A brain glioma gene delivery strategy by angiopep-2 and TAT-modified magnetic lipid-polymer hybrid nanoparticles

Abstract

Owing to the existence of the blood–brain barrier (BBB), most treatments cannot achieve significant effects on gliomas. In this study, synergistic multitarget Ang-TAT-Fe₃O₄-pDNA-(ss)373 lipid-polymer hybrid nanoparticles (LPNPs) were designed to penetrate the BBB and deliver therapeutic genes to glioma cells. The basic material of the nanoparticles was PCL₃₇₅₀-ss-PEG₇₅₀₀-ss-PCL₃₇₅₀, and is called (ss)373 herein. (ss)373 NPs, Fe₃O₄ magnetic nanoparticles (MNPs), DOTAP, and DSPE-PEG-MAL formed the basic structure of LPNPs by self-assembly. The Fe₃O₄ MNPs were wrapped in (ss)373 NPs to implement magnetic targeting. Then, the Angiopep-2 peptide (Ang) and transactivator of transcription (TAT) were coupled with DSPE-PEG-MAL. Both can enhance BBB penetration and tumor targeting. Finally, the pDNA was compressed on DOTAP to form the complete gene delivery system. The results indicated that the Ang-TAT-Fe₃O₄-pDNA-(ss)373 LPNPs were 302.33 nm in size. In addition, their zeta potential was 4.66 mV, and they had good biocompatibility. The optimal nanoparticles/pDNA ratio was 5 : 1, as shown by gel retardation assay. In this characterization, compared with other LPNPs, the modified single Ang or without the addition of the Fe₃O₄ MNPs, the penetration efficiency of the BBB model formed by hCMEC/D3 cells, and the transfection efficiency of C6 cells using pEGFP-C1 as the reporter gene were significantly improved with Ang-TAT-Fe₃O₄-pDNA-(ss)373 LPNPs in the magnetic field.