The PAH-AM-PEG-ApoE@siRNA Nanocarrier Delivery System for Polo-like Kinase 1 Inhibition Suppresses Glioma Progression.

The poor efficacy of chemotherapy for glioma is mainly due to the difficulty of drug penetration through the blood-brain barrier (BBB), as well as the difficulty of drug concentration in the tumor tissue to reach the effective therapeutic level. The emerging tumor-targeted delivery technology can facilitate the precise enrichment of drugs in the tumor site. Apolipoprotein E (ApoE(159-167)2) binds to low-density lipoprotein receptor-related protein 1 (LRP-1) on the blood-brain barrier and helps it to specifically cross the BBB. Based on this, in this study, poly (ethylene glycol) (PEG) dimerized with ApoE(159-167)2 was used for the modification of PAH-AM, and amphiphilic PAH-AM-PEG-ApoE nanocarriers were successfully prepared. Among them, the PEG modification could effectively prolong the retention time of the nanoparticles in vivo and reduce the toxic side effects, while the ApoE(159-167)2 polypeptide could specifically penetrate the blood-brain barrier for intracerebral targeted delivery by binding to LRP-1. The nanocarrier further binds to small interfering RNA (siRNA) targeting PLK1, a key cell cycle factor, by electrostatic interaction to construct the nano-delivery system PAPA@siPLK1. In vitro experiments showed that the nanoparticles significantly inhibited the proliferation of U87MG glioma cells, induced apoptosis, and specifically silenced the mRNA and protein expression of PLK1. The results of in vivo animal experiments showed that PAPA@siPLK1 could effectively inhibit tumor growth and had potential brain permeability; The PAPA@siPLK1 nanocarrier delivery system developed in this study achieves PLK1 gene silencing through efficient siRNA delivery, providing an important basis for novel therapeutic strategies for glioma.