼠(5-6周龄),在小鼠的上肢处接种小鼠4T1乳腺肿瘤(皮下注射1×107个4T1乳腺癌细胞),以建立4T1乳腺肿瘤裸鼠模型。
2、用所述HEPES缓冲溶液配制浓度为1mmol/L纳米超分子药物载体(制备实施例2制得)的溶液;另用所述HEPES缓冲溶液配制浓度为1mmol/LAlPcS4溶液。上面两种溶液按照体积比1∶1充分混合后通过0.45μm的微孔滤膜得到负载AlPcS4的药物。
3、待小鼠肿瘤长大至100mm3左右时,将上述负载AlPcS4的药物通过尾静脉给药200μL,利用小动物成像系统(激发波长630nm,发射波长650~750nm)对裸鼠0、1、4、6、8以及24h进行荧光成像,结果见图12。图12箭头所指位置为肿瘤所在位置,可以看到小鼠静脉给药后0~6h间,肿瘤部位荧光强度逐渐增强,6h时达到最大,此时表明药物释放的量也达到了最大。随着成像时间的增长,肿瘤部位的荧光开始变弱,24h时降到最低,表明药物正在从身体代谢出去。图12的活体成像荧光图证明,所述药物可以将AlPcS4选择性的富集并释放到肿瘤部位,具有优良的信噪比,同时可以根据成像结果指导后期治疗的部位。
Claims (9)
1.一种纳米超分子药物载体,其特征在于,所述纳米超分子药物载体以结构式如(I)所示的化合物和修饰后的聚乙二醇作为构筑单元,所述修饰后的聚乙二醇通过端氨基聚乙二醇酰胺化得到,
其中,M=C1、Br或I;n为1-9的整数。
2.如权利要求1所述的纳米超分子药物载体,其特征在于,n=9。
3.如权利要求1所述的纳米超分子药物载体,其特征在于,M=C1。
4.如权利要求1-3中任一项所述的纳米超分子药物载体,其特征在于,所述修饰后的聚乙二醇的结构式如(II)所示,其中,所述端氨基聚乙二醇NH2(CH2OCH2O)mH的数均分子量为1000-100000,
5.如权利要求4所述的纳米超分子药物载体,其特征在于,所述结构式如(I)所示的化合物与修饰后的聚乙二醇的物质量的比为1∶0.1~1∶1。
6.如权利要求1-3中任一项所述的纳米超分子药物载体,其特征在于,所述纳米超分子药物载体的水合粒径为110~130nm,多分散系数小于0.3。
7.包含权利要求1-6中任一项纳米超分子药物载体的药物,其特征在于,所述药物包含所述纳米超分子药物载体和负载在所述纳米超分子药物载体上的阴离子光敏剂。
8.如权利要求7所述的药物,其特征在于,所述光敏剂为四磺酸基酞菁氯化铝。
9.如权利要求7所述的药物,其特征在于,所述负载的光敏剂与纳米超分子药物载体中所含的结构式如(I)所示的化合物的物质量的比不超过1∶1。
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A general synthesis of water soluble upper rim calix[n]arene guanidinium derivatives which bind to plasmid DNA;Miroslav Dudic et al.;《Tetrahedron》;20041012;20041012;第60卷;第11613—11618页 * |
Amphiphilic Guanidinocalixarenes Inhibit Lipopolysaccharide (LPS)-and Lectin-Stimulated Toll-like Receptor 4 (TLR4)Signaling;Stefania E. Sestito et al.;《Journal of Medicinal Chemistry》;20170504;第60卷;第4882-4892页 * |
DNA Condensation and Cell Transfection Properties of Guanidinium Calixarenes: Dependence on Macrocycle Lipophilicity, Size, and Conformation;Francesco Sansone et al.;《Journal of American Society》;20061019;第128卷;第14528-14536页 * |
Phosphoryl Transfer Processes Promoted by a Trifunctional Calix[4]arene Inspired by DNA Topoisomerase I;Riccardo Salvio et al.;《Journal of Organic Chemistry》;20160708;第81卷;第9012-9019页 * |
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