CN109464677A - 一种用于肿瘤靶向诊疗的近红外光控纳米颗粒及制备方法 - Google Patents
一种用于肿瘤靶向诊疗的近红外光控纳米颗粒及制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于肿瘤靶向诊疗的近红外光控纳米颗粒及制备方法。本发明的近红外光控纳米颗粒由肿瘤靶向性两亲性分子,卵磷脂,脂肪酸低共熔物,DPP‑BT‑CN和抗癌药物通过纳米共沉淀方法制备得到,在近红外光照下该纳米颗粒具有优良的近红外二区荧光成像、光声成像、光动力以及光热转换性能,同时近红外光诱导的高温可使该纳米颗粒实现固液相变,实现负载药物的有效释放,即用于近红外二区荧光成像/光声成像指导的靶向光热/光动力/化疗联合治疗。本发明设计的肿瘤靶向诊疗的近红外光控纳米颗粒为癌症治疗带来了巨大的希望,具有广阔的应用前景。
Description
技术领域
本发明属于生物医药工程领域,具体涉及一种用于肿瘤靶向诊疗的近红外光控纳米颗粒及制备方法。
背景技术
现有技术近年来,随着纳米技术的不断发展,智能药物释放系统取得了重大的进展。智能药物释放系统要求在到达肿瘤位置之前能够保持稳定的结构,同时在一定的刺激响应下(光、超声、pH、温度、氧化还原、酶等)可以有效地释放药物。在各种刺激响应中,光刺激由于具有高时空分辨率、远程操作、无创伤性等优点而受到人们广泛关注。温敏性相转变材料可以在光诱导的高温下发生相转变(固态到液态),可以用于药物的可控释放。在已报道的相变材料中,脂肪酸由于具有低成本、良好的生物相容性、热稳定性及在较窄的温度范围内表现出可逆的固-液转变的性能,被选作包裹药物的温敏性核,在光控药物释放领域具有潜在的应用价值。
在成像技术方面,近红外二区(NIR-II,1000-1700nm)荧光成像技术受到人们广泛的关注,由于该波段发射波长较长,生物组织自身的光散射及自荧光较弱,因此极大地提高了成像的穿透深度及成像效果,在于生物技术及生命科学领域具有重要的应用价值。光声成像(PAI)结合了光学成像和超声成像的特点,具有高对比度、高分辨率等的优点,在实时医学成像领域有着巨大的应用前景。
相比于传统的化疗手段,肿瘤联合治疗技术能够产生协同或者增加效应,从而可以显著提高治疗效果,而且在一定程度上可以预防对正常组织的毒副作用及肿瘤耐药性。光热治疗(PTT)及光动力治疗(PDT)以其毒副作用小、治疗效果好等优点而受到广泛的关注,成为肿瘤治疗的有效手段。因此,将光热、光动力、化疗结合在一起,发展具有多模式联合治疗的纳米颗粒用于肿瘤的治疗具有重要的科学意义及应用前景。
发明内容
针对上述问题,本发明提出一种用于肿瘤靶向诊疗的近红外光控纳米颗粒及制备方法。
实现上述技术目的,达到上述技术效果,本发明通过以下技术方案实现:
一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,所述的纳米颗粒中包括在近红外光照射下释放的药物的光敏剂DPP-BT-CN,所述的DPP-BT-CN的结构为:
其中,R为C5-C12的直链烷烃。
作为本发明的进一步改进,所述的DPP-BT-CN在水溶液中的最大吸收波长为700nm±20nm,该特性使得DPP-BT-CN具有光声成像能力。
作为本发明的进一步改进,所述的DPP-BT-CN在水溶液中的最大荧光发射为1090nm±10nm,该特性使得DPP-BT-CN具有近红外二区荧光成像能力。
作为本发明的进一步改进,所述的DPP-BT-CN的水溶液在600-800nm的激光照射下,溶液的温度随着时间增加而升高。
进一步,在功率密度为0.25-1W/cm2的波长为730nm的激光下照射超过30s,溶液的温度上升至少3℃。
作为本发明的进一步改进,在600-800nm的激光照射下,所述的DPP-BT-CN水溶液具有良好的单线态氧产生能力,使得DPP-BT-CN表现出良好的光动力效果。
作为本发明的进一步改进,所述的纳米颗粒中还包括肿瘤靶向性两亲性分子,卵磷脂,抗癌药物和脂肪酸低共熔物,所述的肿瘤靶向性两亲性分子及卵磷脂将脂肪酸低共熔物,DPP-BT-CN及抗癌药物包裹在颗粒中央;所述的脂肪酸低共熔物的相变温度大约为39±0.5℃。
作为本发明的进一步改进,所述的脂肪酸低共熔物是天然无毒性的相变材料,在近红外的激光照射下所述的DPP-BT-CN使所述的纳米颗粒快速升温,当达到脂肪酸低共熔物的相变温度时由固态转变成液体。
制备以上所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒的制备方法,包括以下步骤:
A1、将月桂酸和硬脂酸溶解在甲醇中,制备浓度为4-5mg/mL的溶液;
A2、将卵磷脂和肿瘤靶向性两亲性分子溶于乙醇水溶液中;
A3、将A2溶液加热至45-50℃,然后将A1溶液、载有DPP-BT-CN的溶液和DOX的DMSO溶液按一定比例采用共沉淀法一起滴加到预热的A2溶液中,涡旋后放入在冰水中冷却;将混合溶液在涡旋的条件下升温至25±0.5℃,然后通过无表面活性剂的乙酸纤维素膜过滤,最后多次使用离子水进行离心洗涤去除未包封的分子和有机溶剂,得到近红外光控纳米颗粒。
作为本发明的进一步改进,所述的DPP-BT-CN制备方法包括:
B1、按摩尔质量比,将BT695和醇(所使用的醇上的碳链为C5-C12的直链烷烃)溶于无水二氯甲烷/甲醇,在氮气氛围下加入4二甲基氨基吡啶(DMAP),1-(3'二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)。将混合物在50-60℃下搅拌10-12h,在真空下除去溶剂后,通过柱色谱提纯,得到中间产物BT-CN;
B2、按摩尔质量比,将2,5-二(2-辛基十二烷基)-3,6-二(5-三甲基锡)-吡咯并吡咯二酮和BT-CN加入无水甲苯中,在氮气氛围下加入催化剂四(三苯基膦)钯,在110-115℃加热搅拌不少于24h,除去溶剂,柱色谱分离后得DPP-BT-CN。
本发明的有益效果:通过本发明所采用纳米共沉淀方法制备得到具有良好水溶性、生物相容性及靶向性的纳米颗粒,该纳米颗粒可以在近红外光刺激下快速有效的释放药物,实现近红外二区荧光成像/光声成像指导下的肿瘤靶向光热/光动力/化疗联合治疗,具有较好的临床应用前景。
附图说明
图1为DPP-BT-CN的1H NMR谱图;
图2为DPP-BT-CN水溶液的紫外谱图;
图3为DPP-BT-CN水溶液的荧光谱图;
图4为DPP-BT-CN水溶液近红外二窗荧光成像图;
图5为DPP-BT-CN水溶液光声成像图;
图6为相同浓度DPP-BT-CN纳米粒子在不同光照功率密度下光热温度随时间变化图;
图7为相同浓度DPP-BT-CN纳米粒子与DPBF混合在不同光功率密度的激光光照后414nm处紫外吸收强度变化图;
图8为近红外光控纳米粒子紫外谱图;
图9为近红外光控纳米粒子荧光谱图;
图10为所制备的纳米颗粒的结构。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
下面结合附图对本发明的应用原理作详细的描述。
本发明的实施例所使用的试剂皆为市购,所使用的仪器分别为:
近红外二窗荧光成像仪:NIRvana 640-Princeton instrument
光声成像仪:Endra Nexus 128
红外热成像仪:TESTO869
激光器:MDL-IH-730-1.5W-PSU-II-LED
部分化学试剂名称的缩写为:
两亲性分子DSPE-PEG-FA:磷脂-聚乙二醇-叶酸。
本发明所制备的用于肿瘤靶向诊疗的近红外光控纳米颗粒包括肿瘤靶向性两亲性分子,卵磷脂,抗癌药物,脂肪酸和DPP-BT-CN。如图10所示的纳米颗粒的结构,所述的肿瘤靶向性两亲性分子及卵磷脂将脂肪酸,DPP-BT-CN及抗癌药物包裹在颗粒中央。其中,所述的脂肪酸低共熔物的相变温度大约为39℃,所述的DPP-BT-CN为在近红外的控制下释放的药物的光敏剂,其结构通式为:
当DPP-BT-CN为在近红外光的照射下能够升高所在溶液的温度,使得脂肪酸由固态转变为液态从而释放所包裹的抗癌药物。
本发明的实施例以以下的DPP-BT-CN的一种结构式为例:
A1、合成路线为:
具体的合成步骤为:
该结构的分子的制备方法包含以下步骤:A1、按1:1摩尔质量比,将BT695和正辛醇溶于无水二氯甲烷/甲醇,在氮气氛围下加入4二甲基氨基吡啶(DMAP),1-(3'二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)。将混合物在55℃下搅拌12小时,在真空下除去溶剂后,通过柱色谱提纯,得到BT-CN。
A2、按1:2.2摩尔质量比,将2,5-二(2-辛基十二烷基)-3,6-二(5-三甲基锡)-吡咯并吡咯二酮,BT-CN加入无水甲苯中,在氮气氛围下加入催化剂四(三苯基膦)钯,加热搅拌(110℃,24h),除去溶剂,柱色谱分离后得DPP-BT-CN。
所获得DPP-BT-CN的结构通过图1所示的1H NMR进行验证。
B、性能表征
B1、DPP-BT-CN的光成像性能测试:
称取DPP-BT-CN药品1mg和F127(20mg)溶于1ml四氢呋喃,然后将DPP-BT-CN溶液缓慢加入5ml超纯水中,边超声边加入,继续超声2分钟,然后真空除去四氢呋喃,最后用3万的超滤管对溶液进行离心去除部分水,最后得到浓度为1mg/ml的DPP-BT-CN水溶液。
(1)如图2所示,使用所配置的DPP-BT-CN水溶液所获得的紫外吸收光谱图,该溶液的最大吸收波长在700nm左右,显示了良好的光声成像能力
(2)如图3所示,使用和图2相同的DPP-BT-CN水溶液获得的荧光光谱图,所述的DPP-BT-CN在水溶液中的最大荧光发射在1090nm左右,因此具有近红外二区荧光成像能力。
DPP-BT-CN近红外二窗荧光成像/光声成像:
(2-1)配制浓度为0.1mg/ml的上述DPP-BT-CN水溶液1ml,放置于小离心管中,在近红外二窗荧光成像仪下,用波长为808nm的激光激发,得到近红外二窗荧光成像,如图4所示。
(2-2)配制浓度为1.0mg/ml的DPP-BT-CN水溶液200μl于小试管中,然后用光声成像仪进行成像,如图5所示。
B2、DPP-BT-CN的光热/光动力测试:
(1)光热性能的测试:
在250μL的小离心管中加入200μL浓度为800μg/ml的DPP-BT-CN纳米粒子水溶液,分别用功率密度为0.5W/cm2、0.75W/cm2及1W/cm2的激光(730nm)照射,由红外热成像仪记录溶液温度随时间变化的趋势,如图6所示,在激光下,在一定的时间内溶液的温度随着激光的强度和光照的时间迅速升高,表明该DPP-BT-CN纳米粒子具有良好的光热性能。当照射超过的时间30s,溶液的温度上升至少3℃,随之而时间的增加,上升的温度能达到40℃,由于人体的正常的平均体温维持在36-37℃,当上升3℃,超过了脂肪酸的相变温度,从而引起药物的释放。而且从以上数据可以看出即便在低能量密度的激光照射下DPP-BT-CN的光热性能依旧能够在短时间中升温,有着很高的灵敏度。
(2)光动力性能的测试:
在比色皿中加入DPP-BT-CN纳米粒子水溶液(0.25mM,2mL),再滴加入40μL浓度为1mM的DPBF的乙醇溶液(DPBF会与单线态氧发生不可逆反应,导致DPBF特征吸收峰降低,从而可以作为单线态氧探针),分别用光功率密度为0、0.5W/cm2、0.75W/cm2及1W/m2的激光(730nm)间断照射,每次光照2min,并监测在DPBF特征峰414nm处的紫外吸收峰的变化,如图7所示DPBF特征峰随着照射时间的增加而不断降低,表明该DPP-BT-CN纳米粒子可以产生单线态氧,具有良好的光动力性能。
近红外光控纳米颗粒制备:
C1、将月桂酸和硬脂酸(按重量计4:1)溶解在甲醇中,浓度为4mg/mL。
C2、将卵磷脂和DSPE-PEG-FA(按重量计3:1)溶于4%乙醇水溶液中,浓度为1mg/mL。
C3、将C2溶液(3mL)加热至50℃,然后将C1溶液(600μL)、DPP-BT-CN的THF溶液(48μL 2.5mg/mL)和DOX的DMSO溶液(48μL 2.5mg/mL)采用共沉淀法一起滴加到预热的C2溶液中,然后剧烈涡旋2分钟。在冰水中冷却2分钟后,将混浊溶液升温至环境温度并涡旋1-2分钟,然后通过无表面活性剂的乙酸纤维素膜(Thermo Fisher Scientific)过滤。使用VIVASPIN 6离心浓缩器(Sartorius,MWCO=10kDa)除去未包封的分子和有机溶剂。用水洗涤三次后,得到近红外光控纳米颗粒,其紫外如图8所示,粒径大小如图9所示。
抗癌药物的释放测试
本发明的实施例中,所使用的抗癌药物为阿霉素(DOX)。为了测量在NIR照射下DOX的释放曲线,用730nm NIR激光器在0.8W/cm2的功率密度下,分别照射近红外光控纳米颗粒水溶液(1mL,10μg/ml)2h,4h,8h,16h,24h。并分别使用酶标仪(Ex=488nm,Em=590nm)对不同光照时间的溶液进行荧光测量。DOX释放率通过(It-I0)/(I100-I0)×100计算,其中It为不同光照时间后溶液的荧光强度,I0是激光照射前光控纳米颗粒溶液的初始荧光强度,并且I100是相同浓度下的DOX荧光强度。同时再做一个不光照测试DOX释放的对照组。
以上显示和描述了本发明的基本原理和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)
1.一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,其特征在于,所述的纳米颗粒中包括在近红外光照射下释放的药物的光敏剂DPP-BT-CN,所述的DPP-BT-CN的结构为:
其中,R为C5-C12的直链烷烃。
2.根据权利要求1所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,其特征在于:所述的DPP-BT-CN在水溶液中的最大吸收波长为700±20nm。
3.根据权利要求1所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,其特征在于:所述的DPP-BT-CN在水溶液中的最大荧光发射在1090±10nm。
4.根据权利要求1所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,其特征在于:所述的DPP-BT-CN的水溶液在600-800nm的激光照射下,溶液的温度随着时间增加而升高。
5.根据权利要求4所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,其特征在于:在功率密度为0.25-1W/cm2的波长为730nm的激光下照射超过30s,溶液的温度上升至少3℃。
6.根据权利要求1所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,其特征在于:在600-800nm的激光照射下,所述的DPP-BT-CN水溶液具有良好的单线态氧产生能力。
7.根据权利要求1所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,其特征在于:所述的纳米颗粒中还包括肿瘤靶向性两亲性分子,卵磷脂,抗癌药物和脂肪酸低共熔物,所述的肿瘤靶向性两亲性分子及卵磷脂将脂肪酸低共熔物,DPP-BT-CN及抗癌药物包裹在颗粒中央;所述的脂肪酸低共熔物的相变温度为39±0.5℃。
8.根据权利要求7所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒,其特征在于:所述的脂肪酸低共熔物是天然无毒性的相变材料,在近红外的激光照射下所述的DPP-BT-CN使所述的纳米颗粒快速升温,当达到脂肪酸低共熔物的相变温度时由固态转变成液体。
9.根据权利要求1-8任一项所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒的制备方法,包括以下步骤:
A1、将月桂酸和硬脂酸溶解在甲醇中,制备浓度为4-5mg/mL的溶液;
A2、将卵磷脂和肿瘤靶向性两亲性分子溶于乙醇水溶液中;
A3、将A2溶液加热至45-50℃,然后将A1溶液、载有DPP-BT-CN的溶液和DOX的DMSO溶液按一定比例采用共沉淀法一起滴加到预热的A2溶液中,涡旋后放入在冰水中冷却;将混合溶液在涡旋的条件下升温至25±0.5℃,然后通过无表面活性剂的乙酸纤维素膜过滤,最后多次使用离子水进行离心洗涤去除未包封的分子和有机溶剂,得到近红外光控纳米颗粒。
10.根据权利要求9所述的一种用于肿瘤靶向诊疗的近红外光控纳米颗粒的制备方法,其特征在于,所述的DPP-BT-CN制备方法包括:
B1、按摩尔质量比,将BT695和醇溶于无水二氯甲烷/甲醇,在氮气氛围下加入4二甲基氨基吡啶(DMAP),1-(3'二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDC)。将混合物在50-60℃下搅拌10-12h,在真空下除去溶剂后,通过柱色谱提纯,得到中间产物BT-CN;
B2、按摩尔质量比,将2,5-二(2-辛基十二烷基)-3,6-二(5-三甲基锡)-吡咯并吡咯二酮和BT-CN加入无水甲苯中,在氮气氛围下加入催化剂四(三苯基膦)钯,在110-115℃加热搅拌不少于24h,除去溶剂,柱色谱分离后得DPP-BT-CN。
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