Development of EphA2 siRNA-loaded lipid nanoparticles and combination with a small‐molecule histone demethylase inhibitor in prostate cancer cells and tumor spheroids

Journal of Nanobiotechnology

Emir Bozkurt¹  Ezgi Oner²  Anne-Marie Baird³  Stephen P. Finn⁴  Bilge Debelec Butuner⁵  Mustafa Kotmakci⁵  Ayse Gulten Kantarci⁵  Steven G. Gray⁶ 

[1] Department of Genetics and Bioengineering, Faculty of Engineering, Izmir University of Economics, Balcova, Izmir, Turkey;Department of Histopathology and Morbid Anatomy, Sir Patrick Dun Translational Research Lab, St. James’s Hospital, Dublin, Ireland;Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey;Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Izmir Katip Celebi University, Balatcik, Izmir, Turkey;Department of Histopathology and Morbid Anatomy, Sir Patrick Dun Translational Research Lab, St. James’s Hospital, Dublin, Ireland;Thoracic Oncology Research Group, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, Ireland;Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland;Department of Histopathology and Morbid Anatomy, Sir Patrick Dun Translational Research Lab, St. James’s Hospital, Dublin, Ireland;Thoracic Oncology Research Group, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, Ireland;Department of Histopathology, Labmed Directorate, St. James’s Hospital, Dublin, Ireland;Cancer Molecular Diagnostics, Labmed Directorate, St. James’s Hospital, Dublin, Ireland;Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Bornova, Izmir, Turkey;Thoracic Oncology Research Group, Trinity Translational Medicine Institute, St. James’s Hospital, Dublin, Ireland;Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland;

关键词: EphA2;    Receptor tyrosine kinase;    siRNA;    Non‐viral gene delivery;    Cationic solid lipid nanoparticles;    DDAB;    DOTMA;    JIB-04;    Histone lysine demethylase inhibitor;    Prostate cancer;   

DOI  :  10.1186/s12951-021-00781-z

来源: Springer

【 摘 要 】

BackgroundsiRNAs hold a great potential for cancer therapy, however, poor stability in body fluids and low cellular uptake limit their use in the clinic. To enhance the bioavailability of siRNAs in tumors, novel, safe, and effective carriers are needed.ResultsHere, we developed cationic solid lipid nanoparticles (cSLNs) to carry siRNAs targeting EphA2 receptor tyrosine kinase (siEphA2), which is overexpressed in many solid tumors including prostate cancer. Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in prostate cancer cells. DDAB-cSLN showed better cellular uptake efficiency with similar silencing compared to commercial transfection reagent (Dharmafect 2). After verifying the efficacy of siEphA2-loaded nanoparticles, we further evaluated a potential combination with a histone lysine demethylase inhibitor, JIB-04. Silencing EphA2 by siEphA2-loaded DDAB-cSLN did not affect the viability (2D or 3D culture), migration, nor clonogenicity of PC-3 cells alone. However, upon co-administration with JIB-04, there was a decrease in cellular responses. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing by siEphA2-loaded nanoparticles was further increased with co-treatment.ConclusionsWe have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on prostate cancer cells and prostate cancer tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows great promise for targeting other genes and cancer types in further in vitro and in vivo studies.

【 授权许可】

CC BY