Nanotherapies for Targeted Treatment of Corneal Neovascularization - Project Summary Corneal neovascularization (CoNV) is a sight-threatening condition characterized by the growth of peri-corneal blood vessels into the normally avascular cornea, disrupting its normal anatomy and leading to corneal opacity. CoNV occurs in various corneal pathologies, including congenital corneal diseases, contact lens-related hypoxia, inflammatory disorders, chemical burns, limbal stem cell deficiency, and corneal graft rejection. Current treatments include medication and surgery. Options include amniotic membrane transplantation, argon laser, photodynamic therapy, fine needle diathermy, cautery, and pharmacotherapies such as topical steroids, immunomodulatory agents, calcineurin inhibitors, and non-steroidal anti-inflammatory drugs (NSAIDs). However, these are not consistently effective, often have adverse effects, and limited clinical efficacy. Cornea transplantation is considered as utmost solution for CoNV, but existing neovascularization at the border of the cornea may rapidly invade the new graft if left untreated. There is no curative therapy available for CoNV necessitating the need to develop novel therapeutic approaches. Growth factors such as vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF), play key roles in the regulation of angiogenesis. Moreover, Src family kinase is the main player in angiogenic signaling cascades activated by these growth factors. Attenuating angiogenesis with inhibitors such as Dasatinib (Dasa) with dual PDGF receptor and Src family kinase inhibiting effects is a promising approach but suffers from drug delivery challenges and side-effects. We synthesized a unique trehalose-based dendrimer (Tre-D), that selectively targets blood vessels in cornea when administered via subconjunctival (SCJ) injection in a rat alkali burn model of CoNV. The Tre-D technology is designed to deliver anti-angiogenic therapies selectively to the blood vessels in cornea with reduced side-effects, and simultaneously achieve in vivo stability, low immunogenicity, high water solubility, ease of scalability, and flexibility in single or multiple drugs delivery. Importantly, a single SCJ administration (1µg, 50µL) of a conjugate of Tre-D with Dasa (Tre-D-Dasa) significantly suppresses neovascularization in rats with alkali burn induced CoNV compared to the free Dasa and Tre-D controls. Building on these positive preliminary results, and the pathology specific targeting of the Tre-D technology, the goal of this R01 proposal is to develop Tre-D-Dasa and validate its efficacy to treat pathological neovascularization. This will be achieved through the following specific aims: Aim 1: Synthesize and characterize Tre-D-Dasa and Tre-D-Dasa-Cy5 conjugates; Aim 2: Assess biodistribution, pharmacokinetics (PK), and toxicity of Tre-D-Dasa in the alkali burn rat CoNV model; and Aim 3: Determine the dose-response efficacy of Tre-D-Dasa in two clinically relevant models of CoNV (rat alkali burn and suture induced CoNV models).
