In Vivo Toxicity Study of Engineered Lipid Microbubbles in Rodents
In Vivo Toxicity Study of Engineered Lipid Microbubbles in Rodents
复制标题
DOI：
10.1021/acsomega.8b03161
复制
发表时间：
2019-03-01
期刊：
影响因子：
4.1
通讯作者：
Grossman, Rachel
中科院分区：
文献类型：
--
作者：
Paradossi, Gaio;Oddo, Letizia;Grossman, Rachel
脑肿瘤手术中实时成像是实现完全切除的关键。我们正在开发新的基于脂质的微泡（MB），与特定的配体工程，这是能够与整合素在脑肿瘤血管内皮过表达的相互作用。这些MB被设计为使肿瘤可视化并将治疗分子携带到肿瘤组织中，从而保留起始普通脂质MB的超声声学特性。通过在两个时间点（10分钟和7天）静脉注射两个剂量的普通MB和针对靶向和近红外荧光可视化而设计的MB，评估了该新技术在大鼠中的潜在毒性[（1）MB、（2）MB-ICG、（3）MB-RGD和（4）MB-ICG-RGD]。在7天研究期间，任何给药组均未发生死亡。所有动物在研究期间均显示体重增加。在一些给药动物中观察到血液学和生化分析的轻微、大部分可逆变化。到7天时间点，所有变化均可逆。高剂量动物的组织病理学检查显示出现异物肉芽肿性炎症。我们的结论是，低剂量的测试项目似乎是安全的。结果允许继续进行产品的临床试验。
Real-time intraoperative imaging for brain tumor surgery is crucial for achieving complete resection. We are developing novel lipid-based microbubbles (MBs), engineered with specific ligands, which are able to interact with the integrins overexpressed in the endothelium of the brain tumor vasculature. These MBs are designed to visualize the tumor and to carry therapeutic molecules into the tumor tissue, preserving the ultrasound acoustic properties of the starting plain lipid MBs. The potential toxicity of this novel technology was assessed in rats by intravenous injections of two doses of plain MBs and MBs engineered for targeting and near-infrared fluorescence visualization at two time-points, 10 min and 7 days, for potential acute and chronic responses in rats [(1) MB, (2) MB-ICG, (3) MB-RGD, and (4) MB-ICG-RGD]. No mortality occurred during the 7-day study period in any of the dosing groups. All animals demonstrated a body weight gain during the study period. Minor, mostly reversible changes in hematological and biochemical analysis were observed in some of the treated animals. All changes were reversible by the 7-day time-point. Histopathology examination in the high-dose animals showed development of foreign body granulomatous inflammation. We concluded that the low-dose tested items appear to be safe. The results allow for proceeding to clinical testing of the product.