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A New Approach of Delivering siRNA to the Cornea and its Application for Inhibiting Herpes Simplex Keratitis

[ Vol. 14 , Issue. 9 ]

Author(s):

Z. Li, F. Duan, L. Lin, Q. Huang and K. Wu   Pages 1215 - 1225 ( 11 )

Abstract:


Small interfering RNA (siRNA) is a potential agent for the treatment of ocular surface diseases. Previous studies delivered siRNA by directly injecting siRNA into cornea or conjunctiva. In the present study we sought to explore an alternative approach to deliver siRNA into mouse cornea via eye drops that contains cy3-labeled siRNA (cy3-siRNA) and different cationic complexing agents and to evaluate the effects of siRNA targeting HSV-1 ICP4 gene (ICP4-siRNA) on mouse herpes simplex keratitis (HSK). Cy3-siRNA was mixed with Lipofectamine 2000, EntransterTM-in vivo, polyethyleneimine (PEI) or PEO-PPO-PEO polymers at different ratios. The efficacy of delivery was analyzed after topical application of the complexes to normal, EDTA treated, and epithelial scraped cornea of BALB/c mouse eyes. Compared to the other delivery agents and schedules, PEI at 0.75 mg/ml with 20 μM cy3-siRNA complex delivered eight times daily for two days was the most efficient as revealed by its production of the greatest fluorescence in cornea epithelial cells. In mouse HSK, the application of ICP4-siRNA+PEI eye drops reduced the damage to the corneal epithelia and decreased viral VP16 expression in the corneal tissue. These results proved the idea that siRNA can be formulated into eye drops with carriers for effective delivery into the cornea and that the formulated eye drops containing ICP4-siRNA can inhibit HSV-1 replication in the mouse corneas.

Keywords:

Cornea, eye drops, herpes simplex virus type 1, infected cell protein 4, polyethyleneimine, siRNA.

Affiliation:

Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, P.R. China.



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