Nanosystems based on siRNA silencing HuR expression counteract diabetic retinopathy in rat

Pharmacol Res. 2016 Sep:111:713-720. doi: 10.1016/j.phrs.2016.07.042. Epub 2016 Jul 27.

Abstract

We evaluated whether specifically and directly targeting human antigen R (HuR), a member of embryonic lethal abnormal vision (ELAV) proteins family, may represent a new potential therapeutic strategy to manage diabetic retinopathy. Nanosystems loaded with siRNA silencing HuR expression (lipoplexes), consisting of solid lipid nanoparticles (SLN) and liposomes (SUV) were prepared. Photon correlation spectroscopy analysis, Zeta potential measurement and atomic force microscopy (AFM) studies were carried out to characterize the complexation of siRNA with the lipid nanocarriers. Nanosystems were evaluated by using AFM and scanning electron microscopy. The lipoplexes were injected into the eye of streptozotocin (STZ)-induced diabetic rats. Retinal HuR and VEGF levels were detected by Western blot and ELISA, respectively. Retinal histology was also carried out. The results demonstrated that retinal HuR and VEGF are significantly increased in STZ-rats and are blunted by HuR siRNA treatment. Lipoplexes with a weak positive surface charge and with a 4:1 N/P (cationic lipid nitrogen to siRNA phosphate) ratio exert a better transfection efficiency, significantly dumping retinal HuR and VEGF levels. In conclusion, we demonstrated that siRNA can be efficiently delivered into the rat retina using lipid-based nanocarriers, and some of the lipoplexes loaded with siRNA silencing HuR expression are potential candidates to manage retinal diseases.

Keywords: Diabetic retinopathy; HuR/ELAV; Liposomes; Solid lipid nanoparticles; VEGF; siRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / therapy*
  • Diabetic Retinopathy / etiology
  • Diabetic Retinopathy / genetics
  • Diabetic Retinopathy / metabolism
  • Diabetic Retinopathy / prevention & control*
  • ELAV-Like Protein 1 / genetics*
  • ELAV-Like Protein 1 / metabolism
  • Injections, Intraocular
  • Lipids / chemistry
  • Liposomes
  • Male
  • Nanomedicine / methods*
  • Nanoparticles
  • RNA Interference*
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics*
  • RNA, Small Interfering / metabolism
  • RNAi Therapeutics / methods*
  • Rats, Sprague-Dawley
  • Retina / metabolism*
  • Retina / pathology
  • Surface Properties
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • ELAV-Like Protein 1
  • Elavl1 protein, rat
  • Lipids
  • Liposomes
  • RNA, Small Interfering
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat