Zhu Xiaoshuang, Guo Xiaonan, Liu Dakan, Gong Yubin, Sun Jin, Dong Changxian
J Biomed Nanotechnol. 2017 Dec 1;13(12):1694-1705. doi: 10.1166/jbn.2017.2449.
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.
婴儿血管瘤是影响儿童的最常见肿瘤。尽管婴儿血管瘤是良性的，但仍可能导致发病和死亡。美国食品药品监督管理局唯一批准用于婴儿血管瘤的药物是盐酸普萘洛尔（Hemangeol™）；然而，其不良反应和高给药频率阻碍了其临床应用。血管内皮生长因子受体（VEGFR）对婴儿血管瘤的血管生成至关重要，因此被认为是婴儿血管瘤的一个有价值的治疗靶点。为了减少普萘洛尔的不良反应和高给药频率，我们开发了与抗VEGFR抗体偶联的载普萘洛尔纳米颗粒（PNP-VEGFR）作为一种控释和靶向释放系统来治疗婴儿血管瘤。在体外和体内研究了PNP-VEGFR的特性、抗血管瘤活性及其作用机制。所开发的PNP-VEGFR粒径小（约100nm）、药物包封率高（约60%），且能持续释药8天。PNP-VEGFR以VEGFR依赖的方式有效地与人脐静脉内皮细胞和人血管瘤内皮细胞结合，与未靶向的载普萘洛尔纳米颗粒（PNP）和普萘洛尔相比，产生了增强的细胞毒性作用和更强的VEGF表达抑制作用。值得注意的是，PNP-VEGFR在婴儿血管瘤中的体内治疗效果优于普萘洛尔和PNP，表现为血管瘤体积、重量和微血管密度显著降低，且没有任何明显的行为变化或体重减轻。PNP-VEGFR被证明能将普萘洛尔靶向递送至婴儿血管瘤并实现持续释放。因此，它是一种有前景的婴儿血管瘤治疗方法。
