Prenatal VEGF Nanodelivery Reverses Congenital Diaphragmatic Hernia-associated Pulmonary Abnormalities

Abstract

Rationale: Congenital diaphragmatic hernia (CDH) results in lung hypoplasia. In severe cases, tracheal occlusion (TO) can be offered to promote lung growth. However, the benefit is limited, and novel treatments are required to supplement TO. VEGF (vascular endothelial growth factor) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known. Objectives: To investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology. Methods: Fetal lungs from patients with CDH were used to determine pulmonary morphology and VEGF expression. A novel human ex vivo model of fetal lung compression recapitulating CDH features was developed and used to determine the effect of exogenous VEGF supplementation. A nanoparticle-based approach for intrapulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds, which was tested in experimental CDH in vivo. Measurements and Main Results: VEGF expression was downregulated in the distal pulmonary epithelium of human CDH fetuses in conjunction with attenuated cell proliferation. The compression model resulted in impaired branching morphogenesis similar to CDH and downregulation of VEGF expression in conjunction with reduced proliferation of terminal bud epithelial progenitors; these could be reversed by exogenous supplementation of VEGF. Prenatal delivery of VEGF with the functionalized nanodiamond VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodeling that was complementary to that achieved by TO alone with appearances comparable to healthy controls. Conclusions: This innovative approach could have a significant impact on the treatment of CDH.

Keywords: VEGF; alveolar epithelium; congenital diaphragmatic hernia; mechanical compression; nanoparticles.