Combined Therapy of Experimental Autoimmune Uveitis by a Dual-Drug Nanocomposite Formulation with Berberine and Dexamethasone

Chang Huang,1,2,* Zhutian Zhang,1,2,* Jifeng Gu,3,* Dan Li,1,2 Shunxiang Gao,1,2 Rong Zhang,1,2 Rong Shi,4 Jianguo Sun1,2 1Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, 200031, People’s Republic of China; 2NHC Key Laboratory of Myopia, Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, 200031, People’s Republic of China; 3Department of Pharmacy, Eye & ENT Hospital, Shanghai Key Laboratory of Bioactive Small Molecules, Fudan University, Shanghai, 200031, People’s Republic of China; 4Science and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianguo Sun, Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China, Email jgsun@fudan.edu.cn Rong Shi, Science and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China, Email rongshi56@126.comPurpose: Autoimmune uveitis is a kind of sight-threatening ocular and systemic disorders. Recent treatments on autoimmune uveitis still remain many limitations due to extreme complexity and undetermined pathogenesis. In this study, a novel dual-drug nanocomposite formulation is developed to treat experimental autoimmune uveitis by a combined and sustained therapy method.Methods: The dual-drug nanocomposite formulation is constructed by integrating berberine (BBR)-loaded mesoporous silica nanoparticles (MSNs) into dexamethasone (DEX)-loaded thermogel (BBR@MSN-DEX@Gel). The BBR@MSN-DEX@Gel is characterized by transmission electron microscopy, dynamic light scattering, Fourier transform infrared spectrometer and rheometer. The in vitro drug release profile, cytotoxicity and anti-inflammation effectiveness of BBR@MSN-DEX@Gel on lipopolysaccharide-stimulated human conjunctival epithelial cells are investigated. After the in vivo drug release profile and biosafety of the dual-drug nanocomposite formulation are confirmed, its treatment effectiveness is fully assessed based on the induced experimental autoimmune uveitis (EAU) Lewis rat’s model.Results: The dual-drug nanocomposite formulation has good injectability and thermosensitivity, suitable for administration by an intravitreal injection. The BBR@MSN-DEX@Gel has been found to sustainably release both drugs for up to 4 weeks. The carrier materials have minimal in vitro cytotoxicity and high in vivo biosafety. BBR@MSN-DEX@Gel presents obviously anti-inflammatory effectiveness in vitro. After administration of BBR@MSN-DEX@Gel into Lewis rat’s eye with EAU by an intravitreal injection, the nanocomposite formulation significantly suppresses inflammatory reaction of autoimmune uveitis via a dual-drug combined and sustained therapy method, compared with the equivalent dose of single-component formulations.Conclusion: BBR@MSN-DEX@Gel serves as a promising dual-drug nanocomposite formulation for future treatment of autoimmune uveitis.Keywords: nanocomposite formulation, combined and sustained therapy, dexamethasone, berberine, experimental autoimmune uveitis