Delivery of antisense oligonucleotide using polyethylenimine-based lipid nanoparticle modified with cell penetrating peptide

Shuang Yang,Dandan Wang,Yaojun Sun,Bin Zheng

doi:10.1080/10717544.2019.1667453

Abstract

Efficient and stable delivery system of antisense oligonucleotide (ASO) is important and urgently needed. Here, an ASO delivery system, Lp-PPRP, which contains a cationic polymer based on PEI (branched, 25 kDa), named PEI-PC and a palmitic acid modified R8 (R8-PA) was prepared to deliver a kind of ASO, LOR-2501. The characteristics of the nanoparticles and the cellular uptake of LOR-2501 in HeLa cells and A549 cells were studied. Lp-PPRP showed suitable particle size and zeta potential to combine with LOR-2501; the particle size and zeta potential of Lp-PPRP/LOR were 276.87 ± 5.63 nm and 18.03 ± 0.25 mV. In vitro experiments suggested that Lp-PPRP had lower cytotoxic and higher transfection efficiency for delivering LOR-2501 compared with PEI. The addition of PEI-PC and R8-PA contributed to enhance the transfection efficiency of the nanoparticles. In HeLa cells and A549 cells, Lp-PPRP could transport LOR-2501 and down-regulate the level of R1 protein efficiently, and the R1 down regulations were 64.56% and 66.34%, respectively. Results suggested potential utility of Lp-PPRP in the development of ASO in tumor therapy.

Highlights

The technology of antisense oligonucleotide (ASO) has been widely used in the field of tumor therapy because it can inhibit the processes of transcription and translation (Wang et al, 2017; Golshirazi et al, 2018; Luna Velez et al, 2019; Raven et al, 2019)
When N/P ratios changed from 2:1 to 12:1; particle sizes were stable in the range of 6:1 to 10:1
The particle size and zeta potential distribution of Lp containing PEI-PC and R8-PA (Lp-PPRP)/LOR prepared by the optimized ratio were 276.87 ± 5.63 nm and 18.03 ± 0.25 mV, which were appropriate for ASO delivery

Summary

Introduction

The technology of antisense oligonucleotide (ASO) has been widely used in the field of tumor therapy because it can inhibit the processes of transcription and translation (Wang et al, 2017; Golshirazi et al, 2018; Luna Velez et al, 2019; Raven et al, 2019). R1 is an important target for the development of anti-tumor drugs (Yang et al, 2015b; Wu et al, 2018b). Efficient and stable delivery system is an effective solution (Yang et al, 2014; Cheng et al, 2017; Mori et al, 2018). High toxicity and low transfection efficiency limit the application of PEI (Zheng et al, 2019). Previous researches have indicated that hydrophobic modification was an effective means to improve the transfection efficiency and reduce the toxicity of PEI (Xie et al, 2013; Zheng et al, 2016; Dube et al, 2017; Feng et al, 2017)

Methods

Results

Conclusion