4.7 Article

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

期刊

JOURNAL OF NANOBIOTECHNOLOGY
卷 19, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s12951-021-00781-z

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

资金

  1. Prostate Cancer Foundation Young Investigator Award
  2. Scientific and Technological Research Council of Turkey (TUBITAK) [217S212]
  3. TUBITAK 2214-A Programme [1059B141700287]

向作者/读者索取更多资源

Researchers successfully developed novel cationic solid lipid nanoparticles carrying siRNA targeting EphA2 receptor, which showed enhanced gene silencing when co-administered with a histone lysine demethylase inhibitor, JIB-04. The delivery system demonstrated high transfection efficiency and holds promise for targeting other genes and cancer types in further in vitro and in vivo studies.
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.

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