CN101780285A - 一种热增强型负载液态氟碳的聚合物纳米超声显像胶束及其制备方法 - Google Patents
一种热增强型负载液态氟碳的聚合物纳米超声显像胶束及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种热增强型负载液态氟碳的聚合物纳米超声显像胶束及其制备方法。本发明负载液态氟碳的聚合物纳米超声显像胶束由以下按重量份数计的组分组成:聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物1,液态氟碳类超声显像试剂1~20。本发明聚合物纳米超声显像胶束负载的液态氟碳为全氟戊烷,所得胶束为纳米级,粒径分布较窄,具有显著的体外超声显像效果及热增强效应,在动物皮下显像明显,可望进一步应用于体内及其它组织器官,在诊断领域有中大的研究价值和应用前景。
Description
技术领域
本发明涉及高分子化学和生物医学工程领域,具体涉及一种热增强型负载液态氟碳的聚合物纳米超声显像胶束及其制备方法。
背景技术
超声是最常用、也是最重要的影像学手段之一,与其它影像手段比较,具有经济、简便、无辐射、可重复多次检查和在床边及术中使用等优势,临床应用广泛,容易普及。
超声造影剂及造影技术的出现及发展,为超声分子影像学带来了契机。目前常用的超声造影剂属于血池显像剂,造影剂微气泡直径与红细胞相近,达到了数微米,经静脉注射入体内后,可通过肺循环到达全身组织脏器的微循环,通过改变扫查对象界面的声阻抗差,产生造影显像效果,提高了超声对病灶的检出能力和鉴别诊断能力。但由于普通造影剂属于无组织特异性的全身性造影剂,对特定病灶的诊断能力尚不足。
为了更好的实现病灶特异性成像,有必要采用颗粒更小的超声造影剂,纳米级超声造影剂是最理想的选择。纳米级微粒具有以下突出优势:1)独特的纳米尺寸,有利于减少肾脏排泄清除、网状内皮系统吸收及吞噬细胞的识别,从而延长在体内的循环时间;2)可顺利通过毛细血管内皮细胞间隙到达组织靶区,并可通过高通透高滞留效应(enhanced permeability and retention effect,EPR效应)在病灶组织中实现被动靶向富集。对于肿瘤组织,由于肿瘤新生血管内皮细胞连接疏松,且缺乏淋巴回流,故纳米微粒更容易从血管进入,但难以通过淋巴回流而返回血管内;3)容易与特异性配体链接,选择性与病灶特异性分子结合,实现主动靶向成像。
目前,国内外研究的纳米级超声造影剂的主要分为纳米级脂质体造影剂、纳米级微泡造影剂和纳米级液态氟碳乳剂三类,但目前存在制作工艺不成熟,颗粒偏大,易被清除,体内循环时间较短,不易进行表面修饰,回声增强效果有限等不足。前两类造影剂由于受外壳材料和制备方法本身的缺陷,均不同程度存在粒径分布范围较广、在体内持续时间短、后方声衰减较明显、效果不稳定等缺点,气体造影剂更由于在组织内部引入气体而可能产生不利影响。而后一类造影剂虽显像效果较好,但表面活性剂的活化十分不稳定,在体内高度稀释和温度较高的情况很容易发生造影剂失活并沉淀的现象。
因此,负载液态氟碳的聚合物纳米自组装载体成为该领域研究的突破口之一。相比于其他纳米微粒,聚合物纳米胶束具有以下优势:1)制备过程简单,利用两亲性聚合物在水溶液中自组装形成粒径相对均一的纳米微粒,并可包载疏水性的内容物;2)粒径小且可控,从几十纳米到几百纳米,具有更强的组织渗透性,不易被清除;3)纳米胶束的临界胶束浓度极低,在水中具有很好的稳定性,在血液循环中具有较长的半衰期;4)容易进行化学修饰或引入靶向基团,实现主动靶向成像和治疗。
另一方面,液态氟碳类造影剂性质稳定,超声回声效果显著,其最突出的优势是其可作为一种潜在的多功能造影剂,即不仅可以作为超声造影剂,还可以作为CT、MRI及核素显像造影剂。
发明内容
本发明的目的在于根据现有超声显像试剂中存在的不足,提供一种热增强型纳米级负载液态氟碳的聚合物超声显像胶束。
本发明另一目的在于提供上述热增强型纳米级负载液态氟碳的聚合物超声显像胶束的制备方法。
本发明上述目的通过以下技术方案予以实现:
一种热增强型负载液态氟碳的聚合物纳米超声显像胶束,由以下按重量份数计的组分制成:聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物1,液态氟碳类超声显像试剂1~20。
其中,所述聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物的结构中,聚乙二醇段的数均分子量为2.0~6.0KD,聚丙交酯或聚己内酯段的数均分子量为15.0~30.0KD。
作为一种优选方案,本发明热增强型负载液态氟碳的聚合物纳米超声显像胶束中,所述液态氟碳类超声显像试剂优选为全氟戊烷(perfluoropentane,可简写为PFP)。
本发明所设计的纳米胶束由聚乙二醇(Polyethyeneglycol,可简写为PEG)与聚丙交酯(poly(D,L-lactic acid),可简写为PDLLA)或聚己内酯(poly(□-caprolactone),可简写为PCL)的两亲性共聚物(可简写为PEG-PDLLA或PEG-PCL)制成。其中亲水的PEG段生物相容性佳,疏水的PDLLA或PCL段更具有良好的生物相容性和生物可降解性。在自组装过程中,PDLLA段或PCL段自发地形成胶束的疏水性内核,PEG段位于该核的表面,其内核则包负有疏水性的液态氟碳类超声显像试剂——全氟戊烷。全氟戊烷,它的沸点为29℃,当被包负后再注入人体内,会由于温度的升高而变为气体,从而大大提高了瞬时超声显像效果,成为热增强型超声显像试剂。
本发明热增强型负载液态氟碳的聚合物纳米超声显像胶束的制备方法包括如下步骤:以聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物为原料,通过超声乳化法在低温下包覆全氟戊烷,得到热增强型负载液态氟碳的聚合物纳米超声显像胶束。
其中,所述聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物的制备方法为:用聚乙二醇在辛酸亚锡的催化下引发单体丙交酯或己内酯的开环聚合,得到聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物。
作为一种优选方案,本发明热增强型负载液态氟碳的聚合物纳米超声显像胶束的制备方法包括如下步骤:将1重量份共聚物与1~20重量份的全氟戊烷共溶于8体积的四氯化碳中,于冰浴中在超声作用下分散至20体积0.5~5.0wt%聚乙烯醇水溶液中,得到热增强型负载液态氟碳的聚合物纳米超声显像胶束。
本发明热增强型负载液态氟碳的聚合物纳米超声显像胶束的研究得到了国家自然科学基金面上项目(30870717)的支持。
与现有技术相比,本发明具有如下有益效果:
(1)该胶束由聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物制成,具有优良的生物相容性和降解性;
(2)该胶束粒径分布集中,位于200~700nm之间,为纳米级载体;
(3)该胶束能够在PEG末端进行化学修饰以链接靶向配体,从而实现该显像试剂的靶向效果、提高显像试剂的局部浓度并提高显像效果等;
(4)全氟戊烷被包负进该纳米胶束后能够显著提高其在水中的稳定性并提高了超声回声特性,相对于表面活性剂活化的液态氟碳造影剂所需浓度更低、显像效果由于热增强效应会更为显著。
附图说明
图1~3分别是实施例3中负载不同体积全氟戊烷的聚合物纳米胶束的动态光散射粒径分布柱状图。其中,图1、图2和图3分别对应的全氟戊烷体积为0.025ml、0.05ml和0.1ml,其粒径分布位于400~500nm之间。
图4~6分别是实施例4中负载不同体积全氟戊烷的聚合物纳米胶束的初始体外超声显像图片。其中,图4、图5和图6分别对应的全氟戊烷体积为0.025ml、0.05ml和0.1ml,均有明显的超声显像效果。
图7是实施例4中经35℃左右水浴加热后负载不同体积全氟戊烷的聚合物纳米胶束的体外超声显像随时间变化的灰度值柱状图。其中,该胶束表现出了明显的瞬时热增强效应。
图8是实施例5中负载0.1ml PFP的聚合物纳米胶束在兔子皮下注射的超声显像图片,其显像效果明显。
具体实施方式
以下结合实施例来进一步解释本发明,但实施例并不对本发明做任何形式的限定。
本发明基于两亲性共聚物PEG-PDLLA或PEG-PCL的纳米胶束被用于负载全氟戊烷,所得胶束的粒径采用动态光散射来测定。同时该胶束还通过不同温度下的体外超声显像和动物皮下注射试验来评价这一热增强型的纳米级超声显像试剂,即采用控温水浴对注射器中相同体积的超声显像胶束溶液加热,同时插入超声探头以对不同温度下的溶液进行显像。动物皮下注射显像则以兔子为试验对象,即时注射并显像。
实施例1
1.聚合物纳米超声显像胶束载体材料PEG-PDLLA或PEG-PCL的制备:
氩气保护下将0.2g端羟基PEG(分子量在2.0~3.0Kg/mol)在50℃左右真空干燥数小时后冷却至室温,然后注入1.6~2.4g干燥的丙交酯或□-己内酯和少量辛酸亚锡。室温下真空干燥1h后加入无水甲苯20ml,在120℃回流12~24h聚合。反应结束后,在无水乙醚中进行重沉淀,过滤后再用二氯甲烷溶解,于无水乙醚中进行二次重沉淀,经过滤和真空干燥得到纯样品。
2.负载全氟戊烷的聚合物纳米超声显像胶束的制备:
将40mg共聚物(PEG-PDLLA或PEG-PCL)分别与0.025、0.05、0.1和0.2ml全氟戊烷共溶于8ml四氯化碳中,在超声作用下于冰浴中分散于20ml 2wt%聚乙烯醇水溶液中,经长时间低温搅拌挥发,除去溶剂四氯化碳即得。
实施例2负载全氟戊烷的聚合物纳米超声显像胶束粒径的测试
所得胶束的粒径大小采用动态光散射系统进行测量,测试结果见图1至3。图1(0.025ml PFP)、图2(0.05ml PFP)和图3(0.1ml PFP)分别为对应PFP浓度胶束的动态光散射粒径分布柱状图。可以看出,负载全氟戊烷的聚合物纳米胶束的粒径分布较窄,主要位于400~500nm之间,为纳米级。
实施例3负载全氟戊烷的聚合物纳米超声显像胶束体外超声显像试验
用2ml注射器吸满制得的超声显像胶束溶液,置于即时温度25℃左右的可控温水浴中并将超声探头置入进行显像,分别记录原始的超声显像图像及加热(即水浴温度提高到35℃左右)后不同时间的超声显像图像,并测定其注射器内部区域的灰度值以进行比较。测试结果见图4至7。图4至6显示了不同PFP浓度的聚合物纳米胶束的初始超声显像图像:0.025ml PFP(图4)、0.05ml PFP(图5)和0.1ml PFP(图6)。从中可以看到,负载全氟戊烷的聚合物纳米胶束在体外有明显的显像效果,其显像效果随PFP的浓度的提高而提高。图7显示了35℃左右水浴加热后不同时间对应胶束的超声显像灰度值。很明显,该负载全氟戊烷的聚合物纳米胶束在加热后具有明显的瞬时增强效应,其超声显像灰度值在一分钟内随时间的延长而有明显增加,两分钟时则显著降低,并且浓度愈高热增强效应越明显。
实施例4负载全氟戊烷的聚合物纳米超声显像胶束动物皮下注射显像试验
用2ml注射器吸满制得负载0.1ml PFP的超声显像胶束溶液并注射于试验动物——兔子的皮下,进行即时超声显像观察,测试结果见图8。可以清楚地看到,图8上部皮下间隔组织区域内注射进入的纳米胶束有明显的超声显像效果。
以上测试结果表明,所得胶束的粒径为400~500nm,为纳米级。体外显像实验表明,该负载全氟戊烷的聚合物纳米胶束具有明显的超声显像效果,其显像效果随全氟戊烷浓度的提高而提高,并且热增强效果显著。动物皮下注射显像实验表明,该纳米胶束在皮下具有较好的超声显像效果。
Claims (7)
1.一种热增强型负载液态氟碳的聚合物纳米超声显像胶束,其特征在于由以下按重量份数计的组分制成:聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物1,液态氟碳类超声显像试剂1~20。
2.根据权利要求1所述的热增强型负载液态氟碳的聚合物纳米超声显像胶束,其特征在于所述聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物的结构中,聚乙二醇段的数均分子量为2.0~6.0KD,聚丙交酯或聚己内酯段的数均分子量为15.0~30.0KD。
3.根据权利要求1所述的热增强型负载液态氟碳的聚合物纳米超声显像胶束,其特征在于所述液态氟碳类超声显像试剂是全氟戊烷。
4.权利要求1~3中任意一条权利要求所述热增强型负载液态氟碳的聚合物纳米超声显像胶束的制备方法,其特征在于包括如下步骤:以聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物为原料,通过超声乳化法在低温下包覆全氟戊烷,得到热增强型负载液态氟碳的聚合物纳米超声显像胶束。
5.根据权利要求4所述热增强型负载液态氟碳的聚合物纳米超声显像胶束的制备方法,其特征在于所述聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物的制备方法为:用聚乙二醇在辛酸亚锡的催化下引发单体丙交酯或己内酯的开环聚合,得到聚乙二醇与聚丙交酯或聚己内酯的两亲性共聚物。
6.根据权利要求4所述热增强型负载液态氟碳的聚合物纳米超声显像胶束的制备方法,其特征在于包括如下步骤:将1重量份共聚物与1~20重量份的全氟戊烷共溶于8体积的四氯化碳中,于冰浴中在超声作用下分散至20体积0.5~5.0wt%聚乙烯醇水溶液中,除去油相溶剂四氯化碳后得到热增强型负载液态氟碳的聚合物纳米超声显像胶束。
7.根据权利要求6所述热增强型负载液态氟碳的聚合物纳米超声显像胶束的制备方法,其特征在于超声作用后,经过低温搅拌挥发以除去四氯化碳。
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