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. 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. Conclusions We 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.

We aimed to develop nanostructured lipid carriers (NLCs) displaying similar characteristics-particle size, polydispersity index, and zeta potential-with the model solid lipid nanoparticles (SLNs) for better comparability. By considering the hydrophilic-lipophilic balance (HLB) values of solid and liquid lipids, five out of six NLCs and eight out of eight cationic NLCs (cNLCs) were successfully prepared with similar characteristics to their precursor SLN and cationic SLNs (cSLNs), respectively. Among cationic formulations, two cSLNs containing different surfactant/co-surfactant concentrations (4% and 8% S/CoS; w/w) and their cNLC versions prepared with Labrafac lipophile WL 1349 (LWL) or Labrafac PG were selected to compare cytotoxicity, stability, and nucleic acid binding ability. All formulations are well-tolerated by L-929 cells, cSLNs being least toxic. The formulations containing 4% S/CoS had higher stability after 24months. All nanoparticles formed complexes with pDNA (Binding ability: cNLCs>cSLNs). cSLN and LWL-cNLC containing 4% S/CoS showed the highest pDNA binding capacity in each group, and their spherical/oval shape was revealed by electron microscopy. However, they did not form complexes with siRNA. The developed approach has the potential to simplify the production of (c)NLCs having similar physicochemical properties with the optimum (c)SLN and may provide better insight for (c)SLN vs. (c)NLC comparison studies.

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