Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250012, China; Department of Oral and Maxillofacial Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250012, China.
Department of Oral and Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Acta Biomater. 2020 Apr 15;107:272-285. doi: 10.1016/j.actbio.2020.02.033. Epub 2020 Mar 4.
Infantile hemangioma is one of the most common vascular tumors, which might result in morbidity and mortality without timely intervention. Propranolol is currently the first-line therapy for hemangiomas, but its potential side effects and high frequency of administration make it urgent to develop a suitable drug delivery system for propranolol. In the present study, we formulated a propranolol delivery system based on mesoporous silica nanoparticles (PRN@MSN) and investigated the interplay between autophagic activities mediated by nanoparticles and improved therapeutic efficacy of PRN@MSN. The results showed that PRN@MSN nanoparticles exhibited higher cytotoxicity compared with free propranolol in vitro and in vivo, which could induce excessive autophagosome accumulation through increased autophagosome formation and impaired autophagic degradation. Inhibition of autophagy in the early stage could attenuate the cytotoxicity of PRN@MSN. ROS generation was essential for nanoparticle-mediated autophagy and cytotoxicity, and PRN@MSN-induced autophagy dysfunction could enhance endoplasmic reticulum (ER) stress in hemangioma stem cells. Our study revealed a promising PRN delivery system based on a mesoporous silica nanoplatform that could induce autophagy dysfunction with excessive autophagosome accumulation to promote the therapeutic efficacy of PRN therapy. PRN@MSN drug delivery system combined with autophagy modulation may act as a promising treatment pattern in the treatment of hemangiomas.
婴儿血管瘤是最常见的血管肿瘤之一，如果不及时干预，可能会导致发病和死亡。普萘洛尔目前是血管瘤的一线治疗药物，但它潜在的副作用和高频率的给药使其迫切需要开发一种合适的普萘洛尔药物传递系统。在本研究中，我们基于介孔硅纳米粒子（PRN@MSN）构建了一种普萘洛尔传递系统，并研究了纳米粒子介导的自噬活性与 PRN@MSN 改善治疗效果之间的相互作用。结果表明，PRN@MSN 纳米粒子在体外和体内均表现出比游离普萘洛尔更高的细胞毒性，可通过增加自噬体形成和损害自噬降解来诱导过量自噬体积累。早期抑制自噬可减轻 PRN@MSN 的细胞毒性。ROS 的产生对于纳米颗粒介导的自噬和细胞毒性是必需的，PRN@MSN 诱导的自噬功能障碍可增强血管瘤干细胞中的内质网（ER）应激。我们的研究揭示了一种基于介孔硅纳米平台的有前途的 PRN 传递系统，该系统可通过过量自噬体积累诱导自噬功能障碍，从而促进 PRN 治疗的疗效。PRN@MSN 药物传递系统联合自噬调节可能成为血管瘤治疗的一种有前途的治疗模式。
