CN107698608A - 一种基于吡咯并吡咯二酮的新型d‑a‑d有机近红外肿瘤治疗试剂及其制备方法 - Google Patents
一种基于吡咯并吡咯二酮的新型d‑a‑d有机近红外肿瘤治疗试剂及其制备方法 Download PDFInfo
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- CN107698608A CN107698608A CN201710887884.0A CN201710887884A CN107698608A CN 107698608 A CN107698608 A CN 107698608A CN 201710887884 A CN201710887884 A CN 201710887884A CN 107698608 A CN107698608 A CN 107698608A
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Classifications
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- A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- 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
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B57/00—Other synthetic dyes of known constitution
- C09B57/004—Diketopyrrolopyrrole dyes
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
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Abstract
本发明公开了一种基于吡咯并吡咯二酮的新型D‑A‑D有机近红外肿瘤治疗试剂的设计合成及应用性能。本发明所述试剂主要是3,6‑二([3,2‑c]并二噻吩)‑2,5‑二氢吡咯并[3,4‑c]吡咯‑1,4‑二酮衍生物与吩噻嗪硼酸酯通过Suzuki偶联反应获得。该试剂通过再沉淀的方法获得吸收波长在近红外区的纳米材料,该纳米材料具有较高的单线态氧产率、良好的光热转换效率、优异的水分散性及肿瘤组织靶向性,可应用到肿瘤细胞及活体治疗中,在有效杀死肿瘤细胞的同时可有效抑制肿瘤细胞转移,从而达到光热光动力协同治疗的效果。因此将此试剂用于肿瘤治疗将有巨大的应用前景。
Description
技术领域
本发明属于材料和生物医药领域,具体涉及一种基于吡咯并吡咯二酮的新型D-A-D有机近红外肿瘤治疗试剂及其制备方法及其在光热/光动力肿瘤协同治疗中的应用。
背景技术
恶性肿瘤,即癌症,是21世纪威胁全世界的重大疾病之一。目前临床上应用的癌症疗法是放疗、化疗及手术等方法。这些方法一定程度上会对有机体造成副作用,如在杀死肿瘤细胞的同时杀死正常细胞,破坏人体免疫系统,增加第二癌症的发病率,且化疗药物的耐药性也极大限制了其应用。因此开发更有效的癌症治疗试剂成为当前的关键问题。
目前有机近红外染料作为一种非常有前景的、可用于肿瘤诊断和癌症治疗的成像与治疗试剂,已引起人们的极大关注。近红外染料会吸收特定波长的近红外光从而达到激发单线态,部分激发单线态的能量会以较长波长的形式释放出来,称为荧光,因此,近红外光可有效用于体内肿瘤荧光成像。而且,肿瘤靶向的近红外纳米材料具有高度特异性,可区分肿瘤组织和正常组织。此外,由于在近红外光谱范围内,器官组织的自发荧光较低,且光散射低,因此近红外荧光成像具有高的敏感性、较小的背景干扰、较深的组织穿透力等特点。一部分激发态的能量还可通过电子振动弛豫或者其他非辐射跃迁途径传递,转化为热量而使近红外纳米材料用作光热试剂。
此外,另有一部分的单重激发态会通过系间窜越过程转移至一个具有较低能量的激发三线态,近红外染料可以诱导活性氧物质的(reactive oxygen species)产生(例如自由基、单线态氧),他们会引起有机体内生物大分子的氧化反应并造成有机体的组织损伤,因此有机近红外染料也可以作为光动力治疗试剂。
光热治疗(PTT)和光动力治疗(PDT)是到目前为止治疗癌症的相对有效的方法。在光疗中光热剂(PT)可以对异常细胞或组织进行有选择性的局部加热,当温度达到45℃以上时,会引起肿瘤组织内部血管的破坏,从而达到癌症治疗的目的。目前,有多种具有光热、光动力效果的纳米材料,例如金属纳米材料(金、银纳米材料),碳纳米材料(碳纳米管、石墨烯),过渡金属双硫化物(二硫化钼、二硫化钨、硫化银),有机纳米材料(小分子、聚合物)。相比无机纳米材料,有机材料具有较好的生物兼容性、潜在的生物降解、加工简易等特点。而小分子有机化合物,例如吲哚菁绿(ICG),该小分子具有良好的体内生物相容性和低毒性的特点,但由于其光稳定性差,难以改性修饰及靶向性差等缺点,同样制约着该类材料的进一步的发展。因此,发展无毒副作用、体内准确定位、生物降解性良好,生物兼容性好的有机小分子光疗试剂尤为重要。
当分子中有给体-受体(D-A)结构或者推-拉电子结构时可以获得能带较低的半导体材料。吩噻嗪和吡咯并吡咯二酮(DPP)分别作为给体和受体可以获得能带较低的小分子材料。噻吩做为桥,可以增强分子内电子转移(由吩噻嗪到DPP核)同时可以降低电子能隙及推动光谱红移。而吡咯并吡咯二酮衍生物具有以下特点:易修饰、高耐热、强耐光、摩尔吸光系数高,使其在有机电子器件和生物领域有着广泛的应用。然而生物医药领域,DPP的水溶性、靶向性仍然是当前需要面对的一个主要问题,通过分子再沉淀的方式获得水分散性较好的有机纳米材料,该纳米颗粒容易通过高通透长滞留效应(EPR)富集于肿瘤组织,从而解决肿瘤细胞靶向性问题。
发明内容
本发明所解决的技术问题是:提供一种基于吡咯并吡咯二酮的新型D-A-D有机近红外肿瘤治疗试剂以及该试剂的制备方法,该试剂具有生物兼容性好、水溶性好、光稳定性好、肿瘤靶向性好等优点。
为了解决上述技术问题,本发明所采用的技术方案是:
提供一种基于吡咯并吡咯二酮的新型D-A-D有机近红外肿瘤治疗试剂及其制备方法,该试剂包含3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮衍生物,即PD-R3NPs,其化学结构式如下:
其中:
R3=Br or I
所述具有以上结构有机近红外肿瘤治疗试剂,其特征在于通过光热、光动力双模式协同作用治疗肿瘤。
一种制备所述的有机近红外肿瘤治疗试剂的方法,反应路线如下:
其中:
R为硼酸或硼酸酯;
R3=Br or I
反应条件为:
(1)氮气保护下3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮加入到甲苯中,加入四三苯基膦钯,碳酸钾,(E)-3-(10-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯,加热搅拌,提纯后得到产物PD。
(2)氮气保护下,将PD加入到二氯甲烷中,加入N-溴代丁二酰亚胺(NBS)或者N-碘代丁二酰亚胺(NIS),搅拌,提纯后得到产物PD-R3。
(3)PD-R3溶于四氢呋喃中,缓慢滴加到快速搅拌的PBS中,搅拌10分钟后,充氮气除去溶液中的四氢呋喃,得到上述有机纳米颗粒PD-R3NPs。
其中,步骤(1)所述3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮与四三苯基膦钯的摩尔比为1:(0.03-0.1),优选摩尔比为1:(0.03-0.05);3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮与碳酸钾的摩尔比为1:(3-6),优选摩尔比为1:(3-4);3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮与(E)-3-(10-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯的摩尔比为1:(2-6),优选摩尔比为1:(2-3);PD与N-溴代丁二酰亚胺(或N-碘代丁二酰亚胺)的摩尔比为1:(2-4),优选摩尔比为1:(2-2.5)。
步骤(1)所述的加热温度搅拌温度为90-110℃,加热搅拌时间为12-24小时,优选加热搅拌温度为100-110℃,加热搅拌时间为12-20小时
步骤(2)所述搅拌温度室温,加热搅拌时间为1-3小时,优选搅拌温度为15-25℃,搅拌时间为1-1.5小时。
步骤(3)所述PD-R3在四氢呋喃中浓度为1-5mg/mL,滴加速度为1-20滴/分钟,快速搅拌搅拌速度为500-1500转/分钟,得到纳米颗粒PD-R3NPs。
以上所述有机纳米材料可以在制备光热、光动力治疗中药物中应用。
本发明的有益效果是:与现有材料相比,本发明的优点如下:
(1)本发明制所述试剂为一种新型所述试剂为一种基于吡咯并吡咯二酮的新型D-A-D近红外有机纳米肿瘤诊断治疗试剂,该试剂结构明确,吸光范围可达到近红外区域;
(2)该治疗试剂具肿瘤特定靶向性,且水分散性优异、光热转换能力与产生单线态氧能力优异;
(3)该治疗试剂可在有效杀死肿瘤细胞的同时,对生物体的毒副作用较小,具有良好的应用前景。
附图说明
图1是本发明实施例近红外有机纳米肿瘤治疗试剂PD-Br NPs的粒径分布测试与扫描电子显微镜测试结果,测试结果显示该纳米颗粒的粒径分布约为100nm。
图2是本发明实施例近红外有机纳米肿瘤治疗试剂PD-Br NPs紫外可见光吸收光谱,其675nm处有吸收峰,且在600-1000nm处有较宽吸收,光谱范围达到近红外区域。
图3是本发明实施例近红外有机纳米肿瘤治疗试剂PD-Br NPs荧光发射光谱,其发射波长在,且在600-900nm处有较宽吸收,光谱范围达到近红外区域。
图4是本发明制备的有机纳米粒子PD-Br NPs溶液测试的光热转换曲线。浓度为150μg/mL PBS溶液与纯PBS溶液在激光的照射下(660nm,1.0W/cm2),温度随时间的变化。
图5是本发明PD-Br溶液(溶剂为二氯甲烷)探针降解曲线。随着光照时间的增加,探针分子在不断地降解。
图6是本发明PD-Br NPs对于HeLa细胞的毒性试验结果,在激光照射下(660nm,1.0W/cm2),PD-Br NPs的细胞毒性较强,可有效杀死肿瘤细胞,而无激光照射下,PD-Br NPs细胞毒性较小。
图7是本发明PD-Br NPs对于A549细胞的毒性试验结果。在激光照射下(660nm,1.0W/cm2),PD-Br NPs的细胞毒性较强,可有效杀死肿瘤细胞,而无激光照射下,PD-Br NPs细胞毒性偏小。
图8是本发明PD-Br NPs用于活体荧光成像的结果,尾静脉注入后,该纳米颗粒可以有效的到达并富集与肿瘤部位,同时随着时间的变化,药物开始代谢。
图9是本发明PD-Br NPs用于活体治疗的结果,肿瘤体积随着治疗时间的变化曲线。PD-Br NPs在激光照射下(660nm,1.0W/cm2),能有效抑制肿瘤生长并杀死肿瘤。
图10是本发明PD-Br NPs用于活体治疗的结果,小鼠体重随治疗时间变化的曲线。在激光照射下(660nm,1.0W/cm2),治愈的老鼠体重在逐渐增加,机体处于恢复状态。
具体的实施方式
本发明设计合成了一种基于吡咯并吡咯二酮的新型D-A-D有机近红外肿瘤治疗试剂及其制备方法,该试剂主要成分为3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮衍生物,合成路线如下:
R为硼酸或硼酸酯;
R3=Br or I
上述衍生物通过再沉淀的方法得到近红外有机纳米颗粒,该纳米颗粒具有良好的荧光及光热转换能力、单线态氧产生能力、优异的水分散性、肿瘤靶向性,应用于肿瘤细胞及活体荧光成像及光热、光动力协同治疗中,可有效杀死肿瘤细胞。因此,该近红外有机纳米材料在癌症治疗上具有潜在的应用价值。
因为PD-Br NPs虽然为PD-R3NPs中的一种,但PD分子本身具有较好的光热转换能力,在分子中引入重原子Br或者I均可增强激子的系间窜越能力从而提高其单线态氧的产生能力。下面以PD-Br NPs为例,进一步阐述本发明。
实施例1PD-Br的制备
两口瓶(250mL)中,将10-(4-溴苯基)-10H-吩噻嗪(3.540g,10mmol)溶解在三氯甲烷30mL中,抽换氮气三次,加入N,N-二甲基甲酰胺(7mL,88.00mmol),加入氧氯化磷(7.8mL,80.00mmol),加热至90℃,搅拌12小时。倒入冰水中,用氢氧化钠调节pH至6-7,二氯甲烷萃取,干燥,浓缩,柱层析分离得到黄色粉末10-(4-溴苯基)-10H-吩噻嗪-3-甲醛2.9g,产率75%。1H NMR(400MHz,CDCl3):δppm7.70(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),7.04(dd,J1=7.4,J2=1.8Hz,2H),6.88(m,4H),6.24(dd,J1=8.0,J2=1.4Hz,2H)。
两口瓶(250mL)中,将1,8-二氮杂二环十一烯碳-7-烯(2mL,6.24mmol),氯化锂(0.308g,7.28mmol)溶解在四氢呋喃(50mL)中,抽换氮气三次,降温到0℃,将2-(二乙氧基磷酰基)乙酸乙酯(1.528g,6.80mmol)加入上述溶液中,搅拌30分钟后,称取10-(4-溴苯基)-10H-吩噻嗪-3-甲醛(2.000g,5.20mmol),0℃搅拌30分钟,乙酸乙酯萃取,干燥,浓缩,柱层分离得到黄色固体乙基(E)-3-(10-(4-溴苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯1.84g,产率80%。1HNMR(400MHz,CDCl3):δppm 7.76(d,J=8.8Hz,1H),7.78(d,J=16Hz,1H),7.28-7.26(m,2H),7.17(d,J=2.0Hz,1H),7.01-6.96(m,1H),6.88-6.82(m,3H),6.23(d,J=16Hz,1H),6.15-6.14(m,2H),1.34~1.30(m,3H)。
两口瓶(250mL)中,将乙基(E)-3-(10-(4-溴苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯(1.000g,2.21mmol),联频哪醇双硼酯(1.120g,4.42mmol),醋酸钾(0.650g,6.63mmol)溶解在N,N-二甲基甲酰胺(40mL)中,抽换氮气三次,加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(0.170g,0.221mmol)100℃搅拌12小时,乙酸乙酯萃取,干燥,浓缩,柱层析分离得到PZ黄色固,即:(E)-3-(10-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯 0.800g,产率72%。1H NMR(400MHz,CDCl3):δppm 8.05(d,J=8.4Hz,2H),7.46(d,J=16Hz,1H),7.37(d,J=8.4Hz,2H),7.15(d,J=2.0Hz,1H),7.00-6.97(m,1H),6.94(dd,J1=8.4,J2=2Hz,1H),6.82-6.80(m,2H),6.21(s,1H),6.14~6.12(m,2H),1.59(s,12H),1.31(t,J=7.2Hz,1H).。
两口瓶(100mL)中,将(3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮(0.100g,0.09mmol)溶解在甲苯(10mL)中,加入四三苯基膦钯(0.012g,0.009mmol),碳酸钾(1M,0.5mL),(E)-3-(10-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯(0.112g,0.22mmol),加热到110℃,搅拌12小时,二氯甲烷萃取,干燥,浓缩,柱层析分离得到PD绿色固体0.100g,产率65%。1H NMR(400MHz,CDCl3):δppm 9.45(s,2H),7.90(d,J=8.4Hz,1H),7.60(s,2H),7.48(d,J=15.6Hz,2H),7.43(d,J=8.4Hz,4H),7.20(d,J=2Hz,2H),7.04-6.70(m,4H),6.89-6.86(m,4H),6.28-6.22(m,6H),6.42(d,J=1.6Hz,4H),4.23(dd,J1=7.0Hz,J2=7.2,4H),4.11(d,J=7.2Hz,4H),2.03~2.00(m,2H),1.60~1.21(m,72H),0.86~0.83(m,12H)。
在Schlenk管(100mL)中,将PD(0.030g,0.017mmol)溶解在二氯甲烷中,抽换氮气三次,0℃下加入N-溴代丁二酰亚胺(0.009g,0.05mmol),若制备PD-I,则将N-溴代丁二酰亚胺(NBS)更换为N-碘代丁二酰亚胺(NIS);室温搅拌2小时,加水淬灭,二氯甲烷萃取,干燥浓缩,柱层析分离得PD-Br绿色固体0.020g,产率62%。1H NMR(400MHz,CDCl3):δppm 9.37(s,2H),7.90(d,J=8.4Hz,4H),7.61(s,2H),7.45(t,J1=4.4,J2=3.6Hz,4H),7.07(t,J1=2.0,J2=5.2Hz,4H),6.89(dd,J1=6.4,J2=2.8Hz,2H),6.35(d,J=8.4,4H),6.26-6.22(m,6H),4.27(m,4H),4.11(d,J=7.2Hz,4H),2.03-2.01(m,2H),1.32-1.21(m,72H),0.86-0.84(m,12H).
实施例2PD-Br NPs制备
将PD-Br(0.002g)溶解到100μL四氢呋喃中,缓慢滴加(滴加速度为15-20滴/分钟)到快速搅拌(1000转/分钟)的10mL PBS中,搅拌5分钟,鼓氮气除去四氢呋喃,得到有机纳米颗粒PD-Br NPs。图1是有机纳米颗粒PD-Br NPs测试的动态光散射(DLS)结果以及透射电子显微镜(TEM)图,所得纳米颗粒的粒径约为100nm。
实施例3PD-Br NPs光谱测试:
选取1cm宽的石英比色皿,加入3mL的PD-Br NPs PBS(50μg/mL)溶液,测试其紫外吸收光谱与荧光发射光谱。如图2所示,在PD-Br NPs紫外可见光吸收光谱中,在600-1000nm范围内均有吸收峰,最大吸收峰在675nm处,光谱范围达到近红外区域。图3是PD-Br NPs荧光发射光谱图,其发射光谱范围在600-900nm,达到近红外区域。
实施例4PD-Br光热转换效率测试:
选取1cm宽的石英比色皿,加入3mL PD-Br NPs PBS(150μg/mL)溶液,使用660nm激光(1.0W/cm2)进行光照,同时实时记录温度的变化,当温度达到稳定阶段,关掉激光器,使溶液处于降温阶段,实时监测温度。将PBS进行同样的升温降温的过程。按照公式计算出该试剂的光热转换效率。如图4所示光热测试的曲线,在升温的情况下,光照10分钟,PD-BrNPs PBS溶液的温度变化值达到18℃,而PBS溶液在同样的条件下升温1.8度。
实施例5PD-Br单线态氧产生能力测试:
将PD-Br溶于二氯甲烷中,加入适量的1,3-二苯基异苯并呋喃(1,3-Diphenylisobenzofuran,DPBF)探针,使PD-Br在660nm的吸光度为0.3左右,DPBF在414nm处的吸光度为1.1左右,使用660nm(0.6W/cm2)激光器进行光照,根据不同的光照时长,使用紫外-可见-光近红外分光光度计实时检测DPBF的降解情况。选取亚甲基蓝(MB)作为参照组,检测DPBF的降解情况。如图5所示DPBF探针在PD-Br存在下的降解曲线,在660nm的激光照射下,随着光照的时间变化,PD-Br溶液中的探针在不断的降解。通过公式计算PD-Br的单线态氧产率为66.5%。而亚甲基蓝参照组中的DPBF探针,在660nm的激光照射下,随着光照的时间变化并没有降解。
实施例6PD-Br NPs肿瘤细胞体外毒性实验:
现已知,Hela细胞源自宫颈癌细胞,而A549细胞是腺癌人类肺泡基底上皮细胞,本实验选取HeLa细胞系与A549细胞系进行体外细胞毒性试验,测试其暗毒和激光光毒性。具体实验步骤如下:200μg/mL的PD-Br NPs PBS溶液,用DMEM配成不同的浓度梯度的溶液(10,20,30,40,50,60,70,80μg/mL)。HeLa细胞与A549细胞分别被接种在黑底96孔的培养板上,37℃下培养24小时使其贴壁生长,用PBS溶液清洗,分别加入不同浓度的药物80μL(两组,每组5个孔),培养24小时后,一组取出,用近红外激光器(660nm,1.0W/cm2)辐射8分钟,另一组仍然避光,继续培养24小时,加入MTT比色法进行测定。取MTT(5mg/mL)20μL添加到细胞中,在相同的环境孵育4小时后,加入DMSO 200μL,使用Bio-Tek微型板块酶标仪测定吸收峰为490nm的吸收值。如图6所示PD-Br NPs对于HeLa细胞的毒性试验结果:光照组约在35μg/mL的浓度下,HeLa细胞成活率为50%;而暗光组,60μg/mL的浓度下,HeLa细胞存活率在90%以上。如图7所示PD-Br NPs对于A549细胞的毒性试验结果:光照组约在70μg/mL的浓度下,A549细胞成活率为50%;而暗光组,70μg/mL的浓度下,细胞存活率在80%以上。由此可知,在激光照射下(660nm,1.0W/cm2),PD-Br NPs的细胞毒性较强,可有效杀死肿瘤细胞,而无激光照射下,PD-Br NPs细胞毒性较小。
实施例7PD-Br NPs活体荧光成像实验:
选择将HeLa细胞注入腋下的裸鼠作为肿瘤模型。当肿瘤体积为200mm3,通过尾静脉注入PD-Br NPs PBS溶液(100μg/mL),通过活体荧光成像监测不同时刻药物在体内的摄取与代谢情况。如图8活体荧光成像的结果所示,尾静脉注入PD-Br NPs PBS溶液后,PD-BrNPs纳米颗粒可以有效的到达并富集于肿瘤部位,同时随着时间的变化,药物开始代谢。
实施例9PD-Br NPs肿瘤细胞体内光疗实验:
选择将HeLa细胞注入腋下的裸鼠作为肿瘤模型。当肿瘤体积为200mm3,将15只裸鼠分为三组。第一组注入PBS,第二、三组的小鼠分别通过尾静脉注入PD-Br NPs PBS溶液(100μg/mL)。6小时后,第一组和第三组小鼠进行近红外光照8分钟,观察肿瘤区域的变化(660nm,1.0W/cm2),而第二组无光照。上述过程重复20天,观察并记录三组小鼠肿瘤体积与体重变化(每两天测量一次)。
图9为小鼠肿瘤体积大小变化曲线,第一组为注入PBS的光照组,小鼠的肿瘤体积在不断的增加;第二组为注入PD-Br NPs PBS溶液的暗光组,肿瘤体积在不断增加,较第一组,生长较为慢些;第三组,为注入PD-Br NPs PBS溶液的光照组,可以明显看出肿瘤体积的减小,直至到肿瘤消失。
图10为小鼠体重变化曲线,第一组为注入PBS的光照组,随着肿瘤的的增大,小鼠的身体机能逐渐衰弱,小鼠较瘦,第二组为小鼠注入PD-Br NPs PBS溶液的暗光组,体重同样不断减轻;第三组,为注入PD-Br NPs PBS溶液的光照组,随着肿瘤的消失,小鼠的健康状况良好,体重在不断增加。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.一种基于吡咯并吡咯二酮的新型D-A-D有机近红外肿瘤治疗试剂,该试剂包含3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮衍生物,即PD-R3NPs,其化学结构式如下:
其中:
R3=Br or I。
2.根据权利要求1所述的有机近红外肿瘤治疗试剂,其特征在于所述试剂可以协同光热、光动力双模式治疗肿瘤。
3.一种制备如权利要求1或2所述的有机近红外肿瘤治疗试剂的方法,其反应路线如下:
其中:
R为硼酸或硼酸酯;
R3=Br or I
反应条件为:
(1)氮气保护下,10-(4-溴苯基)-10H-吩噻嗪溶解在三氯甲烷,加入N,N-二甲基甲酰胺,加入氧氯化磷,加热搅拌,提纯后得到10-(4-溴苯基)-10H-吩噻嗪-3-甲醛,即产物4;
(2)氮气保护下,将1,8-二氮杂二环十一烯碳-7-烯,氯化锂溶解在四氢呋喃中,降温到0℃,将2-(二乙氧基磷酰基)乙酸乙酯和产物4加入上述溶液中,搅拌提纯得到乙基(E)-3-(10-(4-溴苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯,即产物5;
(3)氮气保护下,将产物5,联频哪醇双硼酯,醋酸钾溶解在N,N-二甲基甲酰胺中,再加入[1,1'-双(二苯基膦)二茂铁]二氯化钯,搅拌提纯得到(E)-3-(10-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯,即产物PZ;
(4)氮气保护下,3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮加入到甲苯中,加入四三苯基膦钯,碳酸钾,PZ,加热搅拌,提纯后得到产物PD;
(5)氮气保护下,将PD加入到二氯甲烷中,加入N-溴代丁二酰亚胺(NBS)或者N-碘代丁二酰亚胺(NIS),搅拌,提纯后得到产物PD-R3;
(6)PD-R3溶于四氢呋喃中,缓慢滴加到快速搅拌的PBS中,搅拌10分钟后,鼓氮气除去四氢呋喃,得到上述有机纳米材料PD-R3NPs。
4.根据权利要求3所述的有机近红外肿瘤治疗试剂的制备方法,其特征在于,步骤(4)所述3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮与四三苯基膦钯的摩尔比为1:(0.03-0.1)。
5.根据权利要求3所述的有机近红外肿瘤治疗试剂的制备方法,其特征在于,步骤(4)所述3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮与无水碳酸钾的摩尔比为1:(3-6)。
6.根据权利要求3所述的有机近红外肿瘤治疗试剂的制备方法,其特征在于,步骤(4)所述3,6-二(5-溴噻吩并[3,2-b]2-噻吩基)-2-(十九烷基)-5(2-辛基十二烷基)-2,5-二氢吡咯并[3,4-c]吡咯-1,4-二酮与(E)-3-(10-(4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基)-10H-吩噻嗪-3-基)丙烯酸乙酯的摩尔比为1:(2-6)。
7.根据权利要求3所述的有机近红外肿瘤治疗试剂的制备方法,其特征在于,步骤(4)所述加热搅拌温度为90-110℃,加热搅拌时间为12-24小时。
8.根据权利要求3所述的有机近红外肿瘤治疗试剂的制备方法,其特征在于,步骤(5)所述搅拌温度0-25℃,加热搅拌时间为1-3小时,所述PD与N-溴代丁二酰亚胺的摩尔比为1:(2-4)。
9.根据权利要求3所述的有机近红外肿瘤治疗试剂的制备方法,其特征在于,步骤(6)所述PD-Br在四氢呋喃中浓度为1-5毫克/毫升,滴加速度为1-20滴/分钟,快速搅拌搅拌速度为500-1500转/分钟。
10.权利要求1所述基于吡咯并吡咯二酮的新型D-A-D有机近红外肿瘤治疗试剂在制备应用于光动力、光热协同作用的肿瘤治疗药物中的应用。
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CN113181357A (zh) * | 2020-01-10 | 2021-07-30 | 中国科学院理化技术研究所 | 一种有机纳米肿瘤光热剂及其制法和应用 |
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CN114848817A (zh) * | 2019-05-17 | 2022-08-05 | 北京厚燊维康科技有限责任公司 | 二酮类化合物在光动力治疗或诊断中的用途 |
CN114989174A (zh) * | 2022-06-02 | 2022-09-02 | 南京邮电大学 | 一种有机小分子nir-ii荧光染料、纳米颗粒及其制备方法与应用 |
-
2017
- 2017-09-27 CN CN201710887884.0A patent/CN107698608A/zh active Pending
Non-Patent Citations (1)
Title |
---|
陈瑞等: "有机光热转换材料及其在光热疗法中的应用", 《化学进展》 * |
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CN112566911A (zh) * | 2018-07-18 | 2021-03-26 | 香港科技大学 | 光热试剂 |
CN112566911B (zh) * | 2018-07-18 | 2023-09-01 | 香港科技大学 | 光热试剂 |
CN109206436A (zh) * | 2018-08-06 | 2019-01-15 | 西安理工大学 | 一种以二噻吩并吡咯为给电子中心的齐聚噻吩衍生物及其制备方法 |
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CN114848817A (zh) * | 2019-05-17 | 2022-08-05 | 北京厚燊维康科技有限责任公司 | 二酮类化合物在光动力治疗或诊断中的用途 |
CN113181357A (zh) * | 2020-01-10 | 2021-07-30 | 中国科学院理化技术研究所 | 一种有机纳米肿瘤光热剂及其制法和应用 |
CN113181357B (zh) * | 2020-01-10 | 2022-11-01 | 中国科学院理化技术研究所 | 一种有机纳米肿瘤光热剂及其制法和应用 |
CN112494663A (zh) * | 2020-11-18 | 2021-03-16 | 南京邮电大学 | 一种新型多模态纳米诊疗试剂及其制备方法和应用 |
CN112679707A (zh) * | 2020-12-25 | 2021-04-20 | 华南理工大学 | 一类用于光热治疗的近红外二区聚合物、纳米颗粒及其制备方法与应用 |
CN114853788A (zh) * | 2022-05-23 | 2022-08-05 | 南方科技大学 | 一种铁死亡诱导剂及其制备方法和用途 |
CN114853788B (zh) * | 2022-05-23 | 2023-12-05 | 南方科技大学 | 一种铁死亡诱导剂及其制备方法和用途 |
CN114989174A (zh) * | 2022-06-02 | 2022-09-02 | 南京邮电大学 | 一种有机小分子nir-ii荧光染料、纳米颗粒及其制备方法与应用 |
CN114989174B (zh) * | 2022-06-02 | 2023-07-28 | 南京邮电大学 | 一种有机小分子nir-ii荧光染料、纳米颗粒及其制备方法与应用 |
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