Endothelial-specific targeting of RhoA signaling via CD31 antibody-conjugated nanoparticles

Existing Vascular Endothelial Growth Factor (VEGF)-oriented anti-angiogenic approaches are known for their high potency. However, significant side effects associated with their use drive the need for novel anti-angiogenic strategies. The small GTPase RhoA is an established regulator of actin cytoskeletal dynamics. Previous studies have highlighted the impact of endothelial RhoA pathway on angiogenesis. Rho-associate kinase (ROCK), a direct RhoA effector, is potently inhibited by Fasudil, a clinically-relevant ROCK inhibitor. Here, we aimed to target the RhoA signaling in endothelial cells by generating Fasudil-encapsulated CD31-targeting liposomes as a potential antiangiogenic therapy. The liposomes presented desirable characteristics, preferential binding to CD31-expressing HEK293T cells and to endothelial cells, inhibited stress fiber formation and cytoskeletal-related morphometric parameters and inhibited in vitro angiogenic functions. Overall, this work shows that the nanodelivery-mediated endothelial targeting of RhoA signaling can offer a promising strategy for angiogenesis inhibition in vascular-related diseases. Significance Statement Systemic administration of anti-angiogenic therapeutics induces side effects unrelated to the treatment tissues. We, among others, have shown the impact of the RhoA signaling in the endothelial cells and their angiogenic functions. Here, to minimize potential toxicity, we generated CD31-targeting liposomes with encapsulated Fasudil, a clinically-relevant Rho kinase inhibitor and successfully targeted endothelial cells. In this proof-of-principle study, the efficient Fasudil delivery, its impact on the endothelial signaling, morphometric alterations and angiogenic functions verifies the benefits of site-targeted anti-angiogenic therapy.

 

Comments：

Targeting the RhoA signaling in endothelial cells through Fasudil-encapsulated CD31-targeting liposomes presents a promising anti-angiogenic strategy for minimizing potential toxicity in vascular-related diseases.

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S1573	Fasudil HCl	Fasudil HCl, a potent and selective inhibitor of Rho kinase, displays less potent inhibiton over PKA, PKG, PKC and MLCK with Ki of 1.6, 1.6, 3.3, and 36 μM in cell-free assays, respectively. Fasudil is also a calcium channel blocker.

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Autophagy MLCK Rho PKG Calcium Channel PKA PKC ROCK