CN112121165A - 一种自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的制备方法及应用 - Google Patents
一种自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的制备方法及应用 Download PDFInfo
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Abstract
本发明公开了一种自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的制备方法及应用,涉及有机分子在生物医药领域的应用。光动力/光热联合治疗由于操作方便、无侵入性、局部选择性、耐药性小、副作用小等特点而受到广泛关注。然而光动力治疗具有肿瘤组织氧浓度的依赖性,治疗效率受到限制。本发明选择自携氧型光敏剂蒽内过氧化物与光热制剂连用,并用两亲性高分子对两类有机分子进行包覆,形成水溶性复合纳米粒子,经近红外光(880nm)照射后表现出较高的光热转换效率,活性氧产率及明显抑制肿瘤生长的作用。因此,本发明在新型肿瘤治疗领域具有重要的实用前景和社会价值。
Description
技术领域
本发明属于生物医用材料技术领域,具体涉及一种自携氧型光热制剂分子/蒽内过氧化物衍生物/聚合物复合纳米粒子的制备及作为抗肿瘤药物和诊断制剂在肿瘤光动力/光热联合治疗中的应用。
背景技术
目前,恶性肿瘤已经成为威胁人类健康和导致人类死亡的最严重疾病之一。与手术、放疗、化疗等传统肿瘤治疗手段相比,光学治疗由于具有操作方便、无侵入性、局部选择性、耐药性小、副作用小等特点而受到广泛关注。其中,光动力治疗(photodynamictherapy,PDT)和光热治疗(photothermal therapy,PTT)是两种典型的光学治疗手段,它们的治疗原理是基于光敏剂和光热制剂的光化学反应,光敏剂或光热制剂经静脉注射后会优先被病灶组织吸收并富集其中,对于光动力治疗,利用特定波长的光源直接照射病灶部位来激发光敏剂(目前常用光敏剂为卟啉分子及其衍生物)并发生光化学反应,该过程将能量传递给组织中的氧分子,使其产生多种活性氧簇(Reactive Oxygen Species,ROS,包括单线态氧、氧自由基、羟自由基等),进而对细胞内的蛋白质、核酸以及脂类等生物大分子产生破坏作用,使细胞结构和功能受到严重影响,从而导致肿瘤细胞凋亡和(或)死亡,此过程对氧分子浓度具有较强的依赖性。然而,乏氧却是肿瘤的一个显著特征,因此,在乏氧条件下,PDT的治疗效率会明显降低。光热治疗则是利用特定波长的光源照射病灶部位并激发光热制剂发生光化学反应,进而在病灶部位产生局部高温来诱导癌细胞凋亡或坏死。经PTT治疗后,由于残留肿瘤细胞获得的热抵抗特性,肿瘤可能会复发。为了克服上述氧分子浓度依赖性及单一光学治疗效率低下的问题,开发具有自携氧的PDT/PTT协同治疗体系具有重要意义。
发明内容
本发明目的是解决现有技术存在的上述光动力治疗对肿瘤组织氧浓度依赖性大和单一光学疗法治疗效率低的问题,提供一种自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的制备方法及应用。发展单一近红外波长激发的用于自携氧型PDT/PTT联合治疗的纳米制剂用于肿瘤光学治疗,扩展现有光敏化剂的范围,提高肿瘤光学治疗效率。利用两亲性高分子对光热制剂及自携氧型蒽内过氧化物分子进行包覆形成水溶性复合纳米粒子,复合纳米粒子经近红外照射后表现出较高的光热转换效率,活性氧产率及明显抑制肿瘤生长的作用。本发明克服了两类光敏化剂分子水溶性差,无法直接在生物医药领域应用缺点,改善其水溶性、组织分布,提高肿瘤光疗疗效。
为了达到上述目的,本发明采用的技术方案:
一种自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的制备方法,包括:
1)有机光热制剂分子(PTA)确定;2)自携氧型光敏剂蒽内过氧化物衍生物(EPO)确定;3)两亲性高分子(AP)确定;4)通过纳米沉淀技术制备两亲性高分子/光热制剂分子/蒽内过氧化物衍生物复合纳米粒子(NPs);5)体外光热、光动力活性评价。具体步骤如下:
1)有机分子光热制剂(PTA)的确定
所述光热制剂分子选择了A-D-A型有机小分子光热制剂为模型,该类分子结构具有羰基和氰基等基团作为吸电子单元,以降低LUMO能级;分子中的推拉电子结构在红光范围内具有强而宽的吸收,并诱导分子内电荷转移;分子结构的中间部分为共轭主平面。
2)自携氧型光敏剂蒽内过氧化物衍生物(EPO)的确定
所述的蒽内过氧化物衍生物在室温下的半衰期通常为数年,但当加热时,它们会通过环还原反应迅速分解,同时释放出单线态氧,释放出的单线态氧对细胞内的蛋白质、核酸以及脂类等生物大分子产生破坏作用,使细胞结构和功能受到严重影响,从而导致肿瘤细胞凋亡和/或死亡,达到肿瘤治疗的目的。
3)两亲性高分子(AP)的确定
用于修饰A-D-A型光热制剂及自携氧型蒽内过氧化物衍生物分子选择具有两亲性的高分子材料,包括但不限于FA-PEG-PBLA(叶酸-聚乙二醇-聚天冬氨酸苄酯);FEG-PCL(聚乙二醇-聚己内酯);FEG-PLA(聚乙二醇-聚乳酸);PEG-PLGA(聚乙二醇-聚乳酸/羟基乙酸共聚物)和DSPE-PEG(二硬脂酰基磷脂酰乙醇胺-聚乙二醇)等两亲性聚合物。
4)PTA/EPO/AP复合纳米粒子(NPs)的制备
首先将步骤1)、2)所得的两种有机分子溶于相应的良溶剂THF中混合均匀形成溶液A,将步骤3)的两亲性高分子溶于相应的良溶剂DMSO中形成溶液B(其中,PTA,EPO和AP的质量比为1:1:5),将溶解好并混合均匀的有机分子溶液A缓慢均匀地滴加至两亲性高分子溶液B中,随后通过通入惰性气体除去溶液中的低沸点溶剂,待低沸点溶剂完全除干净后,利用透析方式除掉高沸点溶剂,最终得到纳米粒子水溶液,经冷冻干燥后得到产品携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子,并进行相关测试表征。
5)体外光热、光动力活性评价
光热性质评价:将复合纳米粒子均匀分散在去离子水中,一定波长的激光照射下,利用红外热像仪观测复合纳米粒子溶液的温度变化情况。
光动力性质评价:将复合纳米粒子均匀分散在去离子水中,加入一定浓度的苯并呋喃作为活性氧检测探针,一定波长的激光照射下,利用UV-vis吸收光谱监测混合溶液的紫外吸收强度变化。
自携氧型蒽内过氧化物衍生物可与光热制剂联用,经单一波长激发有用于肿瘤的PDT/PTT联合治疗,该策略可有效克服PDT疗法对肿瘤组织氧分子浓度的依赖性,提高治疗效率。
其中,步骤1)中的光热制剂分子包括但不限于中国专利公布号:CN110898222A中涉及的A-D-A结构光热制剂以及其它结构的光热制剂,如硫化铜、花菁染料,吡咯并吡咯二酮衍生物,卟啉衍生物、共轭聚合物、方酸衍生物和氟硼二吡咯染料(BODIPY)等传统光热制剂。
步骤2)中的自携氧型光敏剂蒽内过氧化物衍生物分子包括但不限于9,10-二苯基蒽内过氧化物,还包括以蒽内过氧化物为母核经修饰变形后具有经加热会释放活性氧的蒽内过氧化物衍生物。
本发明提供的自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子可以拓展其在生物医学领域的应用,包括:用于治疗肿瘤药物的制造;在荧光成像、光声成像制剂制造方面的应用;用于疾病诊断制剂的制造。
本发明的优点和有益效果:
1)本发明选用蒽内过氧化物衍生物作为自携氧型光敏剂并与光热制剂联用,可有效克服光动力治疗对肿瘤组织中氧分子浓度的依赖性,改善PDT/PTT联合治疗效率。
2)本发明利用两亲性高分子对光热制剂及自携氧型蒽内过氧化物分子包覆并形成水溶性复合纳米粒子,该纳米制剂表现良好的光化学性质和无氧分子浓度依赖性,并且在单一近红外光激光(880nm)照射条件下表现良好的抑瘤效果,该发明作为新型的联合抗肿瘤纳米药物具有良好的应用前景。
附图说明
图1示出了光热制剂分子/蒽内过氧化物/双亲高分子复合纳米粒子制备及在光热/光动力联合治疗中的应用示意图。
图2示出了A-D-A型光热制剂PTA(A)和9,10-二苯基蒽内过氧化物EPO(B)结构图。
图3示出制备NPs-1纳米粒子的DLS谱图(A)和透射电镜照片(B)。
图4示出了NPs-1光热转换曲线。
图5示出了在NPs-1存在条件下经880nm激光照射后苯并呋喃紫外吸收强度的变化。
图6示出了NPs-1,NPs-2和NPs-3的生物相容性测试结果。
图7示出了NPs-1,NPs-2和NPs-3在体外进行细胞光毒性测试结果。
图8示出了A-D-A型光热制剂PTA的合成路线图。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步描述,将有助于对本发明的理解。但并不能以此来限制本发明的权利范围,而本发明的权利范围应以权利要求书阐述的为准。
本发明采用的技术方案如图1所示:1)A-D-A型有机分子(PTA)确定;2)蒽内过氧化物衍生物(EPO)确定;3)两亲性高分子(AP)确定;4)通过纳米沉淀技术制备两亲性高分子/A-D-A型有机小分子/蒽内过氧化物衍生物复合纳米粒子(NPs);5)体外光热、光动力活性评价。具体步骤如下:
1)A-D-A型有机分子光热制剂的确定(PTA):
本发明中所述的A-D-A型有机分子光敏制剂多为在有机光伏领域中已经报道过的A-D-A型有机小分子(如:ACS Nano2019,13,11,12901–12911;ACSAppl.Mater.Interfaces,2019,11,6717;Adv.Sci.,2018,1800307;Adv.Funct.Mater.2020,30,1910301)及结构类似的分子。该A-D-A型有机分子具有如下特征:这类分子结构具有羰基和氰基等基团作为吸电子单元可以降低LUMO能级。分子中的推拉电子结构在红光范围内具有强而宽的吸收,并诱导分子内电荷转移。分子结构的中间部分为共轭主平面,结构如图2(A)所示。
2)自携氧型光敏剂蒽内过氧化物衍生物(EPO)确定
本发明中所述的蒽内过氧化物衍生物EPO光敏试剂多为在纳米材料中已经报道过的蒽内过氧化物(如:Angew.Chem.Int.Ed.2016,55,3606–3610;Chem.Commun.2014,50,3317–3320)及结构类似的分子。该类蒽内过氧化物衍生物具有如下特征:这类分子在室温下的半衰期通常为数年,但当加热时,它们会通过环还原反应迅速分解,同时释放出单线态氧,单线态氧对细胞内的蛋白质、核酸以及脂类等生物大分子产生破坏作用,使细胞结构和功能受到严重影响,从而导致肿瘤细胞凋亡和(或)死亡,达到肿瘤治疗的目的。结构如图2(B)所示。
3)两亲性高分子的确定(AP):
本发明专利中选择具有两亲性高分子材料用于修饰光热制剂及蒽内过氧化物分子,如J.Biomater.Appl.,2013,28,434中报道的FA-PEG-PBLA(叶酸-聚乙二醇-聚天冬氨酸苄酯)以及市面有售的FEG-PCL(聚乙二醇-聚己内酯);FEG-PLA(聚乙二醇-聚乳酸);PEG-PLGA(聚乙二醇-聚乳酸/羟基乙酸共聚物)和DSPE-PEG(二硬脂酰基磷脂酰乙醇胺-聚乙二醇)等两亲性聚合物。
4)PTA/EPO/AP复合纳米粒子(NPs)的制备:
首先将步骤1)、2)所得的两种有机分子溶于THF中,随后将溶解好的两种有机分子溶液混合在一起形成溶液A,将购买的两亲性高分子溶于DMSO中形成溶液B(其中,PTA,EPO和AP的质量比为1:1:5),将混合均匀的有机溶液A缓慢均匀地滴加至两亲性高分子溶液B中,随后通过通入惰性气体除去溶液中的低沸点溶剂,待低沸点溶剂完全除干净后,利用透析方式除掉高沸点溶剂,最终得到纳米粒子水溶液,经冷冻干燥后得到产品携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子,并进行相关测试表征。
实施例1
1)PTA的合成
按照Adv.Sci.,2018,1800307报道的方法合成PTA。PTA的合成示意图如图8所示,具体方法如下:
在氩气氛围下,将1g(2.83mmol)(1),3.644g(8.49mmol)(2)和164mg(0.142mmol)Ph(PPh3)4加入到100mL两口圆底中烧瓶,用氩气脱气3次。然后将30mL无水甲苯注入混合物中,并回流反应过夜。将反应溶液冷却至室温,倒入100mL无水甲醇中沉淀并过滤,然后用大量石油醚、乙酸乙酯和甲醇进行洗涤。
在氩气氛围下,将1.2g(4.46mmol)2-乙基己基苯的无水THF(30mL)溶液加至-78℃反应体系中,然后将3mLn-BuLi(1.6M)溶液逐滴加至反应体系中。反应在-78℃条件下搅拌1h。然后将500mg(0.89mmol)的化合物(3)迅速加入反应体系中,并将反应在室温下再搅拌12h。反应结束后用盐水对反应物洗涤3次,并用无水Na2SO4干燥。真空条件下除去溶剂后,将粗产物溶于30mL四氢呋喃,并加入0.3mL浓H2SO4作为催化剂。将反应在90℃下搅拌反应2小时,并用10mL冷水淬灭,反应物用水洗涤4次。真空除去溶剂,得到的初产品经柱层析(洗脱液PE:DCM=40:1,v/v)纯化后得到黄红色固体化合物(4)(62%)。
在氩气氛围下,加入无水DMF(5mL)。然后将无水三氯氧化磷(POCl3)(400μL)在冰水浴条下逐滴注入反应体系中。将反应在0℃下搅拌30分钟。然后,在室温下搅拌3小时以获得Vilsmerier试剂。将500mg(0.42mmol)(4)和80mL1,2-二氯乙烷的反应混合物用氩气脱气15分钟,然后将Vilsmerier试剂缓慢添加到反应混合物中,并在室温下再搅拌1h。最后将反应物在85℃下再搅拌12小时后缓慢加入30mL饱和乙酸钠溶液淬灭反应。反应物用水洗涤三遍,并用无水Na2SO4干燥。真空除去溶剂,得到的初产品经柱层析(洗脱液PE:DCM=1:1,v/v)纯化后得到红色固体化合物(5)。
在氩气氛围下,将100mg(0.08mmol)化合物(5),92mg(0.4mmol)(6)的氯仿溶液(20mL)混合。将反应物在室温条件下搅拌12小时。有机相用水洗涤3次,并用无水Na2SO4干燥。真空除去溶剂,得到的初产品经柱层析(洗脱液PE:CF=1:1,v/v)纯化后得到粗产物,然后使用CF/甲醇进一步重结晶,得到绿色固体PTA。
2)EPO的合成
将9,10-二苯基蒽(429.5mg,1.3mmol)在两口圆底烧瓶中溶解于DCM-THF(100mL-50mL)中,并冷却至-78℃,将亚甲基蓝(0.13mmol)加入溶液中。将混合物在O2气氛下搅拌19h。反应期间进行用400WHg弧光灯(白光)照射。反应结束后通过旋蒸仪将溶剂旋除,得到的初产品通过硅胶柱色谱法(洗脱液PE:EA=100:1,v/v)纯化后,得到白色固体状的最终产品9,10-二苯基蒽内过氧化物(EPO)。
3)NPs-1纳米粒子的制备
本发明采用纳米沉淀的方法制备NPs-1,首先将5mgPTA溶解在5mLTHF中,将5mgEPO溶解在5mLTHF中,随后将溶解好的两种有机分子溶液混合在一起,然后将上述混合溶液缓慢均匀滴加至100mLDSPE-PEG的DMSO溶液中(0.25mg/mL)。(本发明中的AP选用市面有售的二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-PEG)两亲性高分子)。将溶液转移至透析袋(截留分子量:MW3.5kDa)中透析除去THF和DMSO,随后进行冷冻干燥得到产品自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子NPs-1。
实施例2
1)PTA的合成
PTA的合成如实施例1所示。
2)对比例NPs-2纳米粒子的制备
本发明采用纳米沉淀的方法制备NPs-2,首先将5mgPTA溶解在5mLTHF中,然后将PTA溶液缓慢均匀滴加至100mLDSPE-PEG的DMSO溶液中(0.25mg/mL)。(本发明专利中的AP选用市面有售的二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-PEG)两亲性高分子)。将溶液转移至透析袋(截留分子量:MW3.5kDa)中透析除去THF和DMSO,随后进行冷冻干燥,得到对比例纳米粒子NPs-2。
实施例3
1)EPO的合成
EPO的合成如实施例1所示。
2)对比例NPs-3纳米粒子的制备
本发明采用纳米沉淀的方法制备NPs-3,首先将5mgEPO溶解在5mLTHF中,然后将EPO溶液缓慢均匀滴加至100mLDSPE-PEG的DMSO溶液中(0.25mg/mL)。(本发明专利中的AP选用市面有售的二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-PEG)两亲性高分子)。将溶液转移至透析袋(截留分子量:MW3.5kDa)中透析除去THF和DMSO,随后进行冷冻干燥,得到对比例纳米粒子NPs-3。
效果显示:
本发明中以两亲性高分子对A-D-A结构的PTA和蒽内过氧化物衍生物(EPO)进行修饰,经纳米沉淀方法制备的纳米粒子的水合直径由DLS和TEM进行表征,结果如图3所示。
为了显示本发明在肿瘤光学治疗领域中具有应用潜力,本发明中对实例1中的NPs-1进行性质描述。
图4为NPs-1的光热转换曲线,如图所示,在880nm激光的照射下,NPs-1表现良好的光热转换性质,随着纳米粒子浓度的升高,温度升高速度越快。因此NPs-1可用于肿瘤的PTT治疗。
图5为在NPs-1存在条件下经880nm激光照射后苯并呋喃紫外吸收强度的变化。本发明以苯并呋喃为探针检测体系中活性氧的存在,结果显示在NPs-1存在条件下经880nm激光照射后苯并呋喃紫外吸收光谱的吸收强度明显下降,这说明NPs-1在880nm激光照射条件下可产生活性氧,因此NPs-1可用于肿瘤的PDT治疗。
图6为NPs-1的生物相容性测试结果,结果显示在没有激光照射条件下,NPs-1没有表现明显的细胞毒性。
图7为NPs-1体外细胞光毒性测试结果,结果显示经880nm激光照射后,与NPs-2(单一光热治疗)和NPs-3(单一光动力治疗)相比,NPs-1(PDT/PTT联合治疗)表现明显的光毒性和较高的治疗效率。
以上对本发明做了示例性的描述,应该说明的是,本发明与PTA分子,蒽内过氧化物衍生物(EPO)和两亲性高分子具体的结构和种类无关,本发明是发明一种单一近红外波长激发的,自携氧型的,用于PDT/PTT联合治疗的多功能光敏化剂,扩展现有光敏化剂的范围,提高肿瘤光疗疗效的新策略。在不脱离本发明的核心的情况下,任何简单的变形、修改或者其他本领域技术人员能够不花费创造性劳动的等同替换均落入本发明的保护范围。
Claims (7)
1.一种自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的制备方法,其特征是步骤如下:
1)有机分子光热制剂(PTA)的确定,
光热制剂分子选择A-D-A型有机小分子光热制剂为模型,该类分子结构具有羰基和氰基基团作为吸电子单元,以降低LUMO能级;分子中的推拉电子结构在红光范围内具有强而宽的吸收,并诱导分子内电荷转移;分子结构的中间部分为共轭主平面;
2)自携氧型光敏剂蒽内过氧化物衍生物(EPO)的确定,
蒽内过氧化物衍生物在室温下的半衰期通常为数年,但当加热时,它们会通过环还原反应迅速分解,同时释放出单线态氧,释放出的单线态氧对细胞内的蛋白质、核酸以及脂类生物大分子产生破坏作用,使细胞结构和功能受到严重影响,从而导致肿瘤细胞凋亡和/或死亡,达到肿瘤治疗的目的;
3)两亲性高分子(AP)的确定,
两亲性高分子为用于修饰光热制剂和蒽内过氧化物衍生物分子,选择具有两亲性的高分子材料,包括但不限于FA-PEG-PBLA(叶酸-聚乙二醇-聚天冬氨酸苄酯);PEG-PCL(聚乙二醇-聚己内酯);PEG-PLA(聚乙二醇-聚乳酸);PEG-PLGA(聚乙二醇-聚乳酸/羟基乙酸共聚物)和DSPE-PEG(二硬脂酰基磷脂酰乙醇胺-聚乙二醇)两亲性聚合物;
4)PTA/EPO/AP复合纳米粒子(NPs)的制备,
首先将步骤1)和2)的有机分子溶于THF中混合均匀形成溶液A,步骤3)的两亲性高分子溶于DMSO中形成溶液B,随后将溶解混合好的有机分子溶液A缓慢均匀地滴加至两亲性高分子溶液B中,随后通过通入惰性气体除去溶液中的低沸点溶剂,待低沸点溶剂完全除干净后,将利用透析方式除掉高沸点溶剂,最终得到的纳米粒子水溶液,经冷冻干燥后得到产品自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子,并进行相关测试表征。
2.根据权利要求1所述的自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的制备方法,其特征是:
步骤1)中的光热制剂分子包括但不限于A-D-A型光热制剂,还包括硫化铜、花菁染料,吡咯并吡咯二酮衍生物,卟啉衍生物、共轭聚合物、方酸衍生物和氟硼二吡咯染料(BODIPY)这些传统光热制剂。
3.根据权利要求1所述的自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的制备方法,其特征是:
步骤2)中的自携氧型光敏剂蒽内过氧化物衍生物分子包括但不限于9,10-二苯基蒽内过氧化物,还包括以蒽内过氧化物为母核经修饰变形后具有经加热会释放活性氧的蒽内过氧化物衍生物。
4.权利要求1-3任一项所述的自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子在生物医学领域的拓展应用。
5.根据权利要求4所述的自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的应用,其特征是:用于治疗肿瘤药物制造。
6.根据权利要求4所述的自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的应用,其特征是:在荧光成像、光声成像制剂制造方面的应用。
7.根据权利要求4所述的自携氧型光热制剂/蒽内过氧化物/高分子复合纳米粒子的应用,其特征是:用于疾病诊断制剂制造。
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