Systemic targeting of aberrant neovascular tufts using trehalose-dendrimer nanocarriers for the treatment of proliferative retinopathies.

Rationale: Proliferative retinopathies are the leading causes of blindness worldwide. Current treatment paradigms rely heavily on intravitreal injections of anti-vascular endothelial growth factor A (anti-VEGFA) agents, which, despite their efficacy, are associated with ocular complications and patient discomfort. To address these challenges, we have developed a novel mixed-layered trehalose-functionalized dendrimer (Tre-D) conjugated with Axitinib, a multi-receptor tyrosine kinase inhibitor, (Tre-D-Axitinib) for systemic delivery to aberrant neovascular tufts in retina.

Methods

Tre-D is synthesized through a scalable and convenient synthetic methodology using click chemistry. The in vitro cytocompatibility, uptake and angiogenesis assays are carried out in Human Retinal Microvascular Endothelial Cells (HRMECs), Human umbilical vein endothelial cells (HUVECs) and macrophages (RAW-Blue). The in vivo uptake and efficacy of Tre-D-Axitinib are evaluated in a mouse model of oxygen induced retinopathy (OIR) via intraperitoneal (IP) administration of the treatment.

Results

The Tre-D demonstrates inherent targeting to neovascular tufts in an OIR mouse model. Tre-D-Axitinib leads to increased vaso-obliteration in the ischemic retina. The IP administration of Tre-D-Axitinib effectively reduces pathological retinal neovascularization, tuft formation, and vessel anastomoses while showing minimal off-target effects and rapid renal clearance. Mechanistic studies reveal that Tre-D-Axitinib inhibits VEGFA-induced proliferation, migration, and angiogenesis in human retinal endothelial cells.

Conclusions

To date, there are no organic nanoparticles that localize selectively in aberrant neovascular tufts at the site of pathology in retina when systemically administered. By eliminating the need for invasive intravitreal injections and addressing systemic toxicities, Tre-D-Axitinib introduces a novel systemic nanotherapeutic strategy with broad implications for treating ischemic retinopathies.