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

Abstract

Background: siRNAs 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. Results: Here, 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 (PCa). Using DDAB cationic lipid instead of DOTMA reduced nanoparticle size and enhanced both cellular uptake and gene silencing in PCa 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 and 3D), migration, and clonogenicity of PC-3 cells alone. However, upon co-administration, there was a decrease in the aforementioned cellular responses due to JIB-04. Furthermore, JIB-04 decreased EphA2 expression, and thus, silencing efficiency of siEphA2-loaded nanoparticles was further increased with co-treatment. Conclusions: We have successfully developed a novel siRNA-loaded lipid nanoparticle for targeting EphA2. Moreover, detailed preliminary results of the effects of JIB-04, alone and in combination with siEphA2, on PCa cells and tumor spheroids were presented for the first time. Our delivery system provides high transfection efficiency and shows a great promise for targeting other genes and cancer types in further in vitro and in vivo studies.

Co-Delivery of siRNA and Docetaxel to Cancer Cells by NLC for Therapy

“…Although there are many publications in the literature stating that the expression levels of EpH receptors increased in cancer types such as prostate, lung, esophagus, breast, colon, and ovary, the number of studies on the decrease of these expressions with siRNAs is insufficient. Those studies are generally carried out on cancer cells such as prostate, , ovary, − glioma, NSCLC, breast, , squamous-cell carcinoma of the head and neck, , and mesothelioma, where EphA2 is downregulated with siRNA and ASOs in the Eph family. This is because EphA2 is a therapeutic target in many types of cancer, especially since it is associated with poor prognosis, increased metastasis, and decreased survival .…”