<p>Anti-Angiogenic Activity Of Bevacizumab-Bearing Dexamethasone-Loaded PLGA Nanoparticles For Potential Intravitreal Applications</p>

Abstract

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.

Cyclic RGD Peptide Targeting Coated Nano Drug Co-Delivery System for Therapeutic Use in Age-Related Macular Degeneration Disease

“…The aBev/cRGD-DPPNs were prepared by the adsorption method based on the method reported before [ 36 ]. A certain mass of bevacizumab and the cRGD-DPPNs were co-dispersed in PBS (pH 8.0) for 2 h at 25 °C.…”

“…The tube formation assay of capillary-like structures inhibition was performed as described previously [ 36 , 38 ]. The 300 μL matrix gel (8.6 mg/mL) was added to the 24-well plates on ice and kept at 37 °C for 30 min to polymerize into the membrane.…”

“…The aBev/cRGD-DPPNs were prepared by the adsorption method based on the method reported before [36]. A certain mass of bevacizumab and the cRGD-DPPNs were co-dispersed in PBS (pH 8.0) for 2 h at 25 • C. Ultrafiltration tubes (MWCO 300 kDa) were used to remove unconnected bevacizumab and salt ions from the solution.…”

Polymeric Nanoparticles for Drug Delivery: Recent Developments and Future Prospects

“…Qiu et al [ 35 ] proved that the use of these micelles improved retinal dysfunctions, inhibited retinal leukostasis, diminished retinal vascular leakage and regulated the over expression of vascular endothelial growth factor (VEGF) at eight weeks after the application. Lui et al [ 36 ] described a similar PLGA/PVA based on micelles to treat choroidal neovascularization. In this case, the polymer system also included polyethyleneimine (PEI) to incorporate positive charges in the NP, while the medication was a combination of dexamethasone and bevacizumab, which can interact with the positive charges of PEI.…”

Ocular Drug Delivery to the Retina: Current Innovations and Future Perspectives

“…Ye et al prepared PLGA nanoparticles loaded with bevacizumab that were administered intravitreally into rabbit eyes; a substantial increase in the following pharmacokinetic parameters was achieved: intravitreal half-lives, mean concentration, and bioavailability compared with those of the free drug [ 99 ]. After developing dexamethasone-loaded PLGA/PEI nanoparticles with conjugated bevacizumab for a CNV model, Liu et al proposed a strong anti-angiogenic effect as demonstrated via in vitro and in vivo studies [ 100 ].Qiu et al designed fenofibrate-loaded PLGA-nanoparticles that were injected intravitreally into the eyes of rats with diabetic retinopathy and a neovascularization model. Accordingly, reduction of retinal vascular leakage, suppression of VEGF and CNV formation, and inhibition of retinal leukocytosis were observed [ 101 ].…”