PurposeAge-related macular degeneration is a multifactorial disease involving inflammation and choroidal neovascularization. Vascular endothelial growth factor (VEGF) has been regarded as a potential therapeutic target to treat choroidal neovascularization. Dexamethasone can interfere with the expression or action of VEGF while bevacizumab targets and combines with VEGF. We propose electrostatically-conjugated bevacizumab-bearing dexamethasone-loaded poly (D,L-lactide-co-glycolide)/polyethylenimine nanoparticles (eBev-DPPNs) for angiogenic combination treatment of ocular diseases.MethodsWe prepared a novel nanoparticle composed of poly (D, L-lactide-co-glycolide) and polyethylenimine and loaded the nanoparticles with dexamethasone. Bevacizumab was adsorbed onto the surfaces of the nanoparticles by electrostatic interactions. The eBev-DPPNs were evaluated according to their size, polydispersity index, zeta potential, morphology, drug loading, release behavior, and stability. The structural stability of bevacizumab on the surface of the nanoparticles was also analyzed. Subsequently, angiogenesis was investigated in the presence of the eBev-DPPNs using cell apoptosis, wound healing, Transwell invasion, and tube formation assays on the human umbilical vein endothelial cells (HUVECs) in vitro and chick embryo chorioallantoic membrane assay in vivo. The eBev-DPPNs intravitreal injection was applied in the laser-induced rabbit choroidal neovascularization (CNV) model to confirm the role for potential intravitreal applications.ResultsThe eBev-DPPNs was about 200 nm in diameter, with a narrow diameter distribution, and the surface charge was neutral (0.85 ± 0.37mV), which made the eBev-DPPNs stable under physiological conditions. The apoptosis, migration, invasion, and tube formation assays showed that the eBev-DPPNs had a good anti-angiogenic effect on HUVECs. The eBev-DPPNs also provided a strong inhibitory effect on VEGF secretion from HUVECs. Moreover, in vivo chick embryo chorioallantoic membrane assay showed eBev-DPPNs greatly reduced the amount of blood vessels. The leakage area of CNV decreased in the eBev-DPPNs group on rabbit CNV model.ConclusionThe eBev-DPPNs are a promising novel anti-angiogenesis therapeutic for potential intravitreal applications such as age-related macular degeneration.
Vascular endothelial growth factor (VEGF) expression increased significantly in the pathogenesis of age-related macular degeneration, which induced the formation of pathological blood vessels. Dexamethasone is an exogenous anti-angiogenic drug while bevacizumab is an endogenous anti-angiogenic drug. They both have been widely used in ophthalmology. However, independent administration is not enough to completely block the development of choroidal neovascularization (CNV), and the number of eyes vitreous injections is limited. Reasonable combination of drugs may produce significantly better therapeutic effect than single drug treatment. The cyclic RGD (cRGD) peptide has a particularly high affinity with retinal pigment epithelial cells, where VEGF secretes from. In this study, we prepared nanoparticles of bevacizumab and dexamethasone with cRGD peptide as the target (aBev/cRGD-DPPNs). The particle size of the aBev/cRGD-DPPNs was 213.8 ± 1.5 nm, SEM results showed that the nano-carriers were well dispersed and spherical. The cell uptake study demonstrated the selectivity of the aBev/cRGD-DPPN to ARPE-19 with αVβ3 over expressed. The aBev/cRGD-DPPNs had a better apoptosis induction effect and an obvious inhibitory effect on migration, invasion, and capillary-like structures formation of human umbilical vein epithelial cells. The fluorescein fundus angiography study, immunohistochemistry and histopathological evaluation showed the aBev/cRGD-DPPNs greatly reduced the development of CNV on a rabbit model.
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