Promotion of Propranolol Delivery to Hemangiomas by Using Anti-VEGFR Antibody-Conjugated Poly(lactic-co-glycolic acid) Nanoparticles.

Infantile hemangiomas are the most common tumors affecting children. Although infantile hemangiomas are benign, they could result in morbidity and mortality. The only US Food and Drug Administration-approved drug for infantile hemangiomas is propranolol hydrochloride (Hemangeol™); however, its adverse effects and high frequency of administration hamper its clinical application. Vascular endothelial growth factor receptor (VEGFR) is crucial to the angiogenesis of infantile hemangiomas, and thus it is considered a valuable therapeutic target for infantile hemangiomas. To reduce the adverse effects and high administration frequency of propranolol, we developed propranolol-loaded nanoparticles conjugated with anti-VEGFR antibody (PNP-VEGFR) as a controlled- and targeted-release system to treat infantile hemangiomas. The characteristics, anti-hemangioma activity, and mechanisms of PNP-VEGFR were examined in vitro and in vivo. The developed PNP-VEGFR exhibited a small size (∼100 nm), drug encapsulation efficiency (∼60%), and sustained drug release for 8 days. PNP-VEGFR was efficiently bound to human umbilical vein endothelial cells and human hemangioma endothelial cells in a VEGFR-dependent manner, resulting in enhanced cytotoxic effects and stronger inhibition of VEGF expression, compared to that of the untargeted propranolol-loaded nanoparticles (PNP) and propranolol. Notably, the in vivo therapeutic effects of PNP-VEGFR in infantile hemangiomas were superior to that of propranolol and PNP, as reflected by significantly reduced hemangioma volume, weight, and microvessel density, without any noticeable behavioral changes or weight loss. PNP-VEGFR was shown to provide targeted delivery and sustained release of propranolol to infantile hemangiomas. Therefore, it represents a promising treatment for infantile hemangiomas.