CN111012743B - 一种基于分子梭的诊疗型纳米药物 - Google Patents
一种基于分子梭的诊疗型纳米药物 Download PDFInfo
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- CN111012743B CN111012743B CN201811179898.8A CN201811179898A CN111012743B CN 111012743 B CN111012743 B CN 111012743B CN 201811179898 A CN201811179898 A CN 201811179898A CN 111012743 B CN111012743 B CN 111012743B
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Abstract
本发明属生物技术领域,涉及一种基于分子梭的新型诊疗型纳米药物。本发明通过点击化学反应将药物连接到分子梭客体分子两端,利用药物分子尺寸效应,使分子梭客体难以被分子梭主体识别穿环,而在肿瘤还原性微环境中,药物释放同时解放分子梭客体,使其可以被分子梭主体迅速、精准、特异识别并穿环,形成一种梭形近红外超分子探针,可用于体外细胞水平或体内动物水平实时表征药物的释放行为。
Description
技术领域
本发明属生物技术领域,涉及具备靶向和诊疗双重功效的给药系统,具体涉及一种基于分子梭的诊疗型纳米药物。
背景技术
据报道,目前小分子药物仍是人类对抗肿瘤的主要武器。现有技术公开了小分子药物的疗效在很大程度上取决于药物在病灶处的浓度,研究显示,药物一旦进入体内,就被形象的称为一种“薛定谔的猫”,药物的具体体内分布信息很难精确探知。业内公知,无论在临床上还是学术研究上,即时地得到药物从前药系统中释放的信息,包括药物释放的量、地点和时间,在评价药物的分布、控制药物用量、合理化用药领域都是非常关键的。因此对于新型递药系统的设计,不仅要求可以将药物准确地递送至靶组织或靶器官,还要求可以实时、可靠地提供药物在体内的释放时间、释放量与释放地点;当前为达此目的,应用最多的方法为组织提取法,即将实验动物组织取出、研碎、沉淀蛋白、萃取,然后利用高效液相色谱等手段进行分析定量,然而,这种方法属于侵入性非可持续手段,费时费力,重现性差且结果难称可靠。
为解决此难题,近些年来发展起来一种诊疗一体化递药系统,其中,主要是通过聚集诱导发光(AIE,如J.Am.Chem.Soc.2014,136,2546-2554;Chem.Commun.2014,50,3868-3870;Chem.Commun.2015,51,8626-8629;Chem.Commun.2014,50,11465-11468;Chem.Commun.2015,51,17435-17438),荧光能量共振转移(FRET,如J.Control.Release2012,164,276-282;ACS Appl.Mater.Interfaces 2016,8,19084-19091;Chem.Commun.2015,51,4807-4810)或正电子发射计算机断层显像(PET/CT,J.Nucl.Med.2017,58(12),1997-2003)等技术,可在药物释放的同时发射体外可探知的信号。
上述技术的应用,在很大程度上解决了“薛定谔的猫”困境,但是,白璧微瑕,大醇小疵,所述技术均存在一些应用上的缺陷,如:聚集诱导发光技术需要探针在体内达到一定浓度,方可形成聚集体,发射荧光;荧光能量共振转移技术需要药物本身具备一定特殊结构,可以作为探针分子的荧光淬灭剂,方可在药物释放后使探针回复发光态;正电子发射计算机断层显像技术要求更为苛刻,需要使用在PET/CT下可以显影的纳米粒子作为构筑基础(如纳米金等),等等。
基于现有技术的现状,本申请的发明人拟提供一种对底物要求低(如仅依赖分子大小)的策略构建新型诊疗体系;具体涉及一种具备靶向和诊疗双重功效的给药系统。该给药系统将能达到在体内可以即时、原位、高效报告药物释放信息的目的。
发明内容
本发明的目的是基于现有技术的现状和缺陷,提供一种具备靶向和诊疗双重功效的给药系统,具体涉及一种基于分子梭的诊疗型纳米药物。
本发明基于对底物要求低(如仅依赖分子大小)的策略构建新型诊疗体系;基于临床常用抗肿瘤药物的分子量分布均在300以上,相比于体内氨基酸葡萄糖等物质来说具备较大分子体积,本申请直接利用分子梭的概念构建一种具备靶向和诊疗双重功效的给药系统,其组成特征为分子梭主体、分子梭主体修饰基团、分子梭客体、药物分子构成。
本发明中,所谓分子梭,指的是一个环装的主体分子,可以特异性识别梭状的客体分子,构筑成一种分子状态“穿环”的体系,并具备一定的功能性,如穿环后可发射荧光的超分子染料;本发明将药物连接到分子梭客体两端,使其处于封闭状态,由于空间位阻难以穿进分子梭主体;而在肿瘤微环境下,药物释放,使分子梭处于游离态,可以被分子梭主体进行分子识别穿环,发射近红外的荧光,达到在体内可以即时、原位、高效报告药物释放信息的目的。
更具体的,本发明提供了一种基于分子梭的新型诊疗型纳米药物,所述纳米药物由分子梭主体、分子梭主体修饰基团、分子梭客体、药物分子构成。
本发明中通过点击化学反应将药物连接到分子梭客体分子两端,利用药物分子尺寸效应,使分子梭客体难以被分子梭主体识别穿环,而在肿瘤还原性微环境中,药物释放同时解放分子梭客体,使其可以被分子梭主体迅速、精准、特异识别并穿环,形成一种梭形近红外超分子探针,可用于体外细胞水平或体内动物水平实时表征药物的释放行为。
本发明中,分子梭主体为基于蒽的环四内酰胺,分子梭主体修饰基团为油酸与聚乙二醇。
优选地,分子梭主体修饰的油酸分子与基于蒽的环四内酰胺连接方式是双硫键。
优选地,分子梭主体修饰的聚乙二醇分子与基于蒽的环四内酰胺连接方式是点击化学反应生成的三氮唑基团。
优选地,分子梭客体为方酸衍生物,药物分子为奥沙利铂,氧化后可修饰上叠氮基团以便通过点击化学连接到方酸两端;药物分子与方酸基团进行连接方式为点击化学。
优选地,分子梭主体在修饰上聚乙二醇与油酸后可形成两亲分子,进而在水性溶液中可自组装成胶束,可将上述制备得到的方酸-药物连接分子负载至胶束疏水内核中,得到载药胶束。
优选地,在透射电子显微镜下观察表面为规整球形。
优选地,在动态光散射下进行表征,其水化半径为36.2±13.7纳米。
优选地,在动态光散射下进行表征,其表面电势为+1.65毫伏。
优选地,在透射电子显微镜下观察表面为规整球形且具备一个实心内核。
优选地,在动态光散射下进行表征,其水化半径为40.1±14.3纳米。
优选地,在动态光散射下进行表征,其表面电势为-9.16毫伏。
优选地,利用高效液相色谱测得其对方酸-药物连接分子的包封率为79.31±0.71%。
优选地,利用高效液相色谱测得其对奥沙利铂的载药量为3.70±0.19%。
优选地,利用纳米粒子跟踪分析(Nanoparticle Tracking Analysis,NTA)测得其每毫升含有粒子数目为2.2±0.0355×109个。
优选地,其分子组分包含分子梭主体与客体的比例为1:0.45。
优选地,在分子梭主体修饰的聚乙二醇另一末端可通过马来酰亚胺与巯基的特异性反应连接上修饰有巯基的多肽分子;优选地,多肽分子可为末端修饰有巯基的、可靶向三阴性乳腺癌与肿瘤新生血管的F3多肽分子,F3修饰的胶束构筑集团所占总体构筑基元比例为20%可达最佳肿瘤靶向效果;优选地,靶向胶束可特异地靶向并蓄积于三阴性肿瘤处并释放药物,其优势在于:可大幅降低奥沙利铂在健康组织的分布,降低神经毒性与耳毒性。
优选地,靶向胶束双硫键可被肿瘤还原性微环境所破坏断裂,使油酸分子脱落丧失原来分子双亲性,进而使胶束解体;可在肿瘤还原性微环境中还原氧化态奥沙利铂,从方酸两端脱落,解放分子梭客体,可以被分子梭主体迅速、精准、特异识别并穿环,形成一种梭形近红外超分子探针。
优选地,上述诊疗探针或策略可用于体外细胞水平或体内动物水平实时监控奥沙利铂的释放行为。
由上述制备方案及本发明后续实施例表明:本发明的光热辅助穿透的诊疗型纳米药物,至少有以下优点:
1)本发明所述纳米药物构成原料包括聚乙二醇、油酸等,在体内降解后不会对机体产生明显毒性;油酸分子上存在一个双键,可通过π-π堆积作用提高构筑的胶束稳定性;方酸与基于蒽的环四内酰胺也被广泛用于体内生物成像(Bioconjugate Chem.2016,27,1400-1410.),未见有毒性报道。
2)与传统静脉给药相比,本发明的制剂方法可协助化疗药物靶向并蓄积于肿瘤病灶处,实现药物的精确打靶,提高疗效并降低系统毒性。
3)本发明的诊疗一体化体系可以在体内或体外精确、原位、即时的报告药物量、地点和时间,在得到及时有效的药物分布与释放信息并由此调整药物安全剂量等领域,有着广泛应用。
综上,本发明提供了一种可供临床或科研选择的精确、原位、即时的药物释放与分布报告系统。
附图说明
图1为一种基于分子梭的新型诊疗型纳米药物机理示意图。
图2为基于分子梭的新型诊疗型纳米药物涉及化合物的合成步骤。
图3其中,A)为分子梭主体与客体分子之间的分子识别作用;
B)为利用MALDI-TOF表征主客体识别后的分子梭;
C)为奥沙利铂封端的分子梭客体在还原环境下实现的主客体识别作用;
D)为分子梭主客体的核磁氢谱图;
E)为无还原剂环境下奥沙利铂封端的分子梭客体与分子梭主体核磁共振ROESY谱图;
F)为存在还原剂环境下奥沙利铂封端的分子梭客体与分子梭主体核磁共振ROESY谱图;
G)为还原剂诱导的奥沙利铂封端的分子梭客体与分子梭主体核磁共振氢谱位移变化图;
(H)利用Gaussian 16软件计算的分子梭主客体识别后的电子云变化图(侧面),其中蓝色代表电子云增加,红色代表电子云减少;
(I)利用Gaussian 16软件计算的分子梭主客体识别后的电子云变化图(轴面)。图4,A)为未载药胶束的透射电子显微镜全局与放大图;
B)为载药胶束的透射电子显微镜全局与放大图;
C)为载药胶束经维生素C处理12小时后的透射电子显微镜图;
D)为利用动态光散射表征的未载药、载药胶束与经维生素C处理的载药胶束的粒径分布图;
E)为载药胶束经维生素C处理24小时内荧光变化图;
F)为载药胶束经不同浓度维生素C处理24小时内荧光变化趋势;
G)为载药胶束经不同浓度维生素C处理24小时内奥沙利铂累积释放曲线;
H)为载药胶束经无维生素C处理24小时内奥沙利铂累积释放曲线与荧光增长曲线之间的关系;
I)为载药胶束经10-3M维生素C处理24小时内奥沙利铂累积释放曲线与荧光增长曲线之间的关系;
J)为载药胶束经2×10-3M维生素C处理24小时内奥沙利铂累积释放曲线与荧光增长曲线之间的关系;
K)为载药胶束经5×10-3M维生素C处理24小时内奥沙利铂累积释放曲线与荧光增长曲线之间的关系;
L)为利用六孔板孵育三阴性乳腺癌MDA-MB-231细胞37℃下载药胶束荧光增长趋势;
M)为利用流式细胞仪表征37℃下载药胶束处理的六孔板孵育三阴性乳腺癌MDA-MB-231细胞荧光增长趋势;
N)为小动物活体成像仪表征荷三阴性乳腺癌小鼠荧光变化趋势(左:瘤内注射预穿环的分子梭;右:瘤内注射奥沙利铂封端分子梭;注射量均为5mg/kg,溶剂为DMSO);O)胶束构建与细胞内荧光恢复机理图。
图5,A)为利用荧光显微镜观察掺杂不同比例靶向功能基团的负载预穿环的分子梭胶束的细胞摄取(0,20,40,60和100%);
B)为流式细胞仪评估掺杂不同比例靶向功能基团的负载预穿环的分子梭胶束的细胞摄取(0,20,40,60和100%);
C)利用小动物3D活体成像仪观察掺杂20%靶向功能基团的负载预穿环的分子梭胶束尾静脉注射12小时后的体内分布;
D)利用小动物活体成像仪观察不同制剂(预穿环的分子梭,掺杂20%靶向功能基团的负载预穿环的分子梭胶束,非靶向功能基团的负载预穿环的分子梭胶束)尾静脉注射12小时后的离体器官内分布(H:心;L:肝;S:脾;L:肺;K:肾;T:肿瘤);
E)利用小动物活体成像仪观察掺杂20%靶向功能基团的负载预穿环的分子梭胶束尾静脉注射接种不同天数的三阴性乳腺癌小鼠12小时后的体内分布;
F)利用小动物活体成像仪观察掺杂非靶向(左)或20%靶向功能基团(右)的负载预穿环的分子梭胶束尾静脉注射接种三阴性乳腺癌小鼠48小时内体内分布;
G)利用荧光显微镜观察非靶向或20%靶向功能基团的负载预穿环的分子梭胶束尾静脉注射接种三阴性乳腺癌小鼠12小时肿瘤切片(蓝色:DAPI;绿色:CD31染新生血管);
H)利用3D荧光扫描重构(FLECT)观察20%靶向功能基团的负载预穿环的分子梭胶束尾静脉注射接种三阴性乳腺癌小鼠12小时后不同截面荧光分布;
I)利用3D荧光扫描重构(FLECT)观察非靶向负载预穿环的分子梭胶束尾静脉注射接种三阴性乳腺癌小鼠12小时后不同截面荧光分布;
J)利用3D荧光扫描重构(FLECT)观察20%靶向功能基团的负载奥沙利铂封端分子梭胶束尾静脉注射接种三阴性乳腺癌小鼠横切面即时荧光发射随时间变化图。
图6,A)肿瘤接种与治疗策略(注射量为5mg Pt/kg体重);
B)治疗后离体肿瘤大小;
C)利用MTT法评估不同制剂对MD-MBA-231细胞毒性;
D)治疗周期内不同制剂处理下荷瘤鼠瘤体积大小变化趋势(n=10,*P<0.1,**P<0.01,***P<0.001);
E)治疗周期内不同制剂处理下荷瘤鼠体重变化趋势;
F)利用MTT法评估不同制剂对人正常体细胞肾上皮HEK 293细胞毒性;
G)评价耳毒性装置示意图;
H)不同制剂组处理小鼠后听力下限比较(注射量为5mg Pt/kg体重,四次;
I)免疫组化法分析不同制剂组处理心肝脾肺肾损伤程度。
图7,氘代氯仿中化合物2核磁氢谱图。
图8,氘代氯仿中化合物3核磁氢谱图。
图9,氘代氯仿中化合物5核磁氢谱图。
图10,氘代氯仿中化合物7核磁氢谱图。
图11,氘代氯仿中化合物8核磁氢谱图。
图12,氘代氯仿中化合物11核磁氢谱图。
图13,氘代氯仿中化合物12核磁氢谱图。
图14,氘代氯仿中化合物13核磁氢谱图。
图15,氘代氯仿中化合物15核磁氢谱图。
图16,氘代氯仿中化合物16核磁氢谱图。
图17,氘代氯仿中化合物19核磁氢谱图。
图18,氘代氯仿中化合物20核磁氢谱图。
图19,氘代氯仿中化合物21核磁氢谱图。
图20,氘代氯仿中化合物22核磁氢谱图。
图21,氘代氯仿中化合物26核磁氢谱图。
图22,氘代氯仿中化合物27核磁氢谱图。
图23,氘代氯仿中化合物30核磁氢谱图。
图24,氘代氯仿中化合物21核磁氢谱图。
图25,氘代氯仿中化合物32核磁氢谱图。
图26,氘代水中化合物34核磁氢谱图。
图27,氘代水中化合物35核磁氢谱图。
图28,氘代水中化合物36核磁氢谱图。
图29,DMSO-δ6中化合物1核磁氢谱图。
具体实施方式
以下通过具体实施方式详细说明本发明的技术方案,应理解以下的具体实施方案仅为示例性,任何改动或变化只要不脱离本发明的技术方案设计,都应在本发明权利的要求保护范围之内。
实施例1
3-氯丙胺盐酸盐(1.00g,7.69mmol)溶解到水中(4mL),加入叠氮化钠(1.49g,22.7mmol),加热到80℃并保温15小时。降至室温,加入氢氧化钾固体(1.10g,19.2mmol),利用乙醚萃取(5mL×3)。有机相合并,利用无水硫酸钠干燥,减压蒸除溶剂得到化合物2,为无色油状液体(0.77g,100%)。
Rf=0.4(二氯甲烷:甲醇=30:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):3.38(t,J=3.6Hz,2H,H-5,6),2.81(t,J=6.8Hz,2H,H-1,2),1.74(q,J=6.8Hz,2H,H-3,4),1.75-1.00(s,w,2H,H-7,8).
FT-IR(vcm-1):2099.6(vs,vN3),1599.6(s,δNH2),1304.4(s,vC-N).。
实施例2
油酸(140mg,0.5mmol,1eq)溶解至干燥二氯甲烷(5mL)中,加入溶解至干燥二氯甲烷(5mL)中的三乙胺(166μL,120mg,1.2mmol,2.4eq)和苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU,208mg,0.55mmol,1.1eq),并在室温下搅拌半小时。化合物2(250mg,2.5mmol,5eq)溶解至干燥二氯甲烷(5mL)中,并缓慢滴加到上述溶液中没在室温下搅拌四小时。减压蒸除溶剂,加入水(10mL)并且调节pH至2。用石油醚(5mL×3)萃取上述水溶液,有机相合并,利用无水硫酸钠干燥,减压蒸除溶剂得到化合物3,为蜡状物(144g,79%)。
Rf=0.8(二氯甲烷:乙酸乙酯=30:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):5.60(s,w,1H,H-34),5.34(s,2H,H-18,19),3.35(t,J=6.8Hz,4H,H-35,36,39,40),2.80(s,2H,H-37,38),2.16(t,J=6.0Hz,2H,H-32,33),2.06-1.89(m,2H,H-16,17),1.84-1.75(m,2H,H-20,21),1.39-1.21(m,20H,H-4~15,22~29),0.88(t,J=7.2Hz,3H,H-1~3).
MS-ESI Calc.for C21H40N4O[3+H]+365.3,Found,365.0.。
实施例3
胱胺二盐酸盐(4,225mg,1mmol,1eq)和三乙胺(220mg,2mmol,2eq)溶解至干燥四氢呋喃(5mL)中并在室温下搅拌十分钟。油酸(282mg,1mmol,1eq),三乙胺(122mg,1.2mmol,1.2eq)和HBTU(400mg,1.1eq,1.1mmol)溶解至干燥四氢呋喃(10mL)中,并在半小时内缓慢滴入上述溶液中,室温黑暗条件下搅拌过夜。减压蒸除溶剂,加入氯化铵饱和溶液(10mL)并用乙酸乙酯(10mL×3)萃取。有机相合并,利用无水硫酸钠干燥,减压蒸除溶剂得到化合物5,为黄色蜡状物(144g,79%)。
Rf=0.7(二氯甲烷:甲醇=30:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):6.30(s,w,1H,H-34),5.30(s,2H,H-18,19),3.59-3.53(m,2H,H-35,36),2.81-2.73(m,6H,H37~42),2.41-2.24(m,2H,H-43,44),2.19(t,J=3.2Hz,2H,H-32,33),2.09-1.92(m,4H,H-16,17,20,21),1.67-1.62(m,2H,H-30,31),1.42-1.16(m,20H,H-4~15,22~29),0.90(t,J=6.4Hz,3H,H-1~3).
MS-ESI Calc.for C22H44N2OS2[5+H]+417.3,Found,417.0.。
实施例4
3-氯丙酸(6,4g,37mmol)何叠氮化钠(4g,62mmol)溶解至水(15mL)中并加热到85℃,并保温12小时。降至室温,利用乙酸乙酯(20mL×3)萃取,有机相合并,利用无水硫酸钠干燥,减压蒸除溶剂得到化合物7(3.11g,73%),为无色液体。
Rf=0.4(二氯甲烷:甲醇:乙酸=10:1:0.01,v:v:v).
1H NMR(400MHz,CDCl3,δ,ppm):9.60(s,w,2H,H-1),3.61(t,J=4.0Hz,2H,H-2,3),2.60(t,J=4.0Hz,2H,H-4,5).FT-IR(vcm-1):2125.6(vs,vN3),1718.7(s,vC=O),1401.7(m,coupling of vC=O andδ-OH),1269.9(s,βCH2).。
实施例5
化合物7(60mg,0.4mmol),HBTU(150mg,0.4mmol)和三乙胺(TEA,40mg,0.4mmol)溶解至干燥N,N’-二甲基甲酰胺(DMF,3mL)中,凝在室温下搅拌十分钟,缓慢加入到溶解有化合物5(42mg,0.1mmol)和三乙胺(10mg,0.1mmol)的干燥DMF(5mL)中。在室温下搅拌三小时,加入乙酸乙酯(20mL),分别用水(15mL×3)、饱和氯化铵(15mL)、饱和碳酸氢钠(15mL)、水(20mL)和饱和食盐水(20mL)洗涤,有机相合并,利用无水硫酸钠干燥,减压蒸除溶剂得到化合物8(45mg,87%),为白色蜡状物。
Rf=0.8(二氯甲烷:乙酸乙酯=30:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):6.31(s,w,1H,H-34),5.30(s,2H,H-18,19),3.59-3.53(m,2H,H-35,36),2.92-2.78(m,6H,H37~42),2.23(t,J=3.2Hz,2H,H-32,33),2.09-1.92(m,4H,H-16,17,20,21),1.56-1.40(m,6H,H-30,31,44~47),1.42-1.16(m,20H,H-4~15,22~29),0.90(t,J=6.4Hz,3H,H-1~3).
MS-ESI Calc.for C25H48N5O2S2[8+H]+514.8,Found,515.0.FT-IR(vcm-1):2112.2(vs,vN3),1656.3(s,vC=O),1172.8(s,βCH2),717.7(m,vc-s).。
实施例6
二碳酸二叔丁酯((Boc)2O,7.05g,32.1mmol)溶解至正丁醇(30mL)中,逐滴加入到溶解有三(羟基甲基)氨基甲烷(9,3g,24.6mmol)的甲醇/正丁醇(1:1,v:1,45mL)溶液中,在室温下搅拌18小时,减压蒸除溶剂沉淀到冷乙酸乙酯中,滤得沉淀,空气中干燥得到化合物11(12.2g,95%),为白色固体。
Rf=0.6(二氯甲烷:甲醇=5:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):3.08(d,J=4.0Hz,6H,H-5~10),3.40(s,w,1H,H-4),1.60(s,3H,H-1~3),1.44(s,9H,H-11~19).
FT-IR(vcm-1):3294.0(vs,v-OH),1675.2(m,vC=O),1009.0(s,βC-COH).。
实施例7
化合物11(5g,22.6mmol)溶解至干燥四氢呋喃(20mL)中,并在0℃下搅拌加入溴丙炔(16.18g,136mmol)。研碎的氢氧化钾(9.5g,136mmol)分成五份在15分钟内加入到上述溶液中,然后在35℃氩气气氛下搅拌24小时。乙酸乙酯(50mL)加入到上述溶液中,然后用水(100mL×3)和饱和食盐水(50mL)洗涤。有机相合并,利用无水硫酸钠干燥,减压蒸除溶剂利用柱色谱分离纯化(石油醚:乙酸乙酯由95:5至90:10,v:v)可得化合物12(6.99g,92%),为黄色液体.
Rf=0.75(二氯甲烷:乙酸乙酯=30:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):4.93(s,w,1H,H-34),4.19(s,6H,H-4~9),3.79(s,6H,H-10~15),2.43(s,3H,H-1~3),1.42(s,9H,H-17~25).。
实施例8
化合物12(300mg,0.894mmol)溶解至干燥二氯甲烷(3.5mL)中并冰浴至0℃,在半小时内加入三氟醋酸(TFA,1.43mL,19.25mmol),并在室温下搅拌2小时后,减压蒸除溶剂。加入饱和碳酸钠溶液(10mL),乙酸乙酯(10mL×3)萃取,并合并有机相,利用水(10mL)和饱和食盐水(10mL)洗涤,并利用无水硫酸钠干燥,减压蒸除溶剂得到化合物13(201mg,98%),为无色液体。
Rf=0.8(二氯甲烷:乙酸乙酯:三乙胺=10:1:0.01,v:v:v).
1H NMR(400MHz,CDCl3,δ,ppm):4.16(s,6H,H-4~9),3.47(s,6H,H-10~15),2.42(s,3H,H-1~3),1.69(s,w,2H,H-16,17).
MS-ESI Calc.for C13H18NO3[13+H]+236.1,Found,236.0.。
实施例9
蒽(10g,56mmol)和多聚甲醛(3.4g)溶解至乙酸(40mL)中,并在室温下搅拌均匀。氢溴酸的乙酸溶液(33wt%,55mL)一小时内逐滴加入至上述溶液中,然后升温到80℃,保温过夜,降至室温后,滤得产生的固体并利用水洗涤,空气中干燥得到粗品。之后在甲苯中重结晶(1L)得到化合物15(18.7g,87%),为黄色固体。
Rf=0.8(二氯甲烷).
1H NMR(400MHz,CDCl3,δ,ppm):8.38(dd,J1=3.2Hz,J2=6.8Hz,4H,H-1~4),7.08(dd,J1=3.2Hz,J2=6.8Hz,4H,H-5~8),5.52(s,4H,H-9~12).
MS-ESI Calc.for C16H13Br2[15+Na]+385.0,Found,385.6.
FT-IR(vcm-1):2920.3(s,vC=C),1529.3and 1441.4(s,vC-C of Ar),1199.2(s,ωCH2),1118.8(m,vC-Br),1001.5(w,βCH),760.2(w,γCH).。
实施例10
化合物15(1.0g,2.7mmol)和六次甲基四胺(1.0g,7.1mmol)分散到氯仿(150mL)中加热至回流,保温48小时,然后降至室温,滤得固体,空气干燥并分散到乙醇(130mL)中,加入37%浓盐酸(25mL),加热至回流,保温48小时,将至0℃,滤得固体,冷乙醇洗涤空气干燥,并在搅拌下分散到碳酸钠饱和溶液(10mL,2M)中,氯仿(150mL×2)萃取。合并有机相,利用水(10mL)和饱和食盐水洗涤,利用无水硫酸钠干燥,蒸除溶剂,得到化合物13(0.57g,89%),为暗绿色晶体。
Rf=0.1(二氯甲烷).
1H NMR(400MHz,CDCl3,δ,ppm):8.44(dd,J1=3.2Hz,J2=6.8Hz,4H,H-1~4),7.60(dd,J1=3.2Hz,J2=6.8Hz,4H,H-5~8),4.87(s,4H,H-9~12).
MS-ESI Calc.for C16H15N2[16-H]-235.1,Found,235.0.
FT-IR(vcm-1):3278.9(vs,vNH2),2876.7(s,vC=C),1551.1(s,vC-C of Ar),1104.5(s,ωCH2),1030.8(w,βCH),942.9(w,γCH).。
实施例11
五氟苯酚(9.19g,50.0mmol)和二环己基碳二亚胺(DCC,8.84g,42.8mmol)溶解至干燥四氢呋喃(100mL)中,均苯三甲酸(3g,14.28mmol)溶解至干燥四氢呋喃(150mL)中并加入至上述溶液中,并在氩气气氛和室温下搅拌72小时。减压蒸除溶剂并均匀分散到二氯甲烷(250mL)中,滤除固体,滤液蒸除溶剂并用柱色谱进行分离纯化(二氯甲烷:石油醚1:1to纯二氯甲烷,v:v)得到化合物19(22.7g,75%),为白色固体。
Rf=0.4(二氯甲烷:石油醚1:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):9.29(s,3H,H-1~3).
13C NMR(400MHz,CDCl3,δ,ppm):160.3(6C),137.6(6C),129.4(6C),142.4(3C),141.3(3C),140.0(3C).
19F NMR(400MHz,CDCl3,δ,ppm):-152.2(5F),-156.3(5F),-161.5(5F).
FT-IR(vcm-1):1763.2(s,vC=O),1521.8(s,vC-C of Ar),1192.5(s,βCH2),994.7(s,vAr-F)。
实施例12
化合物19(4.3g,6.1mmol)和化合物13(530mg,2.3mmol)溶解至干燥四氢呋喃(20mL)中,并加热至40℃。N,N-二异丙基乙胺(DIPEA,2mL)在氩气和室温下缓慢加入到上述溶液中,并搅拌4小时。减压蒸除溶剂,并用柱色谱进行分离纯化(二氯甲烷:石油醚1:1,v:v)得到化合物20(1.3g,76%),为白色油状物。
Rf=0.5(二氯甲烷:石油醚1:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):9.07(s,1H,H-3),8.87(s,2H,H-1,2),6.63(s,w,1H,H-4),4.20(s,6H,H-8~13),4.01(s,6H,H-14~19),2.49(s,3H,H-5~7).
FT-IR(vcm-1):3278.9(s,vC≡C),2934.6(m,vNH),2839.8(m,vC-O of ether),1763.0(s,vC=O of easter),1645.9(s,vC=O of amide),1512.9(s,vC-C of Ar),1257.9(m,δCH of alkyne),1206.8(s,βCH2),994.8(s,vAr-F).。
实施例13
化合物20(1.2g,1.6mmol)溶解至干燥四氢呋喃(50mL)中,同时化合物16(373mg,1.6mmol)溶解至干燥四氢呋喃(50mL)中,并分别置于100毫升的玻璃注射器中,并于室温氩气气氛下24小时内分别逐滴滴入一个包含干燥四氢呋喃(200mL)的烧瓶中,之后再氩气下持续搅拌24小时。减压蒸除溶剂,残余固体分散至二氯甲烷中并溶解于最少量二氯甲烷中,利用硅藻土过滤,滤液减压蒸除溶剂,利用柱色谱进行分离纯化(0~10%丙酮于氯仿中,v:v)得到化合物21(420mg,46.7%),为黄色固体。
Rf=0.6(丙酮:氯仿=1:9,v:v).
1H NMR(400MHz,DMSO-δ6,δ,ppm):8.83(t,J=5.2Hz,4H,H-33,34,36,37),8.48-8.40(m,8H,H-51,54,55,58,59,62,63,66),8.03-8.00(m,1H,H-35),7.74-7.71(m,1H,H-38),7.48-7.44(m,8H,H-52,53,56,57,60,61,64,65),5.43-5.40(m,8H,H-43~50),4.23-4.19(m,12H,H-7~18),3.90-3.85(m,12H,H-19~30),3.50-3.42(m,6H,H-1~6).
MS-ESI Calc.for C76H66N6NaO12[21+H]+1277.6,Found,1277.2.
FT-IR(vcm-1):3169.4(m,vC≡C),2934.8(m,vNH),2803.3(w,vC-O of ether),1778.7(s,vC=O of amide),1522.3(s,vC-C of Ar),1207.4(m,δCH of alkyne),1206.8(s,βCH2).。
实施例14
F3-SH多肽(20mg,0.006mmol)和三(2-羰基乙基)磷盐酸盐(TCEP,2mg,0.008mmol)溶解至HEPES缓冲液(pH=7.0,5mL)中,并在氩气气氛室温下搅拌一小时,然后加入Mal-PEG5k-N3(20mg,0.004mmol)并搅拌3小时,纯水透析24小时,冻干得到F3-PEG-N3。F3-PEG-N3(20mg,0.003mmol)在氩气气氛室温下和化合物21(4mg,0.003mmol)、抗坏血酸钠(20mg,0.1mmol),N,N,N',N”,N”-五甲基二乙烯基三胺(PMDETA,5mg,0.029mmol)、碘化亚铜(2mg,0.01mmol)分散到干燥DMF(1mL)中,并搅拌过夜,之后再乙醚中沉淀三次,固体复溶至最少量水中,在EDTA溶液(100mmol,1L)中透析24小时,然后在纯水中透析24小时,冻干得到化合物23,为黄绿色固体。
化合物22:Rf=0.4(二氯甲烷:甲醇=20:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):8.80-8.75(m,4H,H-33,34,36,37),8.29-8.23(m,8H,H-51,54,55,58,59,62,63,66),7.99(m,1H,H-35),7.54(m,1H,H-38),7.48-7.19(m,8H,H-52,53,56,57,60,61,64,65),5.58-5.51(s,w,6H,H-31,32,39~42),5.35-5.30(s,8H,H-43~50),4.28-4.23(m,12H,H-7~18),4.17-4.05(m,12H,H-19~30),3.85-3.81(m,4H,H-3~6),3.77-3.21(m,448H,H-protons of PEG),2.10-2.05(m,3H,H-MeO of PEG).。
实施例15
氩气气氛和室温下,化合物22(65mg,0.01mmol),化合物3(30mg,0.08mmol),碘化亚铜(20mg,0.1mmol)和PMDETA(50mg,0.30mmol)分散到干燥DMF(2mL)中并搅拌过夜,在乙醚中沉淀三次,,固体复溶至最少量水中,在EDTA溶液(100mmol,1L)中透析24小时,然后在纯水中透析24小时,冻干得到化合物24,为黄绿色固体。
For 26:1H NMR(400MHz,DMSO-δ6,δ,ppm):8.93-8.87(m,H-triazole),8.40-8.37(m,H-aromatic rings),5.49-5.35(m,H-CH of oleic acid),5.31-5.23(m,H-CH2of thehost),4.59-4.30(m,H-CH2of linker to oleic acid),3.88-2.82(m,H-protons ofPEG),3.24(s,H-MeO of PEG),2.07-1.87(m,H-CH2of linker to oleic acid),1.32-1.22(m,H-protons of oleic acid),0.89-0.75(m,H-MeO of oleic acid).。
实施例16
2-吲哚噻吩(29,4.2g,20mmol),2-(甲胺基)乙醇(28,18g,240mmol),铜粉(20mol%,254mg)和一水磷酸三钾(9.2g,40mmol)在氩气气氛下分散至烧瓶中,并加热至70℃,保温24小时,降至室温,加入水(80mL),利用乙醚(100mL×3)萃取。有机相合并,无水硫酸钠干燥,减压蒸除溶剂,利用柱色谱分离纯化(二氯甲烷:石油醚3:2至1:2,v:v)得到化合物30(0.6g,15.9%),为黄色油状物。.
Rf=0.5(石油醚:乙酸乙酯=1:1,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):6.77(t,J=4.8Hz,1H,H-1),6.51(d,J=4.8Hz,1H,H-2),6.01-6.00(m,1H,H-3),3.81(d,J=5.2Hz,2H,H-4,5),3.38(t,J=5.2Hz,2H,H-6,7),2.96(s,3H,H-8~10),1.87(s,1H,H-11).
MS-ESI Calc.for C7H12NOS[30+H]+158.1,Found,158.0.。
实施例17
化合物30(1.32g,8.4mmol)和溴丙炔(3.46mL,31.1mmol)溶解至甲苯(35mL)中,四丁基硫酸氢铵(250mg,0.74mmol)溶解至50%氢氧化钠水溶液(30mL)中并加至上述溶液中,在室温下搅拌72小时,有机层分离出来,减压蒸除溶剂,重新分散于氯仿(100mL)红,并用水(50mL×3)洗涤,无水硫酸钠干燥,减压蒸除溶剂,利用柱色谱分离纯化(2%至12%乙酸乙酯:shiyoumi,v:v)得到化合物31(1.0g,60.9%),为黄色液体。
Rf=0.8(petroleum ether:ethyl acetate 1:3,v:v).
1H NMR(400MHz,CDCl3,δ,ppm):6.76(t,J=4.8Hz,1H,H-1),6.51(d,J=4.8Hz,1H,H-2),5.92-5.89(m,1H,H-3),4.16(d,J=5.2Hz,2H,H-4,5),3.74(t,J=5.2Hz,2H,H-11,12),3.46(t,J=5.2Hz,2H,H-6,7),2.98(s,3H,H-8~10),2.43(s,1H,H-13).
MS-ESI Calc.for C10H14NOS[31+H]+196.1,Found,196.0.。
实施例18
方酸(171mg,1.5mmol)和化合物31(590mg,3.0mmol)溶解到干燥的苯/正丁醇(3:1,v:v,80mL)中,在氩气气氛下加热至回流,并利用Dean-Stark分水器除水,处理8小时。降至室温后,减压蒸除溶剂,之后利用柱色谱分离纯化(0%至15%甲醇于二氯甲烷,v:v)得到化合物32(480mg,31.1%),为蓝色固体。
Rf=0.7(氯甲烷:甲醇20:1,v:v).
紫外吸收(氯仿中)λabs=656nm.
荧光发射(氯仿中)λem=670nm.
1H NMR(400MHz,CDCl3,δ,ppm):7.93(d,J=4.8Hz,2H,H-12,13),6.23(d,J=4.8Hz,2H,H-11,14),4.14-4.10(m,4H,H-2,3,22,23),3.78(t,J=4.0Hz,4H,H-6,7,18,19),3.67(t,J=4.0Hz,4H,H-4,5,20,21),2.40(s,4H,H-1,24),1.52(s,6H,H-8~10,15~17).
MS-ESI Calc.for C24H25N2O4S2[32+H]+469.1,Found,469.0.
FT-IR(vcm-1):2371.4(m,vC-S),1616.5(s,vC=O),1412.0(m,δCH of alkyne),1089.5(s,βCH2).。
实施例19
奥沙利铂(33,100mg,0.25mmol)分散到双氧水溶液(30%aqueous solution,4mL)中,并在暗处室温搅拌24小时。之后冻干得到化合物34(108mg,100%),为黄色粉末
Rf=0.7(二氯甲烷:甲醇=10:1,v:v).
1H NMR(400MHz,D2O,δ,ppm):2.70-2.57(m,2H,H-1,10),2.12-2.02(m,2H,H-2,8),1.50-1.29(m,4H,H-4~7),1.12-1.00(m,2H,H-3,9).
FT-IR(vcm-1):1727.1(m,vC=O),1660.9(s,vPt-O).。
实施例20
化合物34(135mg,0.31mmol)分散到干燥DMF(6mL)中并加入丁二酸酐(34mg,0.35mmol)。50℃暗处搅拌24小时,降至室温,在乙醚中沉淀三次,得到化合物35(165mg,100%),为白色粉末。
Rf=0.6(二氯甲烷:甲醇:乙酸=10:1:0.01,v:v:v).
1H NMR(400MHz,D2O,δ,ppm):2.84-2.71(m,2H,H-1,10),2.68-2.61(m,2H,H-13,14),2.60-2.45(m,2H,H-11,12),2.28-2.15(m,2H,H-2,8),1.63-1.41(m,4H,H-4~7),1.29-1.08(m,2H,H-3,9).
MS-ESI Calc.for C12H21N2O9Pt[35+H]+532.1(100%),531.1(86.1%),533.1(80.7%),Found,532.0,531.0,533.0;MS-ESI Calc.for C12H20N2HNaO9Pt[35+Na]+554.1(100.0%),553.1(85.8%),555.1(79.4%),Found,554.0,553.0,555.0.
FT-IR(vcm-1):1778.2(m,vC=O),1529.3(s,vPt-O).。
实施例21
化合物35(53mg,0.1mmol),3-叠氮基丙胺(30mg,0.3mmol),HBTU(114mg,0.3mmol)和三乙胺TEA(30mg,0.3mmol)溶解到干燥DMF(1mL)中并在暗处搅拌过夜,沉淀至二氯甲烷中得到化合物36(60mg,98%),为白色固体。
Rf=0.8(二氯甲烷:甲醇=20:1,v:v).
1H NMR(400MHz,D2O,δ,ppm):3.36(t,J=6.4Hz,1H,H-13),3.24(t,J=6.4Hz,1H,H-14),2.90-2.76(m,2H,H-16,17),2.62(t,J=6.0Hz,1H,H-1),2.54-2.50(s,w,1H,H-15),2.44(t,J=6.0Hz,1H,H-1),2.33-2.21(m,2H,H-2,8),1.76(t,J=6.4Hz,1H,H-3),1.69-1.47(m,7H,H-4~7,9,11,12),1.32-1.10(m,4H,H-18~21).
MS-ESI Calc.for C15H27N6O8Pt[36+H]+614.2(100.0%),613.2(95.4%),615.2(75.6%),Found,614.0,613.0,615.0;MS-ESI Calc.for C15H26N6NaO8Pt[36+Na]+636.1(100.0%),635.1(83.7%),637.1(81.0%),Found,554.0,553.0,555.0.
FT-IR(vcm-1):2102.6(vs,vN3),1731.2(m,vC=O),1560.4(s,vPt-O),1352.9(s,βCH2).。
实施例22
氮气保护下,化合物36(15mg,0.023mmol),化合物32(4.5mg,0.009mmol),碘化亚铜(9mg,0.046mmol),和PMDETA(22mg,0.13mmol)分散到干燥DMF(1mL)中,室温黑暗处搅拌过夜,沉淀到乙醚中三次,得到的白色固体.利用柱色谱(二氯甲烷:甲醇10:1,v:v)分离纯化得到化合物1(13mg,87%),为蓝色固体。
Rf=0.6(二氯甲烷:甲醇=10:1,v:v).
1H NMR(400MHz,DMSO-δ6,δ,ppm):8.09(s,1H,H-21),7.87(s,w,1H,H-14),7.75(d,J=4.8Hz,H-32),6.60(d,J=4.8Hz,H-32),4.17(s,2H,H-22,23),3.74(dd,J1=4.8Hz,J2=4.4Hz,2H,19,20),3.45(d,J=1.2Hz,2H,H-24,25),3.32(merged into water peak,m,2H,H-26,27),3.22(s,3H,H-28~30),3.08-3.04(m,2H,H-13,14),2.40-2.34(partlymerged into solvent peak,m,2H,H-15,16),2.30-2.19(m,2H,H-1,10),2.11-1.95(m,2H,H-2,8),1.62(t,J=6.0Hz,H-3),1.54-1.38(m,7H,H-4~7,9,11,12),1.18-1.02(m,2H,H-17,18).Since 1is symmetrical,1H NMR proton distribution was shown on halfmolecule.
13C NMR(400MHz,DMSO-δ6,δ,ppm):181.0(2C),170.2(2C),170.1(2C),168.5(2C),164.3(2C),163.7(2C),136.0(2C),114.0(2C),109.9(2C),79.9(2C),77.3(2C),66.1(2C),61.0(2C),60.2(2C),59.9(2C),57.6(2C),54.6(2C),48.8(2C),414.4(2C),35.6(2C),32.0(2C),31.1(2C),30.7(2C),30.5(2C),30.3(2C),28.9(2C),23.6(2C),23.4(2C).
MS-ESI Calc.for C56H79K2N15O20Pt2S2[1+CH3CN+2K]2+906.7,Found,906.6.
HRMS Calc.for C63H100N17NaO20Pt2S2[1+PMDETA+Na+H]2+945.7977,Found,945.7974.
FT-IR(vcm-1):1675.2(m,vC=O),1558.6(s,vPt-O),1089.5(s,βCH2).。
Claims (14)
1.一种基于分子梭的诊疗型纳米药物,其特征在于:所述纳米药物由基于蒽的环四内酰胺结构的分子梭主体、分子梭主体修饰基团油酸与聚乙二醇、基于方酸结构的分子梭客体、药物分子构成,所述纳米药物为胶束;
所述的分子梭主体修饰的油酸分子与基于蒽的环四内酰胺连接方式是双硫键;所述的分子梭主体修饰的聚乙二醇分子与基于蒽的环四内酰胺连接方式是点击化学反应生成的三氮唑基团;所述的分子梭客体为方酸的长链脂肪烃衍生物;所述的药物分子为奥沙利铂,氧化后修饰上叠氮基团,通过点击化学连接到分子梭客体两端;
所述的分子梭主体在修饰上聚乙二醇与油酸后形成两亲分子,在水性溶液中自组装成胶束,所述的胶束中将制得的方酸-药物连接分子负载至胶束疏水内核中,制得载药胶束;
所述分子梭主体修饰基团油酸与聚乙二醇的另一末端通过马来酰亚胺与巯基的反应连接上修饰有巯基的多肽分子。
2.根据权利要求1所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的胶束在透射电子显微镜下观察表面为规整球形。
3.根据权利要求1所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的胶束在动态光散射下进行表征,其水化半径为36.2±13.7纳米。
4.根据权利要求1所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的胶束在动态光散射下进行表征,其表面电势为+1.65毫伏。
5.根据权利要求2所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的载药胶束在透射电子显微镜下观察表面为规整球形且具备一个实心内核。
6.根据权利要求1所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的胶束在动态光散射下进行表征,其水化半径为40.1±14.3纳米。
7.根据权利要求2 所述的基于分子梭的诊疗型纳米药物,其特征在于,所述载药胶束在动态光散射下进行表征,其表面电势为-9.16毫伏。
8.根据权利要求2所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的载药胶束高效液相色谱测得其对方酸-药物连接分子的包封率为79.31±0.71%。
9.根据权利要求2所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的载药胶束高效液相色谱测得其对奥沙利铂的载药量为3.70±0.19%。
10.根据权利要求2所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的载药胶束其溶液中每毫升含有粒子数目为2.2±0.0355×109个。
11.根据权利要求1所述的基于分子梭的诊疗型纳米药物,其特征在于,胶束中其分子组分包含分子梭主体与客体的比例为1:0.45。
12.根据权利要求1所述的基于分子梭的诊疗型纳米药物,其特征在于,所述的多肽分子为末端修饰有巯基的、靶向三阴性乳腺癌与肿瘤新生血管的F3多肽分子。
13.根据权利要求1所述的基于分子梭的诊疗型纳米药物,其特征在于,所述载药胶束中,F3修饰的胶束构筑集团所占总体构筑基元比例为20%。
14.权利要求1所述的基于分子梭的诊疗型纳米药物在用于制备梭形近红外超分子探针中的用途,所述探针用于实时监控药物的释放行为。
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