Construction of self-assembled nanomedicine and evaluation on its targeting role in preeclampsia treatment

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 H2O2 stimulation (P < 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 (P < 0.05), proteinuria level (P < 0.05) and uterine artery blood flow resistance index (UARI, P < 0.05) and expression levels of inflammatory factors IL-6 and TNF-α (P < 0.05), and increased expression levels of anti-oxidative stress-related proteins UCP-1 and Nrf-2 (P < 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 (P < 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.

Keywords

• nanomedicine
• placental targeting
• preeclampsia
• nifedipine