自组装新型纳米药物的构建及其靶向治疗子痫前期的作用评价

张思祺; 李科; 贾小燕; 张瀚文; 成娟

doi:10.16016/j.2097-0927.202201174

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自组装新型纳米药物的构建及其靶向治疗子痫前期的作用评价

基础医学 | 更新时间：2026-01-09

- 自组装新型纳米药物的构建及其靶向治疗子痫前期的作用评价
- Construction of self-assembled nanomedicine and evaluation on its targeting role in preeclampsia treatment
- 陆军军医大学学报 2022年44卷第12期页码：1187-1198
- 作者机构：
  
  400016 重庆，重庆医科大学附属第一医院产科
- 作者简介：
  
  [成娟，E-mail：juancheng1201@163.comCHENG Juan, E-mail: juancheng1201@163.com
- 基金信息：
  
  国家自然科学基金面上项目(82171662)
- DOI：10.16016/j.2097-0927.202201174
  中图分类号： R714.245; R944.9; R972.4
- 收稿：2022-01-19，
  
  修回：2022-02-24，
  
  纸质出版：2022-06-30
- 稿件说明：
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张思祺, 李科, 贾小燕, 等. 自组装新型纳米药物的构建及其靶向治疗子痫前期的作用评价[J]. 陆军军医大学学报, 2022,44(12):1187-1198.

Siqi ZHANG, Ke LI, Xiaoyan JIA, et al. Construction of self-assembled nanomedicine and evaluation on its targeting role in preeclampsia treatment[J]. Journal of Army Medical University, 2022, 44(12): 1187-1198.
张思祺, 李科, 贾小燕, 等. 自组装新型纳米药物的构建及其靶向治疗子痫前期的作用评价[J]. 陆军军医大学学报, 2022,44(12):1187-1198. DOI： 10.16016/j.2097-0927.202201174.

Siqi ZHANG, Ke LI, Xiaoyan JIA, et al. Construction of self-assembled nanomedicine and evaluation on its targeting role in preeclampsia treatment[J]. Journal of Army Medical University, 2022, 44(12): 1187-1198. DOI： 10.16016/j.2097-0927.202201174.

摘要

目的

构建具有体内降压效果和胎盘靶向性的纳米药物，探讨其在胎盘的靶向效果和体内外治疗子痫前期(preeclampsia，PE)的作用。

方法

应用载体材料聚乳酸-羟基乙酸共聚物(PLGA)和降压药物硝苯地平(nifedipine)，通过自组装纳米沉淀法制备纳米药物(PN NP)，利用化学键合的方式将胎盘靶向肽plCSA-BP连接到PN NP表面形成靶向纳米药物(pl-PN NP)。对纳米药物的物理、化学性质进行表征，选用人绒毛膜滋养层细胞系HTR8进行细胞实验，采用激光共聚焦和流式细胞仪考察滋养层细胞吞噬纳米药物的功能以及纳米药物抗凋亡、抗氧化应激效果。通过大鼠子宫缺血灌注动物模型(reduced uterine perfusion pressure

RUPP)探讨纳米药物的胎盘靶向性及其在子痫前期大鼠模型中的治疗效果，评价纳米药物对胎鼠发育的影响。

结果

粒径分布和电镜检测结果显示：PN NP和pl-PN NP粒径分布狭窄，粒径分别为(160.9±5.3) nm和(163.5±3.4) nm，表面电荷分别为(-45.5±2.6) mV和(-48.3±4.5) mV，纳米药物为球形且分布均匀。体外细胞实验结果证明HTR8细胞对纳米药物的吞噬具有时间和浓度依赖性，且纳米药物能显著抑制H

刺激下的细胞凋亡和氧化应激水平(

0.05)，并且pl-PN NP较PN NP具有更好的效果。体内动物实验结果显示：与硝苯地平相比，PN NP和pl-PN NP能显著降低子痫前期大鼠模型的血压、蛋白尿、子宫动脉阻力指数及炎症因子(IL-6、TNF-α)的表达(

0.05)，增加其抗氧化应激相关蛋白(UCP-1、Nrf-2)的表达(

0.05)。纳米药物可改善母鼠肾脏和胎盘血流，增加胎鼠和胎盘质量，以逆转胎鼠发育障碍。与PN NP比较，pl-PN NP在体内降低血压、蛋白尿、血流阻力、炎症因子、氧化应激水平，改善血流，增加胎鼠和胎盘质量的效果更显著(

0.05)。

结论

使用自组装纳米沉淀法成功合成纳米降压药物(PN NP)和具有胎盘靶向性的纳米降压药物(pl-PN NP)，在细胞水平和动物模型中证明PN NP和pl-PN NP具有治疗子痫前期的效果。

Abstract

Objective

To construct nanomedicine with

antihypertensive effect and explore its targeting ability and therapeutic efficacy on preeclampsia (PE)

in vitro

and

in vivo

Methods

The carrier material poly (lactic-co-glycolic acid

PLGA) encapsulated nifedipine was self-assembled to construct a new nanomedicine (PN NP)

and the placenta-targeting peptide (plCSA-BP) was linked to the surface of the nanomedicine (named pl-PN NP) by chemical bonding. Microscopy and laser particle analyzer were utilized to characterize these nanomedicines (PN NP and pl-PN NP). Confocal laser scanning microscopy (CLSM) and flow cytometry were used to investigate the phagocytosis

anti-apoptosis and antioxidant levels in HTR8 cells after treatment of different doses of nanomedicines. The reduced uterine perfusion pressure (RUPP) model was used to explore the targeting and therapeutic effect of PN NP and pl-PN NP in preeclampsia rats

and their influence on fetal development.

Results

The nanoparticles

PN NP and pl-PN NP are in a well-defined spherical shape

in a narrow particle size distribution

at a mean diameter of 160.9±5.3 and 163.5±3.4 nm

and with a surface charge of -45.5±2.6 and -48.3±4.5 mV

respectively.

In vitro

cell experiments showed that HTR8 cells phagocytosed the nanoparticles in a time- and concentration-dependent manner

and they inhibited cell apoptosis and oxidative stress after H

stimulation (

0.05)

with pl-PN NP showing better effect than PN NP.

In vivo

animal experiments showed that the PN NP and pl-PN NP treatment groups had significantly reduced blood pressure (

0.05)

proteinuria level (

0.05) and uterine artery blood flow resistance index (UARI

0.05) and expression levels of inflammatory factors IL-6 and TNF-α (

0.05)

and increased expression levels of anti-oxidative stress-related p

roteins UCP-1 and Nrf-2 (

0.05) when compared with the nifedipine group. Moreover

these nanoparticles improved blood supply of the kidneys and placenta

increased fetal and placental weight

and alleviated developmental disorders of fetus. And pl-PN NP exerted better effects on blood pressure

proteinuria

UARI

inflammatory factors

oxidative stress

blood supply and weights of placenta and fetus than PN NP (

0.05).

Conclusion

Nanomedicine loaded with nifedipine (PN NP) and the placenta-targeted nanomedicine (pl-PN NP) are successfully synthesized

and PN NP and pl-PN NP show efficacy in treatment of preeclampsia at both cell and animal experiments.

关键词

Keywords

references

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