Assessment of a New Nanostructured Microemulsion System for Ocular Delivery of Sorafenib to Posterior Segment of the Eye

被引:15
作者
Santonocito, Manuela [1 ]
Zappulla, Cristina [1 ]
Viola, Santa [1 ]
La Rosa, Luca Rosario [1 ]
Solfato, Elena [1 ]
Abbate, Ilenia [1 ]
Tarallo, Valeria [2 ]
Apicella, Ivana [2 ]
Platania, Chiara Bianca Maria [3 ]
Maugeri, Grazia [3 ]
D'Agata, Velia [3 ]
Bucolo, Claudio [2 ]
De Falco, Sandro [2 ]
Mazzone, Maria Grazia [1 ]
Giuliano, Francesco [1 ]
机构
[1] SIFI SpA, Res Preclin Dev & Patents, I-95025 Catania, Italy
[2] CNR, Inst Genet & Biophys Adriano Buzzati Traverso, I-80131 Naples, Italy
[3] Univ Catania, Sch Med, Dept Biomed & Biotechnol Sci, I-95123 Catania, Italy
关键词
ocular drug delivery system; retina; angiogenesis; anti-VEGF; tyrosine kinase inhibitors; sorafenib; eye drops; ENDOTHELIAL GROWTH-FACTOR; ISCHEMIA-REPERFUSION INJURY; MACULAR DEGENERATION; CHOROIDAL NEOVASCULARIZATION; GENE-EXPRESSION; VEGF; TOXICITY; DISEASE; SAFETY; ANGIOGENESIS;
D O I
10.3390/ijms22094404
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Eye drop formulations allowing topical treatment of retinal pathologies have long been sought as alternatives to intravitreal administration. This study aimed to assess whether a novel nanostructured microemulsions system (NaMESys) could be usefully employed to deliver sorafenib to the retina following topical instillation. NaMESys carrying 0.3% sorafenib (NaMESys-SOR) proved to be cytocompatible in vitro on rabbit corneal cells, and well-tolerated following b.i.d. ocular administration to rabbits during a 3-month study. In rats subject to retinal ischemia-reperfusion, NaMESys-SOR significantly inhibited retinal expression of tumor necrosis factor-alpha (TNF alpha, 20.7%) and inducible nitric oxide synthase (iNos, 87.3%) mRNAs in comparison to controls. Similarly, in streptozotocin-induced diabetic rats, NaMESys-SOR inhibited retinal expression of nuclear factor kappa B (NF kappa B), TNF alpha, insulin like growth factor 1 (IGF1), IGF1 receptor (IGF1R), vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2) mRNAs by three-fold on average compared to controls. Furthermore, a reduction in TNF alpha, VEGFR1 and VEGFR2 protein expression was observed by western blot. Moreover, in mice subject to laser-induced choroidal neovascularization, NaMESys-SOR significantly inhibited neovascular lesions by 54%. In conclusion, NaMESys-SOR was shown to be a well-tolerated ophthalmic formulation able to deliver effective amounts of sorafenib to the retina, reducing proinflammatory and pro-angiogenic mediators in reliable models of proliferative retinopathies. These findings warrant further investigations on the full therapeutic potential of NaMESys-SOR eye drops, aiming to address unmet needs in the pharmacotherapy of retinal neovascular diseases.
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页数:17
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