Theranostic Nanovesicles for Ocular Angiogenesis Therapy

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The current standard of care for wet age-related macular degeneration (AMD) with intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors has transformed the treatment paradigm. However, many AMD patients with choroidal neovascularization (CNV) either fail to respond to anti-VEGF therapy or suffer from complications associated with repeated intravitreal injections. Therefore, there is great need for developing alternative treatment modalities, including novel therapeutic agents and delivery methods, to combat CNV for patients with AMD. The selective expression of certain integrins on choroidal and retinal neovasculature makes integrin an ideal target, while delivery of integrin antagonists can be engineered using stem cell-derived nanovesicle system that is biocompatible and amenable for crossing the ocular barriers. We hypothesize that modification of the stem cell-derived, superparamagnetic iron oxide particle (SPIO)-labeled exosomes to deliver an integrin antagonist will provide a potent theranostic agent to effectively inhibit or regress CNV with the ability to directly visualize and quantitatively assess drug distribution in vivo. In Specific Aim 1, we will develop and fully characterize the nanovesicle formulations and test their cytotoxicity, antiangiogenic property, as well as magnetic particle imaging (MPI) sensitivity. In Specific Aim 2, we will test the hypothesis that the engineered nanovesicle system improves the therapeutic efficacy of CNV in vivo and enables MPI imaging for longitudinal quantification of drug distribution. In this aim, we will determine the effect of SPIO-labeled, drug-conjugated nanovesicles on Iaser-induced CNV and analyze the kinetics of drug distribution by noninvasive MPI imaging. The proposed study brings a unique combination of expertise in ophthalmology, drug delivery, MPI imaging, and animal model of retinal diseases, to address the critical challenges for efficient drug delivery into the posterior segment of the eye. Successful completion of the proposed activities will have vast ramifications for advancing the development of stem cell-derived nanovesicles as novel theranostic agent for treating ocular vascular diseases and other angiogenesis-related disorders.