Self-Assembling Tacrolimus Nanomicelles for Retinal Drug Delivery.

Vrinda Gote,Meshal Alshamrani,Abhirup Mandal,Dhananjay Pal

doi:10.3390/pharmaceutics12111072

Vrinda Gote, Meshal Alshamrani + Show 2 more

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https://doi.org/10.3390/pharmaceutics12111072

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Journal: Pharmaceutics	Publication Date: Nov 10, 2020
Citations: 22	License type: CC BY 4.0

Affiliation: University of Missouri–Kansas City

Abstract

Neovascular age-related macular degeneration (AMD) is characterized by an increase in reactive oxygen species (ROS) and pro-inflammatory cytokines in the retinal pigment epithelium cells. The primary purpose of this study was the development of a clear, tacrolimus nanomicellar formulation (TAC-NMF) for AMD. The optimized formulation had a mean diameter of 15.41 nm, a zeta potential of 0.5 mV, and an entrapment efficiency of 97.13%. In-vitro cytotoxicity studies revealed the dose-dependent cytotoxicity of TAC-NMF on various ocular cell lines, such as human retinal pigment epithelium (D407), monkey retinal choroidal endothelial (RF/6A) cells, and human corneal epithelium (CCL 20.2) cells. Cellular uptake and in-vitro distribution studies using flow cytometry and confocal microscopy, respectively, indicated an elevated uptake of TAC-NMF in a time-dependent manner. Biocompatibility assay using macrophage RAW 264.7 cell line resulted in low production of inflammatory cytokines such as IL-6, IL-1β and TNF-α after treatment with TAC-NMF. There was a decrease in ROS in D407 cells pre-treated with sodium iodate (ROS inducing agent) after treating with TAC-NMF and tacrolimus drug. Similarly, there was a reduction in the pro-inflammatory cytokines and VEGF-A in D407 cells pretreated with sodium iodate. This indicates that TAC-NMF could lower pro-inflammatory cytokines and ROS commonly seen in AMD.

Highlights

Age-related macular degeneration (AMD) is one of the most common back of the eye disorders in the United States [1,2,3,4]
The results obtained from analyzing formulations F1-F11 were added to the full factorial design of experiment in the JMP®® 10.0 software and a least square analysis of the independent variables on the dependent variables was performed (Table 2)
We developed and optimized a clear Tacrolimus nanomicellar formulation (TAC-NMF) solution having potential to be used as an intravitreal injection or a topical formulation for wet AMD

Summary

Introduction

Age-related macular degeneration (AMD) is one of the most common back of the eye disorders in the United States [1,2,3,4]. AMD can cause severe vision impairment and lead to vision loss It is one of the most imperative causes of blindness in people above 55 years of age, and it is estimated that more than 3.5 million people will be affected by this ocular disorder in the United States by 2030 [5]. AMD is characterized by an increase in reactive oxygen species (ROS) and pro-inflammatory cytokines in the RPE layer This results in a cascade of inflammatory response and development of tissue atrophy [9,10]. Inflammation in the RPE can lead to infiltration of macrophages and T cells [14] This further augments to upregulation of COX-2, ICAM-1, caspase 1, iNOS, nitric oxide, IL-1β, prostaglandin E2, VEGF-A, NF-kB and cytokines production [9,15]. Elevated oxidative stress followed by inflammation and angiogenesis results in AMD progression [17]

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