Abstract
Prolonged uncontrolled hyperglycemia is reported to lead to a chronic progressive disease called diabetic retinopathy (DR). It is associated with and characterized by neurodegeneration, increased vascular permeability, progressive vascular occlusion, followed by neovascularization at later stages due to increased expression of vascular endothelial growth factor (VEGF) and proliferation of basal epithelial cells. Celecoxib is reported to be useful in the treatment of DR due to its anti-VEGF activity and anti-proliferative effects on the retinal pigment epithelial (RPE) cells. Another drug memantine is reported to prevent the neurodegeneration in DR by blocking the overexcitation of N-Methyl-D-aspartate (NMDA) receptors. Thus, the simultaneous administration of both the drugs would provide a complete neurovascular treatment for DR as the current therapy targets only anti-VEGF activity. Furthermore, this study used conjugation of reactive oxygen species (ROS) sensitive moiety which triggered the release of incorporated drugs in response to ROS in DR. Beta-cyclodextrin was conjugated with a ROS sensitive moiety (Ox-β-cyclodextrin), 4-(hydroxymethyl) phenylboronic acid pinacol ester (PBAP) and was characterized by FTIR and NMR. Nanoparticles were prepared from Ox-β-cyclodextrin by nanoprecipitation. The size of the nanoparticles and the surface charge was found to in the range of 230 to 295 nm and -15 to -20 mV, respectively. An LC-MS/MS-based analytical method was developed to quantify both drugs simultaneously in aqueous matrix which was validated as per the USP guidelines. The developed analytical method was used to determine drug load and its release from nanoparticles. The drug load of celecoxib and memantine was found to be 9.64±0.57% and 4.80±1.18%, respectively. The drug release from the nanoparticles was found to be significantly higher (p<0.05) in the presence of ROS. MTT study did not indicate any significant (p<0.05) difference for cell viability between blank nanoparticles or drug loaded nanoparticles and blank (growth media). Future studies should attempt to increase the drug load and further extend the period of sustained release. The successful outcomes of this kind of study would provide a better DR treatment as well as its prevention or delaying the appearance of disease symptoms. Such a successful outcome will help 126.6 million DR patients in the world.