Abstract
BackgroundDiabetic retinopathy is the most common complication in diabetic patients relates to high expression of VEGF and microaneurysms. Scutellarin (Scu) turned out to be effective against diabetes related vascular endothelial cell dysfunction. However, its clinical applications have been limited by its low bioavailability. In this study, we formulated and characterized a novel intestinal target nanoparticle carrier based on amphiphilic chitosan derivatives (Chit-DC-VB12) loaded with scutellarin to enhance its bioavailability and then evaluated its therapeutic effect in experimental diabetic retinopathy model.ResultsChit-DC-VB12 nanoparticles showed low toxicity toward the human colon adenocarcinoma (Caco-2) cells and zebra fish within concentration of 250 μg/ml, owing to good biocompatibility of chitosan. The scutellarin-loaded Chit-DC-VB12 nanoparticles (Chit-DC-VB12-Scu) were then prepared by self-assembly in aqueous solution. Scanning electron microscopy and dynamic light scattering analysis indicated that the Chit-DC-VB12-Scu nanoparticles were spherical particles in the sizes ranging from 150 to 250 nm. The Chit-DC-VB12-Scu nanoparticles exhibited high permeation in Caco-2 cell, indicated it could be beneficial to be absorbed in humans. We also found that Chit-DC-VB12 nanoparticles had a high cellular uptake. Bioavailability studies were performed in Sprague–Dawley rats, which present the area under the curve of scutellarin of Chit-DC-VB12-Scu was two to threefolds greater than that of free scutellarin alone. Further to assess the therapeutic efficacy of diabetic retinopathy, we showed Chit-DC-VB12-Scu down-regulated central retinal artery resistivity index and the expression of angiogenesis proteins (VEGF, VEGFR2, and vWF) of retinas in type II diabetic rats.ConclusionsChit-DC-VB12 nanoparticles loaded with scutellarin have better bioavailability and cellular uptake efficiency than Scu, while Chit-DC-VB12-Scu nanoparticles alleviated the structural disorder of intraretinal neovessels in the retina induced by diabetes, and it also inhibited the retinal neovascularization via down-regulated the expression of angiogenesis proteins. In conclusion, the Chit-DC-VB12 nanoparticles enhanced scutellarin oral delivery efficacy and exhibited potential as small intestinal target promising nano-carriers for treatment of type II diabetes induced-retinopathy.
Highlights
Diabetic retinopathy is the most common complication in diabetic patients relates to high expression of vascular endothelial growth factor (VEGF) and microaneurysms
We evaluated the release and pharmacodynamics of scutellarin via complexation with amphiphilic chitosan derivatives Chit-DC and Chit-DCVB12, which were developed in our previous study, and our results indicated that the amphiphilic chitosan derivatives and VB12 labeled process were able to increase the bioavailability and targeted release of scutellarin
Synthesis and structural analysis of vitamin B12‐modified amphiphilic chitosan derivatives Based on the synthesis method as illustrated in Fig. 2, the Chit-DC derivative was firstly synthesized using ethylcarbodiimide hydrochloride (EDC) as a coupling reagent at room temperature and its productivity is 86%
Summary
Diabetic retinopathy is the most common complication in diabetic patients relates to high expression of VEGF and microaneurysms. Scutellarin (Scu) turned out to be effective against diabetes related vascular endothe‐ lial cell dysfunction. Gao et al [14] reported that high glucose or hypoxia could induce expression of VEGF and proliferation of human retinal endothelial cells. Low oral bioavailability and low water solubility (0.16 mg/ml) [15] of scutellarin limited its’ therapeutic application [16]. In this regard, Xiao et al [17] increased the Papp(AP-BL) of scutellarin by 3.5 fold by using membranes over expressing several common transporters, which enhanced the transportation of scutellarin and improved the oral absorption of scutellarin
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