CN106166141A - 一种用于肿瘤成像与治疗的多功能复合纳米药物及其制备方法 - Google Patents
一种用于肿瘤成像与治疗的多功能复合纳米药物及其制备方法 Download PDFInfo
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Abstract
本发明属于医药技术领域,具体为一种用于肿瘤治疗与成像的多功能复合纳米药物及其制备方法。本发明的复合纳米药物包括活性分子‑1、活性分子‑2和稳定剂;其中活性分子‑1包括抗肿瘤药物索拉非尼或其衍生物,活性分子‑2包括近红外荧光分子吲哚菁绿或其衍生物,稳定剂包括Pluronic®、PLGA‑PEG、TPGS、DPSE‑mPEG、PVA、Tween、PEG、Lipid。所述复合纳米药物可通过简单方便的纳米沉淀法获得,尺寸为50‑800nm。该复合纳米药物具有肿瘤化疗、光热/光动力治疗多种功能,且吲哚菁绿可用于近红外荧光成像。该复合纳米药物具有良好的肿瘤靶向性,且两种药物分子表现显著的协同效应,提高了肿瘤治疗效率,可应用于肿瘤的治疗与荧光成像。
Description
技术领域
本发明属于医药技术领域,具体涉及一种用于肿瘤治疗与成像的多功能复合纳米药物及其制备方法。
背景技术
癌症是严重危害人类健康的重大疾病之一,近年来发病率以惊人的速度增长,自2010年起已成为除心血管疾病以外引起人类死亡的“一号杀手”。化疗是临床上治疗肿瘤的主要途径之一,但是化疗药物通常存在着药物生物利用度低、肿瘤靶向性差、对正常组织毒副作用大等缺点。随着纳米技术的飞速发展,其与肿瘤治疗结合所形成的纳米医药技术为癌症治疗打开了新思路。
纳米药物是指粒径介于1-1000nm的药物输送系统,包括负载于载体的纳米药物和无载体的纯药纳米药物。纳米药物相比于传统的肿瘤化疗药物具有显著优势,包括(1)有纳米尺寸,可通过人体最小的毛细血管又不易肾等器官代谢,提高了药物的生物利用度;(2)纳米粒子的表面可通过功能化修饰而达到隐蔽和靶向的功能,使不易被体内的免疫系统识别同时对肿瘤组织具有靶向性,可大大提高药物在肿瘤组织的聚集;(3) 靶向性使化疗药物对其他器官的毒副作用大大降低等。此外,纳米药物还可以通过多重负载实现联合治疗、诊治一体化等。
索拉非尼是一种多激酶抑制剂,同时抑制多种存在于细胞内和细胞表面的激酶,包括RAF激酶、血管内皮生长因子受体-2(VEGFR-2)、血管内皮生长因子受体-3(VEGFR-3)、血小板衍生生长因子受体-β(PDGFR-β)、KIT和FLT-3,它是FDA批准的唯一一个用于肝癌治疗的一线靶向药物。但在临床治疗中索拉非尼通常有很大的毒副作用。目前,已报道几种用于索拉非尼输送的纳米载体,但载药量低(<10%)是它们的共同缺陷。
发明内容
针对目前索拉非尼载药体系的不足,本发明提供了一种用于肿瘤治疗与成像的多功能复合纳米药物及其制备方法,不仅实现了索拉非尼的高含量负载,还通过引入具有光热/光动力疗效的近红外荧光分子吲哚菁绿衍生物,实现了化疗、光热、光动联合治疗与荧光成像一体化。
本发明提供的用于肿瘤治疗与成像的多功能复合纳米药物,具有光热/光动治疗、化疗、荧光成像一体化的多功能,该复合纳米药物组成包括:活性分子-1、活性分子-2和稳定剂,其中,所述活性分子-1包括抗肿瘤药物索拉非尼及其衍生物,所述活性分子-2包括近红外荧光分子吲哚菁绿及其衍生物,所述稳定剂选自Pluronic®、PLGA-PEG、TPGS、DPSE-mPEG、PVA、Tween、 PEG、Lipid;所述复合纳米药物中,活性分子-1与活性分子-2的摩尔比0.5:1-4:1(即(0.5-4):1);所述复合纳米药物的粒径尺寸为50-800nm。
优选地,所述多功能复合纳米药物的粒径尺寸为50-300nm。
优选地,所述多功能复合纳米药物中活性分子-1与活性分子-2的摩尔比为1:1。
本发明还提供上述多功能复合纳米药物的制备方法,具体步骤为:
S01:将所述活性分子-1和活性分子-2溶于有机溶剂中,0℃-24℃下搅拌10-15小时(优选搅拌12h小时),得复合药物溶液;
S02:将所述稳定剂溶于蒸馏水中,得稳定剂水溶液;
S03:向所述复合药物溶液中在剧烈搅拌或超声下加入步骤S02所述稳定剂水溶液,搅拌下挥发有机溶剂后离心或冷冻干燥,即得复合纳米药物(微粒);
优选地,步骤S01中所述有机溶剂为乙醇、甲醇、二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜中的一种或几种;
步骤S02中所述稳定剂为Pluronic®、PLGA-PEG、TPGS、DPSE-mPEG、PVA、Tween、 PEG、Lipid中的一种或几种,所述稳定剂水溶液的质量浓度为0.25%-15%。
此外,本发明还提供上述多功能复合纳米药物在肿瘤治疗中的应用,该多功能复合纳米药物可用于制备肿瘤治疗药物。其中,活性分子-1提供肿瘤化疗效果,活性分子-2提供光热/光动力治疗效果,两者联合用药可以提高治疗效率。
本发明还提供上述多功能复合纳米药物在肿瘤成像的应用。该复合纳米药物可作为肿瘤成像药物。其中,活性分子-2在近红外照射下荧光成像,且具有肿瘤靶向性。
附图说明
图1为本发明的复合纳米药物的制备方法与应用的示意图。
图2为实施例1制备的具有肿瘤治疗与成像功能的自组装纳米药物的透射电镜图(TEM)。其中,a为粒径尺寸约350nm,b为粒径尺寸约250nm,c为粒径尺寸约80nm。
图3为实施例1制备的具有肿瘤治疗与成像功能的自组装纳米药物的对肝癌细胞Huh7的杀伤作用。
图4为实施例1制备的具有肿瘤治疗与成像功能的自组装纳米药物的的肿瘤靶向性和荧光成像能力实验(荧光活体成像)。
具体实施方式
为了使本发明实现的技术手段、特征、达成的目标与效果易于明白了解,以下通过实施例并结合附图对本发明的一种用于肿瘤治疗与成像的多功能复合纳米药物及其制备方法作具体阐述。本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和过程,但本发明的包含范围不限于下述的实施例。下面的实施例中未注明的条件和方法等,按照本领域内的文献所描述的技术或条件,或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者,均为可通过正规渠道商购买得到的常规产品。
实施例1
将索拉非尼(活性分子-1, 4.65 mg, 10 mMol)和吲哚菁绿衍生物(活性分子-2,6.64mg, 10 mMol)溶于10 mL 甲醇中,20℃下避光搅拌20h。反应毕,在超声下快速加入TPGS水溶液(质量分数9%, 40 mL)。加毕,继续在通风橱中保持搅拌24h后,冷冻干燥,-4℃下保存。可得到如图2所示的复合纳米药物粒子。通过改变药物溶液的浓度,稳定剂溶液的浓度等,可得到不同尺寸的纳米粒子(如图2所示)。
实施例2
对实施例1中所述的多功能复合纳米药物用透射电镜(美国FEI,Tecnai G2 20S-TWIN,200kV)测定,如图2所示。将实施例1制得的多功能复合纳米药物对肝癌细胞Huh7进行肿瘤细胞杀伤实验。培养肝癌细胞Huh7,温度为37℃,将处于对数生长期的Huh7细胞分别按5000个/孔的密度接种于96孔培养板,12小时后,分别加入不同浓度的药液以及多功能复合纳米药物,每种浓度平行6孔。分别采用含有10重量%胎牛血清的DMEM培养基,每孔加100μL,培养48h后,使用CCK试剂盒对细胞活性进行测定。具体操作完全按照试剂盒的说明进行。
对于肿瘤细胞的活力影响的实验结果如图3所示。从实验结果可以看出,本发明提供的多功能复合纳米药物具有酸性响应性,且在近红外激光照射下,吲哚菁绿(活性分子-2)与索拉非尼(活性分子-1)表现出显著的协同作用,对肿瘤细胞具有极强的杀伤作用。
实施例3
将实施例1制得的多功能复合纳米药物对裸鼠的肝癌模型进行肿瘤靶向性和荧光成像能力的实验。经裸鼠尾静脉注射实施例1制得的多功能复合纳米药物的PBS溶液,在小动物活体成像系统(美国Bruker,in VivoXtreme)检测吲哚菁绿的荧光(激发760 nm, 发射830nm)。对肿瘤的靶向性和荧光成像能力的实验结果如图4所示。从实验结果可以看出,本发明提供的多功能复合纳米药物具有很好的肿瘤靶向性和荧光成像能力。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对本发明涉及的活性分子(索拉非尼和吲哚菁绿)的结构进行衍生化,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上,以活性分子-1的衍生物和活性分子-2的衍生物为基础获得的纳米粒子,均属于本发明要求保护的范围。
Claims (8)
1. 一种用于肿瘤成像与治疗的多功能复合纳米药物,具有光热/光动治疗、化疗、荧光成像一体化的多功能,其特征在于,组成包括:活性分子-1、活性分子-2和稳定剂;其中,所述活性分子-1包括抗肿瘤药物索拉非尼或其衍生物,所述活性分子-2包括近红外荧光分子吲哚菁绿或其衍生物,所述稳定剂选自Pluronic®、PLGA-PEG、TPGS、DPSE-mPEG、PVA、Tween、 PEG、Lipid;活性分子-1与活性分子-2的摩尔比0.5:1-4:1;所述复合纳米药物的粒径为50-800nm。
2.根据权利要求1所述的多功能复合纳米药物,其特征在于,活性分子-1与活性分子-2的摩尔比为1:1。
3.根据权利要求1所述的多功能复合纳米药物,其特征在于,所述复合纳米药物的粒径为50-300nm。
4.一种如权利要求1-3之一所述多功能复合纳米药物的制备方法,其特征在于,具体步骤为:
S01:将所述活性分子-1和活性分子-2溶于有机溶剂中,0℃-24℃下搅拌10-15h,得复合药物溶液;
S02:将所述稳定剂溶于蒸馏水中,得稳定剂水溶液;
S03:向所述复合药物溶液中在剧烈搅拌或超声下加入步骤S02所述稳定剂水溶液,搅拌下挥发有机溶剂后离心或冷冻干燥,即得复合纳米药物。
5.根据权利要求4所述的制备方法,其特征在于,步骤S01中所述有机溶剂为乙醇、甲醇、二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜中的一种或几种。
6. 根据权利要求4所述的制备方法,其特征在于,步骤S02中所述稳定剂为Pluronic®、PLGA-PEG、TPGS、DPSE-mPEG、PVA、Tween、 PEG、Lipid中的一种或几种,所述稳定剂水溶液的质量浓度为0.25%-15%。
7.如权利要求1-4之一所述的多功能复合纳米药物在制备治疗肿瘤药物中的应用。
8.如权利要求1-4之一所述的多功能复合纳米药物在肿瘤成像中作为成像粒子的应用。
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