Abstract

Sonodynamic therapy (SDT) has aroused great interest for its potential in the treatment of glioblastoma (GBM). SDT relies on tumor-selective accumulation of a sonosensitizer that is activated by ultrasound irradiation (UI) to generate cytotoxic actions. The efficacy of GBM-SDT depends on sufficient sonosensitizer buildup in the tumor, which is, however, seriously hampered by the anatomical and biochemical barriers of the GBM. To overcome this difficulty, we herein propose a delivery strategy of ‘platelets with ultrasound-triggered release property’, which takes advantage of 1) the platelets’ ability to carry cargo and release cargo upon activation, and 2) the ROS-generating property of SDT. To provide proof of concept for the strategy, we first stably loaded platelets with IOPD-Ce6, a nano-formed sonosensitizer consisting of iron oxide nanoparticles coated with polyglycerol and doxorubicin and loaded with chlorine e6. UI of the IOPD-Ce6-loaded platelets (IOPD-Ce6@Plt) elicited ROS generation in the IOPD-Ce6@Plt, which were immediately activated to release IOPD-Ce6 into GBM cells in co-culture which, when subjected to a second time of UI, exhibited pronounced ROS production, DNA injury, viability loss, and cell death in the GBM cells. In the in vivo experiments, mice bearing intracranial GBM grafts exhibited substantial tumor distribution of IOPD-Ce6 following intravenous injection of IOPD-Ce6@Plt and subsequent UI at the tumor site. The GBM grafts then exhibited pronounced cell injury and death after another round of UI of the tumors. Finally, the growth of intra-cranial GBM grafts was significantly slowed when an SDT protocol consisting of an intravenous IOPD-Ce6@Plt injection followed by multiple times of tumor UI had been applied twice to the mice. Our results are strong evidence for the idea that platelets are sound and amenable carriers to deliver sonosensitizers in the GBM in an ultrasound-triggered manner and thus to produce highly targeted and effective SDT of GBM.

摘要

声动力疗法（SDT）因其在治疗胶质母细胞瘤（GBM）方面的潜力而引起了人们的极大兴趣。SDT 依赖于声敏剂的肿瘤选择性积累，该声敏剂由超声辐射 (UI) 激活以产生细胞毒性作用。GBM-SDT 的疗效取决于肿瘤中足够的声敏剂积聚，然而，这受到 GBM 的解剖和生化屏障的严重阻碍。为了克服这一困难，我们在此提出了一种“具有超声触发释放特性的血小板”的递送策略，该策略利用了 1) 血小板在激活后携带货物和释放货物的能力，以及 2) 血小板的 ROS 生成特性。 SDT。为了为该策略提供概念证明，我们首先用 IOPD-Ce6 稳定负载血小板，一种纳米声敏剂，由涂有聚甘油和阿霉素并负载有氯 e6 的氧化铁纳米颗粒组成。负载 IOPD-Ce6 的血小板 (IOPD-Ce6@Plt) 的 UI 引发了 IOPD-Ce6@Plt 中的 ROS 生成，这些 ROS 立即被激活，将 IOPD-Ce6 释放到共培养的 GBM 细胞中，当进行第二次处理时， UI 期间，GBM 细胞表现出明显的 ROS 产生、DNA 损伤、活力丧失和细胞死亡。在体内实验中，在静脉注射 IOPD-Ce6@Plt 并随后在肿瘤部位注射 UI 后，携带颅内 GBM 移植物的小鼠表现出 IOPD-Ce6 的大量肿瘤分布。在另一轮肿瘤 UI 治疗后，GBM 移植物表现出明显的细胞损伤和死亡。最后，当对小鼠进行两次 SDT 方案（包括静脉内 IOPD-Ce6@Plt 注射，然后多次肿瘤 UI）时，颅内 GBM 移植物的生长显着减慢。我们的结果有力地证明了这一观点，即血小板是健全且适宜的载体，可以以超声触发的方式在 GBM 中传递声敏剂，从而产生高度针对性和有效的 GBM SDT。