posted on 2023-12-06, 20:09authored byRita E. Atalor, Blake W. Dieckmann, John S. Penn, MD Imam Uddin
Circulating monocytes
migrate into the retina in response to inflammation
and neovascularization. Furthermore, under inflammatory conditions
such as diabetes, healthy monocytes become activated in the circulation.
However, the contribution of activated monocytes to neovascularization
is largely unknown. HIF-1α has been shown to contribute to the
pathogenesis of neovascularization. We describe here the synthesis
of a hybrid nanomaterial for targeted delivery and gene silencing
in activated monocytes that are associated with pathological neovascularization.
To test the gene silencing ability of AS-shRNA-lipids in vitro, we
used the probe to inhibit HIF-1α mRNA induced in mouse monocytes
by exposing them to hypoxia. In addition, we tested AS-shRNA-lipids
for inhibition of neovascularization in vivo using the mouse model
of oxygen-induced retinopathy (OIR). Significant reduction of neovascularization
was achieved in mouse OIR by targeting activated monocytes using intraperitoneal
injections of AS-shRNA-lipids. Expression of HIF-1α and CD14
mRNA were both inhibited in circulating cells, suggesting normalization
of the activated monocytes in P17 OIR animals treated with AS-shRNA-lipids.
We hypothesized that inhibition of HIF-1α mRNA in activated
monocytes may have a direct impact on VEGF expression in the retinal
tissues in vivo. We observed that VEGF mRNA expression was inhibited
in P17 retinal tissues after systemic treatment with HIF-1α-targeted
AS-shRNA-lipids. These findings may provide a framework for a strategy
to inhibit retinal neovascularization by targeting circulating activated
monocytes.