Arginine-rich Peptide Coated PLGA Nanoparticles Enhance Polymeric Delivery of Antisense HIF1α-oligonucleotide to Fully Differentiated Stiff Adipocytes
- 6 Downloads
The purpose of this study was developing the new delivery system of antisense HIF1α oligodeoxynucleotide (ASO) into the stiff adipocytes. As the adipogenesis progressed, accumulating lipid droplet in cytosol lead adipocytes membrane stiffness and difficulties in the delivery of therapeutic agents into the cytosol. Hypoxia affects a number of biological functions including angiogenesis, apoptosis, inflammation, and adipogenesis. Hypoxia-inducible transcription factor-1 alpha (HIF1α) is a major transcription factor that controls metabolic and adipogenic gene expression under hypoxia. Controlling HIFα expression can be a promising therapy for obesity treatment.
The ASO was synthesized and used in a complex with polylactic-co-glycolic acid (PLGA) nanoparticles (NP). To enhance the cell-penetrating capacity, the PLGA-ASO-NP complex was coated with arginine-rich peptide (ARP) in different N:P molar ratios (PLGA-ASO-NP:ARP = 1: 1, 2: 1, 5: 1). To examine the intracellular and intranuclear delivery, these complexes were treated to fully differentiated adipocyte.
The PLGA-ASO-NP/ARP improved the efficacy of ASO-delivery into stiff adipocytes by increasing the cell surface charge, determined by the zeta potential, and forming polyplexes with small particle size. The proper N:P molar ratio of PLGA-ASO-NP/ARP synthesis was 5:1 with significantly improved gene delivery efficiency and intracellular uptake in adipocytes. Furthermore, PLGA-ASO-NP/ARP was stable in serum for 8 h compared to naked ASO.
These results suggest that the PLGA-ASO-NP/ARP can provide an effective and serum-stable gene-delivery system, especially for cells with a stiff cell membrane.
KeywordsArginine-rich peptide Hypoxia-inducible transcription factor-1α PLGA Adipogenesis Antisense oligonucleotide
Unable to display preview. Download preview PDF.
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (2017R1A2B4002611), and partly by the Technological innovation R&D program of SMBA (S2449311).
- 5.Le, T. D., Nakagawa, O., Fisher, M., Juliano, R. L. & Yoo, H. RGD Conjugated Dendritic Polylysine for Cellular Delivery of Antisense Oligonucleotide. J. Nanoc. 17, 2353–2357 (2017).Google Scholar
- 13.McClorey, G. & Banerjee, S. Cell-Penetrating Peptides to Enhance Delivery of Oligonucleotide-Based Therapeutics. Biomedicines 6 (2018).Google Scholar
- 14.Astriab-Fisher, A., Sergueev, D., Fisher, M., Shaw, B. R. & Juliano, R. L. Conjugates of antisense oligonucleotides with the Tat and antennapedia cell-penetrating peptides: effects on cellular uptake, binding to target sequences, and biologic actions. Pharm. Res. 19, 744–754 (2002).CrossRefGoogle Scholar
- 39.Pindiprolu, S., Chintamaneni, P. K., Krishnamurthy, P. T. & Ratna Sree Ganapathineedi, K. Formulation-optimization of solid lipid nanocarrier system of STAT3 inhibitor to improve its activity in triple negative breast cancer cells. Drug Dev. Ind. Pharm. 1–10 (2018).Google Scholar