Emily J. Anglin, Ph.D. - US grants

PROJECT SUMMARY/ABSTRACT Visual impairment is a global epidemic affecting millions of individuals currently. A large portion of these individuals suffer from chronic age-related macular degeneration (AMD), characterized by progressive neovascularization and vascular leakage near the central region (macula) of the retina. Current treatments for AMD, including laser photocoagulation, photodynamic therapy, and surgery, only benefit patients in the advanced stages and temporarily alleviate the progression of the disease. The need for more effective therapies has fostered the development of anti-vascular endothelial growth factor (VEGF) treatments. Although anti- proliferative agents have shown improved efficacy, repeated injections with 6-8 week intervals are often required to maintain therapeutic efficacy of these drugs, leading to inconvenience, higher cost and risk of injection-related complications such as endophthalmitis and retinal detachment. The overall goal of this project is to develop a yearly or bi-yearly injectable ocular delivery system with the ability to prolong the release of active drug and to self-report the amount of drug left in the system simultaneously, reducing the occurrence of injection-related complications and the cost of frequent re-visitations and post-injection examinations. Spinnaker Biosciences has licensed this technology, which is based on utilizing photonic microparticles of electrochemically prepared porous silicon or oxidized porous silicon (porous silica) for intraocular drug delivery, from the University of California, San Diego. In this system, anti- proliferative drugs are hosted inside the carefully devised and biologically inert porous material, protecting the drugs from unwanted enzymatic digestions. The porous particles are also prepared with one or more distinct layers, which reflect distinctive optical spectra that change as the particles dissolve and release their drug payload. Our UCSD collaborators have demonstrated the key features important for the ophthalmic application; in particular, the ability to deliver a constant release profile of active antibody-based drug for several months, and the ability to non-invasively observe the residual capacity of the microparticles via ophthalmoscope. However, the particles have not been formulated for the optimal injection, drug delivery regimen, and therapeutic levels. In addition, the production methods used in the UCSD research laboratories are not of the scale, reproducibility, sterility, or consistency needed to support our planned clinical trials. This STTR Phase I project will transition and scale up the particle production and drug loading technology, and it will determine the optimal formulation and administration method to enable translation to clinical trials. Besides AMD, the proposed ocular delivery system can be formulated to accommodate a wide range of drugs (e.g. non-steroidal anti-inflammatory drugs, doxorubicin, etc.) used to treat serious eye diseases such as macular edema, uveitis and proliferative vitreoretinopathy (PVR). The findings in this study can be extrapolated to other therapeutic agents intended for treating other ocular disorders.

Abstract A significant limitation in the development of nanoparticle-based therapeutics is the lack of in vitro models that can predict in vivo behavior, in particular with respect to rate of release and steady state concentration of the therapeutic. This proposal focuses on development, testing, and validation of an in vitro device that can accurately predict therapeutic levels delivered from nanomaterials injected intravitreally or placed on the back of the eye. The testbed nanomaterial we will use is based on nanostructured porous silicon (pSi) and its composites with various biocompatible polymers. Porous silicon has been identified as an ideal drug carrier for ocular therapeutics. It has demonstrated excellent biocompatibility and biodegradability in vivo and versatile surface chemistry that enables incorporation of a wide range of drug types, including antibodies, oligonucleotides, and hydrophilic or hydrophobic small molecules. Although there has been significant progress in this area, testing candidate nanotherapeutic formulations in live animal eyes poses a challenge due to low drug levels in vitreous taps or expensive and time- consuming harvesting of the entire vitreous at each time point. For this proposal, we will design and construct a simulator that will mimic the vitreous to enable a more accurate correlation with in vivo drug release profiles than has been achieved previously. Formulations of pSi will be developed in collaboration with Spinnaker Biosciences, a small California company that has expertise in fabrication and testing of pSi particles for ocular therapeutics. Crosslinked hyaluronic acid and polyvinyl alcohol mixtures and copolymers will be used in conjunction with buffer solutions to imitate the viscous environment of the vitreous. Flow characteristics, viscosity, and temperature will be systematically varied for real-time and accelerated testing conditions. We will use a range of different pSi formulations to test nanoparticle degradation, dissolution, and drug release/leaching under a variety of experimental conditions. The results will be compared with in vivo tests of the same materials in rabbits. To provide additional correlative data, we will exploit the photonic properties of pSi to monitor its degradation and temporal drug release profile. The primary goal of the research is to develop a better understanding of the key in vitro characteristics needed to accurately mimic in vivo drug delivery in the eye.