CN113413468A - 一种光热-硬化联合治疗的靶向纳米药物递送系统 - Google Patents
一种光热-硬化联合治疗的靶向纳米药物递送系统 Download PDFInfo
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Abstract
本发明公开了一种光热‑硬化联合治疗的纳米药物递送系统,其特征在于,所述药物递送系统由药物载体、硬化剂和植物多酚铁络合物构成,具体由药物载体包被硬化剂和植物多酚铁络合物制备得到。所述硬化剂与药物载体通过静电吸附作用进行包合,植物多酚铁络合物由植物多酚与三价铁Fe(Ⅲ)络合形成,由于高表面能而包被于药物载体中。本发明提供的药物递送系统是基于纳米共载的光热‑硬化协同治疗体系,能实现在光声成像引导下对患处精准给药,并且将光热治疗与硬化治疗联合应用,对淋巴管畸形的治疗效果更好。
Description
技术领域
本发明属于生物医药领域,具体涉及一种光热-硬化联合治疗的靶向纳米药物递送系统及其制备方法与应用。
背景技术
脉管畸形是人类软组织中最常见的良性肿瘤或先天畸形,尤其好发于婴幼儿,常常侵犯颜面部皮肤,造成颜面畸形和功能障碍,且可继发感染和出血,是危害人类身心健康的重要疾患之一。目前,临床上对于脉管性疾病常用的治疗方式有:手术治疗、激光治疗、硬化治疗、射频消融和经导管栓塞术等。其中,硬化治疗作为保守性治疗具有较好的临床治疗效果,如博来霉素、平阳霉素等硬化剂是当前临床一线用药。但是,时至今日,脉管性疾病的治疗仍然是一项很大的挑战,单一治疗手段已经无法实现对不同类型脉管性疾病的安全、高效治疗。所以,硬化治疗疗效及安全性的提高、新型治疗方法的开发和运用已成为亟待解决的临床问题。
脉管畸形包括低流速型(静脉畸形、微静脉畸形、淋巴管畸形)和高流速型(动静脉畸形)。除部分血管瘤患者可自行消退外,大部分无法自愈。其中,淋巴管畸形是儿童临床较为常见的脉管畸形,在新生儿中的发病率可高达1/4000-1/2000,病变好发于头颈部。
淋巴管内皮细胞间隙较大、淋巴液的流动速率较慢,仅为血液流动速率的1/500-1/100。小分子药物及粒径小于10 nm的纳米载体可以自由出入淋巴管和血管内皮细胞。在淋巴管畸形病变部位注射小分子硬化剂,药物极易扩散到血液循环中,造成药效的损失以及较大的毒副作用。由此可见,药物载体(>10 nm)在淋巴系统药物递送方面具有独特的优势:可以实现小分子药物在病变部位的浓聚和缓释,延长药物在病变部位的作用时间,有效降低小分子药物的毒副作用。透明质酸(Hyaluronic acid, HA)是一种组织相容性良好的高分子粘多糖。在生物体内,HA 是细胞外基质的重要组分,作为天然生物大分子,透明质酸具有良好的生物相容性、亲水性、无免疫原性。基于HA的纳米材料在药物递送、疾病诊断及生物医学成像等领域具有广阔的应用前景。
光热治疗是非侵入性的治疗方法。在近红外光照射下,光敏剂在病变部位可以将光能转化为局部热量杀死靶细胞。组织中的血红蛋白和水对近红外波段的光吸收相对较低,因此近红外光在深入地穿透病变组织的同时对病变周围正常组织的损伤较小。相比于传统的治疗手段(如放疗、化疗和手术),光热治疗具有如下优点:微创疗性,较大程度减轻患者的疼痛;具有靶向性,可以实现病变部位局部温度升高,较少对周围组织的损伤。光热治疗应用于淋巴管畸形治疗研究尚未见报道。淋巴管畸形病变常表现为好发于头颈部且位置较为表浅的囊腔,适于进行光热治疗。将光热转化效率良好、制备方法简单、体内可降解的光敏剂应用于淋巴管畸形治疗中,有望大大提高疗效,实现临床淋巴管畸形治疗的新突破。
本领域技术人员知晓,硬化剂局部注射存在外渗的风险,可导致局部软组织损伤或全身静脉回流路径栓塞。因此,为保证治疗安全性,硬化治疗需要在影像引导下完成注射。光声成像(Photoacoustic imaging,PAI)是一种非常有前景的非侵入性生物医学成像手段。PAI 依靠生物组织吸收近红外激光后发射出的声波信号进行成像,有效地整合了光学成像和声学成像在医学诊断中的优势:相比于传统的超声和光学成像,PAI 成像兼具了较高的分辨率和较好的组织穿透能力。目前 PAI 已被广泛用于高对比度的组织结构和功能成像研究,包括大脑结构与功能成像、肿瘤血管生长的监控。此外,光声成像速度快,可以实现50帧/秒的图像拍摄。PAI与超声成像相结合,可以满足不同类型淋巴管畸形病变区域的定位以及硬化注射术中的影像导航。
基于上述研发背景以及淋巴管畸形临床治疗研究的迫切需要,本发明提供一种靶向纳米药物递送系统,所述药物递送系统是基于纳米共载的光热-硬化协同治疗体系,能实现在光声成像引导下对病变部位的精准给药,并且将光热治疗与硬化治疗联合应用,为淋巴管畸形的高效、安全治疗提供研究思路和参考依据。
发明内容
本发明的一个目的是提供一种光热-硬化联合治疗的靶向纳米药物递送系统,本发明另一个目的是提供一种所述纳米药物递送系统的制备方法及应用。
本发明的目的是通过以下技术方案实现的。
第一方面,本发明提供一种光热-硬化联合治疗的靶向纳米药物递送系统,其特征在于,所述药物递送系统由药物载体、硬化剂和植物多酚铁络合物构成;具体由药物载体包被硬化剂和植物多酚铁络合物制备得到。
在所述药物递送系统中,硬化剂与药物载体的摩尔质量比为1:1-4,植物多酚铁络合物与药物载体的摩尔质量比为1:2-6。
所述药物载体为含有羧基和/或羟基的带负电荷的线性高分子聚合物,在本发明的优选实施方式中,所述药物载体选自透明质酸(HA)。
所述硬化剂选自鱼肝油酸钠、明矾、平阳霉素(PYM)、博来霉素(BLM)、乙醇胺、泛影酸、喹啉、四环素、强力霉素、脲素中的一种或两种以上的组合。
优选的,所述硬化剂选自平阳霉素和/或博来霉素。
所述植物多酚铁络合物由植物多酚与三价铁Fe(Ⅲ)络合形成,所述植物多酚选自单宁酸(TA)、白藜芦醇、阿魏酸、绿原酸、肉桂酸中的一种或两种以上的组合,植物多酚与Fe(Ⅲ)络合摩尔质量比为1:4-6。
在本发明的优选实施方式中,所述植物多酚为单宁酸。
在本发明的最优选实施方式中,药物递送系统由HA包被硬化剂博来霉素或平阳霉素和单宁酸铁络合物制备得到,本发明将其命名为HA-Fe(Ⅲ)TA-BLM或HA-Fe(Ⅲ)TA-PYM。
本发明提供的靶向纳米药物递送系统形成机理如下:HA骨架含有大量羧基、羟基等功能基团,是一种带负电的天然线性高分子物质,硬化剂平阳霉素或博来霉素分子中含有大量氨基,为带正电的小分子药物,两者在静电作用下HA对硬化剂进行包载。单宁酸与三价铁Fe(Ⅲ)在室温下很容易发生络合反应,络合物Fe(Ⅲ)TA表面能很高,容易复合在HA内部,最终形成结构稳定的靶向纳米药物递送系统。
本发明中药物载体优选为透明质酸(HA),因为HA骨架含有大量羧基、羟基等功能基团,可通过静电吸附作用对博来霉素等带正电荷的小分子硬化剂药物进行包载。此外,HA作为药物载体可实现LYVE-1介导的靶向药物递送。研究表明,淋巴管内皮细胞高表达淋巴管内皮透明质酸受体(Lymphatic Vessel Endothelial Hyaluronic Acid Receptor 1,LYVE-1),LYVE-1特异性地表达在淋巴管内皮细胞上,而在病变部位周围的脂肪、肌肉、血管内皮细胞上低表达。综上,利用HA对硬化剂进行包载,小分子硬化剂可以通过HA受体LYVE-1介导的靶向递送更有效地进入病变细胞中,实现硬化剂的靶向运输及在病变部位的缓释,有效延长硬化剂在病变部位的作用时间。
本发明所述的植物多酚优选为单宁酸(Tannic Acid,TA),因为TA是天然植物来源的多酚化合物,具有抗氧化、捕捉自由基、抑菌等特性;生物相容性良好,目前已被FDA批准应用于食品和医药领域。TA分子结构中丰富的酰基基团可以作为螯合位点与三价铁d轨道中的电子相互作用形成稳定的络合物Fe(Ⅲ)TA。相比于纳米Fe3O4等铁基光敏剂,Fe(Ⅲ)TA制备方法简单,不需要有机试剂和高温等条件,真正实现了“绿色合成”。
第二方面,本发明提供一种光热-硬化联合治疗的靶向纳米药物递送系统的制备方法,所述方法包括:
室温下将药物载体和植物多酚按照摩尔质量比为2-6: 1溶于超纯水中,搅拌下滴加三价铁Fe(Ⅲ)溶液,搅拌10-15min;按照硬化剂与药物载体的摩尔质量比为1:1-4滴加硬化剂水溶液,继续搅拌1-2h;超滤浓缩,得到纳米药物递送系统。
优选的,所述药物载体为含有羧基和/或羟基的带负电荷的线性高分子聚合物。
所述硬化剂选自鱼肝油酸钠、明矾、平阳霉素(PYM)、博来霉素(BLM)、乙醇胺、泛影酸、喹啉、四环素、强力霉素、脲素中的一种或两种以上的组合。
所述植物多酚选自单宁酸(TA)、白藜芦醇、阿魏酸、绿原酸、肉桂酸中的一种或两种以上的组合,植物多酚与Fe(Ⅲ)络合摩尔质量比为1:4-6。
优选的,所述方法为:室温下将透明质酸和单宁酸按照摩尔质量比为4-6:1溶于超纯水中,搅拌下滴加FeCl3溶液,单宁酸与FeCl3摩尔质量比为1:5-6,搅拌10min后滴加硬化剂博来霉素或平阳霉素水溶液,硬化剂与透明质酸的摩尔质量比为1:3-4,继续搅拌1-2h后超滤浓缩,得到纳米药物递送系统HA-Fe(Ⅲ)TA-BLM或HA-Fe(Ⅲ)TA-PYM。
第三方面,本发明提供一种光热-硬化联合治疗的靶向纳米药物递送系统在制备预防和/或治疗脉管性疾病药物中的应用,所述脉管性疾病选自血管瘤或脉管畸形中的一种或两种。
优选的,所述脉管畸形选自静脉畸形、微静脉畸形、淋巴管畸形、动静脉畸形中的一种或两种以上的组合。
更优选的,所述脉管畸形选自淋巴管畸形。
第四方面,本发明提供一种光热-硬化联合治疗的靶向纳米药物递送系统在光声成像引导给药方式中的应用。
本发明提供的靶向纳米药物递送系统课进行光声成像的原理如下:由于TA分子上的酚羟基与Fe(Ⅲ)产生强螯合配位作用,该纳米药物表现出强烈的近红外吸收。在近红外区域具有强吸收的材料在脉冲激光的照射下能够产生明显的超声信号,因此,该靶向纳米药物递送系统可以作为光声造影剂使用。
附图说明
图1 HA-Fe(Ⅲ)TA-BLM的构建及其在光声引导精准注射下的光热-硬化联合治疗示意图;
图2 HA-Fe(Ⅲ)TA-BLM透射电镜图示;
图3 HA-Fe(Ⅲ)TA-BLM的制备及稳定性白光照片;
图4 HA-Fe(Ⅲ)TA-BLM的体外光热升温曲线测定;
图5 HA-Fe(Ⅲ)TA-BLM的细胞治疗实验结果;
图6 HA-Fe(Ⅲ)TA-BLM光声成像引导局部精准注射图示;
图7 淋巴管畸形小鼠局部病变升温曲线;
图8 淋巴管畸形小鼠光热-硬化联合治疗结果白光照片;
图9 HA-Fe(Ⅲ)TA-BLM及BLM对淋巴管畸形小鼠硬化治疗效果对比。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅是本发明的部分实施例,而不是全部。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1 HA-Fe(Ⅲ)TA-BLM的制备
将HA(20 mM,1 mL)与TA(5 mM,1 mL)混合溶解于中性超纯水中,在磁力搅拌下滴加FeCl3溶液(100 mM,250 μL),搅拌10min,搅拌状态下继续滴加BLM溶液(20 mM,300 μL),磁力搅拌1 h后超滤纯化,得到产物HA-Fe(Ⅲ)TA-BLM。
实施例2 HA-Fe(Ⅲ)TA-PYM的制备
将HA(20 mM,1 mL)与TA(5 mM,1 mL)混合溶解于中性超纯水中,在磁力搅拌下滴加FeCl3溶液(100 mM,250 μL),搅拌10min,搅拌状态下继续滴加PYM溶液(20 mM,300 μL),磁力搅拌1 h后超滤纯化,得到产物HA-Fe(Ⅲ)TA-PYM。
效果实施例
1、HA-Fe(Ⅲ)TA-BLM表征及稳定性
利用透射电子显微镜对实施例1制备的纳米药物递送系统的形貌、尺寸和单分散性进行观测,结果如图2所示,本发明实施例1制备的纳米药物递送系统粒径为15-24nm,粒径均一,分散性良好。
将实施例1制备的纳米药物递送系统HA-Fe(Ⅲ)TA-BLM放置48 h后观察其稳定性状况,结果如图3所示,结果证明通过本发明提供的制备方法得到的HA-Fe(Ⅲ)TA-BLM在放置48 h后不产生沉淀或分层,稳定性良好。
、HA-Fe(Ⅲ)TA-BLM体外光热升温效果
以BLM浓度计,将实施例1制备的纳米药物递送系统HA-Fe(Ⅲ)TA-BLM使用生理盐水配置成浓度为50μg/mL,分别使用强度分别为0.5W/cm2、1.0 W/cm2、1.5 W/cm2、2.0 W/cm2,波长为808 nm 的激光激光照射HA-Fe(Ⅲ)TA-BLM溶液生理盐水10 min,在光照液体升温过程中,使用红外热值相机记录HA-Fe(Ⅲ)TA-BLM溶液的温度变化热值,结果如图4所示。在纳米药物递送系统浓度一致的情况下,光照强度越强,光热升温效果越好。
、HA-Fe(Ⅲ)TA-BLM用于细胞治疗
将对数生长期的淋巴管内皮细胞接种于96孔细胞培养板中,1×104细胞/孔,置于EGM完全培养基环境在培养箱中培养24小时。用EGM完全培养基配制BLM浓度分别为0 μg/mL、 5μg/mL、10μg/mL、20μg/mL、 50μg/mL的新鲜培养液;另外,以BLM浓度计,用EGM完全培养基将实施例1制备的纳米药物递送系统HA-Fe(Ⅲ)TA-BLM配置成浓度分别为0 μg/mL、 5μg/mL、10μg/mL、20μg/mL、 50μg/mL的新鲜培养液。设置3组实验,一组为BLM,其他两组为HA-Fe(Ⅲ)TA-BLM,分别将上述配置好的培养液加入96孔板中,37 ℃、5% CO2培养箱中培养8h,弃掉培养液,用PBS清洗后,加入EGM完全培养基。其中一组HA-Fe(Ⅲ)TA-BLM用功率密度为 0.5W/cm2的808nm激光器照射10 min,随后在37 ℃、5% CO2培养箱中继续培养24 h,用CCK8试剂盒检测细胞存活率,结果如图5所示。
所加药物中BLM浓度越高,细胞存活率越小,说明此时药物对淋巴管内皮细胞的杀伤效果越好。其中,HA-Fe(Ⅲ)TA-BLM+激光照射组的细胞存活率比不进行激光照射的组显著降低,比BLM直接治疗组也是显著降低。说明BLM硬化治疗合并光热治疗对淋巴管内皮细胞的杀伤作用比单独BLM硬化治疗的效果更好。
、HA- Fe(Ⅲ)TA -BLM光声成像引导注射探究
实时光声成像引导局部注射给药:将实施例1制备的纳米药物递送系统HA-Fe(Ⅲ)TA-BLM配置成浓度为1 mg/mL的生理盐水溶液,抽取150 μL在光声引导下经皮穿刺进入病灶,与超声影像相结合,监视针体的行进方向和针尖抵达的深度,尽可能刺破囊腔的同时避开周围的血管组织及正常组织,通过光声成像信号对注射过程进行精准引导,同时在光声成像影像下观察HA-Fe(Ⅲ)TA-BLM的弥散范围,结果如图6所示。箭头所指区域为病灶区域,可以看到在光声成像引导下药物精准注射到病变囊腔内,没有造成病变周围区域浸润。
、HA-Fe(Ⅲ)TA-BLM在体光热-硬化联合治疗评价
淋巴管畸形小鼠模型的构建:将弗氏不完全佐剂体积比1:1稀释于PBS溶液(pH7.3,0.1 M;1:1v/v),再向注射液中加入200 μL浓度为1 nM的VEGF-C蛋白,在BALB/c雌性小鼠左侧颈部皮下注射200μL注射液;15天后在相同位置重复注射。随后观察6-8周,待颈部皮下有明显的透明或半透明囊性病变形成。
将淋巴管畸形小鼠分为2组,每组5只。实验组:光声成像引导下精准注射HA- Fe(Ⅲ)TA-BLM生理盐水溶液(1 mg/mL,100 μL),并予以 808 nm 激光照射(2 W/cm2)5 min;对照组:局部注射BLM(1 mg/mL,100 μL)。在激光照射期间,通过红外热值成像仪拍摄记录两组小鼠局部病变的升温情况。每组小鼠每10天进行一次治疗,直至病变消失。病变区域组织升温情况如图7所示,与BLM相比,由于HA- Fe(Ⅲ)TA-BLM产生的光热效应,使病变区域温度明显升高。
实验组小鼠治疗效果如图8所示,光热-硬化联合治疗后第1天病变部位呈红色,有结痂产生,光热-硬化联合治疗后第5天结痂脱落,第10天后病变完全消失。
对治疗前后对两组小鼠病变部位体积大小进行记录,结果如图9所示。只注射BLM进行硬化治疗的小鼠,病变部位在40-60天内消除,大多数在治疗50天后才消失,治疗进程缓慢。而注射HA- Fe(Ⅲ)TA-BLM进行光热-硬化联合治疗组,有一只试验鼠在治疗后10天病变部位就已经消失,多数在治疗后20天消失,治疗效果显著优于BLM硬化治疗组。
本发明制备的HA-Fe(Ⅲ)TA-PYM具有与HA- Fe(Ⅲ)TA-BLM相近的治疗效果,为了节省篇幅,关于HA-Fe(Ⅲ)TA-PYM的治疗效果数据不再赘述。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (10)
1.一种光热-硬化联合治疗的靶向纳米药物递送系统,其特征在于,所述药物递送系统由药物载体、硬化剂和植物多酚铁络合物构成,具体由药物载体包被硬化剂和植物多酚铁络合物制备得到。
2.根据权利要求1所述的药物递送系统,其特征在于,在所述药物递送系统中,硬化剂与药物载体的摩尔质量比为1:1-4,植物多酚铁络合物与药物载体的摩尔质量比为1:2-6。
3.根据权利要求1所述的药物递送系统,其特征在于,所述药物载体为含有羧基和/或羟基的带负电荷的线性高分子聚合物;所述硬化剂选自鱼肝油酸钠、明矾、平阳霉素、博来霉素、乙醇胺、泛影酸、喹啉、四环素、强力霉素、脲素中的一种或两种以上的组合。
4.根据权利要求1所述的药物递送系统,其特征在于,所述植物多酚铁络合物由植物多酚与三价铁Fe(Ⅲ)络合形成,所述植物多酚选自单宁酸、白藜芦醇、阿魏酸、绿原酸、肉桂酸中的一种或两种以上的组合,植物多酚与Fe(Ⅲ)络合摩尔质量比为1:4-6。
5.根据权利要求1-4任一所述的药物递送系统,其特征在于,药物递送系统由透明质酸包被硬化剂博来霉素或平阳霉素和单宁酸铁络合物制备得到。
6.一种权利要求1所述的光热-硬化联合治疗的靶向纳米药物递送系统的制备方法,所述方法包括:室温下将药物载体和植物多酚按照摩尔质量比为2-6: 1溶于超纯水中,搅拌下滴加三价铁Fe(Ⅲ)溶液,搅拌10-15min;按照硬化剂与药物载体的摩尔质量比为1:1-4滴加硬化剂水溶液,继续搅拌1-2h;超滤浓缩,得到纳米药物递送系统。
7.根据权利要求6所述的制备方法,其特征在于,室温下将透明质酸和单宁酸按照摩尔质量比为4-6:1溶于超纯水中,搅拌下滴加FeCl3溶液,单宁酸与FeCl3摩尔质量比为1:5-6,搅拌10min后滴加硬化剂博来霉素或平阳霉素水溶液,硬化剂与透明质酸的摩尔质量比为1:3-4,继续搅拌1-2h后超滤浓缩,得到纳米药物递送系统。
8.一种权利要求1所述的光热-硬化联合治疗的靶向纳米药物递送系统在制备预防和/或治疗脉管性疾病药物中的应用,所述脉管性疾病选自血管瘤或脉管畸形中的一种或两种,所述脉管畸形选自静脉畸形、微静脉畸形、淋巴管畸形、动静脉畸形中的一种或两种以上的组合。
9.根据权利要求8所述的应用,其特征在于,所述脉管畸形选自淋巴管畸形。
10.一种权利要求1所述的光热-硬化联合治疗的靶向纳米药物递送系统在光声成像引导给药方式中的应用。
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