CN113967268A - 一种子宫内膜异位症病灶靶向纳米投递系统及其制备方法和应用 - Google Patents
一种子宫内膜异位症病灶靶向纳米投递系统及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种子宫内膜异位症病灶靶向纳米投递系统及其制备方法和应用。投递系统包括位于中心的疏水内核、包绕所述疏水内核的脂质单分子层和亲水靶向多肽层,多肽包括以下序列中的一条或多条组合的多肽,或以下序列中的一条或多条组合的多肽的衍生物,SEQ ID No.1,SEQ ID No.2,SEQ ID No.3,SEQ ID No.4,SEQ ID No.5,SEQ ID No.6。利用纳米颗粒包裹技术,结合具有靶向能力的多肽表面修饰后,可特异的识别子宫内膜异位症病灶,从而为该类病患的诊治提供一种高效的药物投递系统。由于纳米颗粒包裹技术可将适宜的诊断试剂或治疗药物,投递到病灶部位,从而可实现其诊断治疗工具的作用。
Description
技术领域
本发明属于纳米医学细胞生物学领域,涉及一种子宫内膜异位症病灶靶向纳米投递系统及其制备方法和应用。
背景技术
子宫内膜异位症是指子宫内膜外活跃的子宫内膜细胞异常生长和存活,从而导致患病。其发病机制尚未阐明,有多种假说,如内分泌因素、炎症、免疫、新生血管、遗传因素、干细胞学说等。“外周血流”内膜异位植入理论是目前公认的腹腔子宫内膜异位症形成的主要原因。子宫内膜细胞通过腹膜细胞,尤其是腹膜细胞外基质,完成粘附、侵袭、血管生成,形成异位病变引起各种疾病症状。由此可见,该疾病的早期诊断和治疗是关键所在。因此,开发一种具有靶向投递功能的投递系统对本疾病的诊断治疗具有重要的应用价值。
发明内容
为了解决上述背景技术中所提出的问题,本发明的目的在于提供一种子宫内膜异位症病灶靶向纳米投递系统及其制备方法和应用。
为了达到上述目的,本发明所采用的技术方案为:
本发明一方面提供了一种子宫内膜异位症病灶靶向纳米投递系统,包括位于中心的疏水内核、包绕所述疏水内核的脂质单分子层和亲水靶向多肽层,所述亲水靶向多肽层暴露在所述脂质单分子层外,所述亲水靶向多肽层中所述靶向多肽包括以下序列中的一条或多条组合的多肽,或以下序列中的一条或多条组合的多肽的衍生物,
EDVKDINFDTKEKFLAGCLIVSFHEGKC SEQ ID No.1
GKKTQELKNIRTNSELLKEWIIAAFHEGKC SEQ ID No.2
LKPSHEKKNDDNGKKLCKAC SEQ ID No.3
EDVKDINFDTKEKFLAGCLIVSFHEGK SEQ ID No.4
GKKTQELKNIRTNSELLKEWIIAAFHEGK SEQ ID No.5
LKPSHEKKNDDNGKKLCKA SEQ ID No.6。
进一步地,所述的衍生物为多肽进行末端或侧链的修饰得到的产物,或多肽进行荧光基团的标记修饰得到的产物,或多肽进行同位素标记得到的产物,或多肽进行磷酸化修饰得到的产物,或多肽进行基于二硫键的环化修饰得到的产物,或多肽进行生物素的标记得到的产物,或多肽进行光敏剂修饰得到的产物,或多肽进行叠氮修饰得到的产物,或多肽进行PEG修饰得到的产物,或多肽进行甲基化修饰得到的产物,或多肽进行荧光淬灭基团修饰得到的产物,或多肽进行蛋白偶联修饰得到的产物,或多肽进行小分子化合物修饰得到的产物。
进一步地,所述多肽进行末端或侧链的修饰包括但不限于N端乙酰化修饰,C端的胺化修饰。
进一步地,所述多肽进行荧光基团的标记修饰中所用的荧光染料包括但不限于FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7,该修饰以便用于荧光检测目的。
进一步地,所述多肽进行同位素标记中所用的同位素包括但不限于13C,该修饰用于追踪目的。
进一步地,所述多肽进行的磷酸化修饰包括但不限于p-Ser、p-Thr、p-Tyr。
进一步地,所述多肽进行生物素的标记,用于定位检测目的等。
进一步地,所述多肽进行光敏剂修饰,以便于制备光敏感制剂。
进一步地,所述多肽进行叠氮修饰,有利于次级的连接反应。
进一步地,所述多肽进行PEG修饰,用于药物载体制备。
所述的多肽可通过一般有机化学实验室条件自主合成,也可以通过常规的商业化试剂公司工业合成,即利用固相法合成多肽,在树脂上不同氨基酸之间缩合反应实现定向氨基酸链的合成。多肽的衍生物则在氨基酸完成连接后,施加所需的修饰基团。
进一步地,所述子宫内膜异位症病灶靶向纳米投递系统的粒径为10~1000纳米。
进一步地,还包括目标投递物,所述目标投递物被所述疏水内核包裹。
进一步地,所述目标投递物包括诊断化合物、治疗子宫内膜异位症的药物中的一种或至少两种的组合。
进一步地,所述诊断化合物包括量子点、稀土纳米粒子、金属纳米晶簇、菁类、罗丹明类、芳酸类、卟啉类、BODIPY类荧光材料中的一种或至少两种的组合;
优选地,所述诊断化合物为菁类;更优选地,所述菁类包括吲哚菁绿。
进一步地,所述治疗子宫内膜异位症的药物包括孕激素类药物、雄激素类药物、促性腺激素释放激素激动剂中的一种或至少两种的组合;
优选地,所述孕激素类药物包括普维拉、黄体酮、内美通、己酸孕酮;
优选地,所述雄激素类药物包括丹那唑;
优选地,所述促性腺激素释放激素激动剂包括戈舍瑞林。
本发明另一方面提供了一种上述任一所述的子宫内膜异位症病灶靶向纳米投递系统的制备方法,包括以下步骤:
a)将具有两性性质的分子在有机溶剂中混匀;
b)将上述混合物,在超声环境下逐滴加入水中,形成新的混合液体;
c)经过超声处理,和氮气吹打出去有机溶剂后形成纳米颗粒;
d)将纳米颗粒和靶向多肽反应实现连接后得到所述子宫内膜异位症病灶靶向纳米投递系统;
或a)将具有两性性质的分子在有机溶剂中混匀;
b)加入所需量的目标投递物,再次混匀;
c)将上述混合物,在超声环境下逐滴加入水中,形成新的混合液体;
d)经过超声处理,和氮气吹打出去有机溶剂后形成纳米颗粒;
e)将纳米颗粒和靶向多肽反应实现连接后得到所述子宫内膜异位症病灶靶向纳米投递系统;
所述具有两性性质的分子为聚合物修饰的脂类分子;
优选地,所述聚合物包括聚乙二醇;
优选地,所述脂类分子包括硬脂酸、卵磷脂、三酰甘油中的一种或至少两种的组合。
所述的靶向多肽与纳米颗粒可通过有机化学方法,如氨基羧基羧化反应,点击化学法等(具体例如1-(3-二甲氨基百丙基)-3-乙基碳二亚胺盐酸盐法),实现完整纳米颗粒的组装。
进一步地,所述纳米颗粒和靶向多肽的摩尔比例为1:0~1:1,不包括1:0,优选为1:0.5~1:1。
本发明再一方面提供了一种上述任一所述的子宫内膜异位症病灶靶向纳米投递系统在制备诊断和/或治疗子宫内膜异位症的药物中的应用。
本发明的有益效果:
(1)本发明提供的纳米投递系统,可用于子宫内膜异位症的诊断目的。
(2)本发明提供的纳米投递系统,可作为子宫内膜异位症治疗工具。
(3)本发明提供的纳米投递系统,制备工艺相对简单且成本低廉,因此有良好的市场前景。
(4)本发明利用纳米颗粒包裹技术,结合具有靶向能力的多肽表面修饰后,可特异的识别子宫内膜异位症病灶,从而为该类病患的诊治提供一种高效的药物投递系统。由于纳米颗粒包裹技术可将适宜的诊断试剂或治疗药物,投递到病灶部位,从而可实现其诊断治疗工具的作用。本发明适用于人类子宫内膜异位症疾病的诊治,也适用于子宫内膜异位症造模实验动物的基础应用转化研究。
附图说明
图1为本发明实施例中病灶位点小动物成像仪检测结果图。
具体实施方式
为了更好地理解本发明的内容,下面结合具体实施方法对本发明内容作进一步说明,但本发明的保护内容不局限以下实施例。
本发明以SEQ ID No.1所述多肽序列为例。
实施例1:SEQ ID No.1所述多肽序列的制备
所述多肽序列由专门的多肽制备公司工业合成。
利用固相合成多肽法,从C端的氨基酸向N端进行链接,经过树脂活化、氨基酸链接、洗脱保护、检测步骤,逐个链接氨基酸,然后使用过量乙醚沉淀离心,对粗肽过HPLC纯化,最后,质谱分析,液氮速冷冻干备用。
实施例2:脂质-聚合物纳米微球颗粒的制备
先将二硬脂酰基磷脂酰乙醇胺-聚乙二醇(DSPE-mPEG)和二硬脂酰基磷脂酰乙醇胺-聚乙二醇-二苯并环辛炔(DSPE-PEG-DBCO)溶解在四氢呋喃中,混合均匀后加入荧光染料,将混合物在超声条件下逐滴加入到水中。形成澄清溶液后转到细胞破碎仪(频率设置为20%)中超声5min,用氮气吹5min去除四氢呋喃从而形成纳米颗粒。
实施例3:子宫内膜异位症病灶靶向纳米投递系统的制备
选取实施例1制备得到的多肽序列,将其修饰于实施例2制备得到的纳米颗粒表面。纳米颗粒和多肽连接采用的是经典的点击化学的方法,纳米颗粒和多肽摩尔比例为1:0.5,4℃下孵育过夜备用。
实施例4:子宫内膜异位症小鼠动物模型制备
购买7-8周的成年C57雌鼠,麻醉后,取一侧正位的子宫组织,切取2平方毫米大小含子宫内膜组织,异位接种于腹腔肠系膜部位,然后缝合腹壁肌肉及皮肤,整合手术操作充分消毒,将小鼠静养一个月以上备用。
实施例5:异位子宫内膜组织病灶处取材成像观察
对实施例4中制备的子宫内膜异位症小鼠模型,静养1-2月后,待其异位病灶形成后,对其进行尾静脉注射实施例3中所制备的子宫内膜异位症病灶靶向纳米投递系统,24小时后,在小动物成像仪中对异位子宫内膜组织进行观察,可见病灶位点有特异的荧光信号(如图1所示)。
综上,本申请提供的子宫内膜异位症病灶靶向纳米投递系统可用于子宫内膜异位症的诊疗目的。
以上所述仅为本发明的具体实施方式,不是全部的实施方式,本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换,均为本发明的权利要求所涵盖。
SEQUENCE LISTING
<110> 深圳先进技术研究院
<120> 一种子宫内膜异位症病灶靶向纳米投递系统及其制备方法和应用
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Claims (10)
2.根据权利要求1所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,所述子宫内膜异位症病灶靶向纳米投递系统的粒径为10~1000纳米。
3.根据权利要求1所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,所述的衍生物为多肽进行末端或侧链的修饰得到的产物,或多肽进行荧光基团的标记修饰得到的产物,或多肽进行同位素标记得到的产物,或多肽进行磷酸化修饰得到的产物,或多肽进行基于二硫键的环化修饰得到的产物,或多肽进行生物素的标记得到的产物,或多肽进行光敏剂修饰得到的产物,或多肽进行叠氮修饰得到的产物,或多肽进行PEG修饰得到的产物,或多肽进行甲基化修饰得到的产物,或多肽进行荧光淬灭基团修饰得到的产物,或多肽进行蛋白偶联修饰得到的产物,或多肽进行小分子化合物修饰得到的产物;
优选地,所述多肽进行末端或侧链的修饰包括N端乙酰化修饰,C端的胺化修饰;
优选地,所述多肽进行荧光基团的标记修饰中所用的荧光染料包括FITC、Rhodamine、Cy3、Cy5、Cy5.5、Cy7;
优选地,所述多肽进行同位素标记中所用的同位素包括13C;
优选地,所述多肽进行的磷酸化修饰包括p-Ser、p-Thr、p-Tyr。
4.根据权利要求1所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,还包括目标投递物,所述目标投递物被所述疏水内核包裹。
5.根据权利要求4所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,所述目标投递物包括诊断化合物、治疗子宫内膜异位症的药物中的一种或至少两种的组合。
6.根据权利要求5所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,所述诊断化合物包括量子点、稀土纳米粒子、金属纳米晶簇、菁类、罗丹明类、芳酸类、卟啉类、BODIPY类荧光材料中的一种或至少两种的组合;
优选地,所述诊断化合物为菁类;更优选地,所述菁类包括吲哚菁绿。
7.根据权利要求5所述的子宫内膜异位症病灶靶向纳米投递系统,其特征在于,所述治疗子宫内膜异位症的药物包括孕激素类药物、雄激素类药物、促性腺激素释放激素激动剂中的一种或至少两种的组合;
优选地,所述孕激素类药物包括普维拉、黄体酮、内美通、己酸孕酮;
优选地,所述雄激素类药物包括丹那唑;
优选地,所述促性腺激素释放激素激动剂包括戈舍瑞林。
8.权利要求1-7任一项所述的子宫内膜异位症病灶靶向纳米投递系统的制备方法,其特征在于,包括以下步骤:
a)将具有两性性质的分子在有机溶剂中混匀;
b)将上述混合物,在超声环境下逐滴加入水中,形成新的混合液体;
c)经过超声处理,和氮气吹打出去有机溶剂后形成纳米颗粒;
d)将纳米颗粒和靶向多肽反应实现连接后得到所述子宫内膜异位症病灶靶向纳米投递系统;
或a)将具有两性性质的分子在有机溶剂中混匀;
b)加入所需量的目标投递物,再次混匀;
c)将上述混合物,在超声环境下逐滴加入水中,形成新的混合液体;
d)经过超声处理,和氮气吹打出去有机溶剂后形成纳米颗粒;
e)将纳米颗粒和靶向多肽反应实现连接后得到所述子宫内膜异位症病灶靶向纳米投递系统;
所述具有两性性质的分子为聚合物修饰的脂类分子;
优选地,所述聚合物包括聚乙二醇;
优选地,所述脂类分子包括硬脂酸、卵磷脂、三酰甘油中的一种或至少两种的组合。
9.根据权利要求8所述的制备方法,其特征在于,所述纳米颗粒和靶向多肽的摩尔比例为1:0~1:1,不包括1:0,优选为1:0.5~1:1。
10.权利要求1-7任一项所述的子宫内膜异位症病灶靶向纳米投递系统在制备诊断和/或治疗子宫内膜异位症的药物中的应用。
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