Division of Vascular and Interventional Radiology, The Russell H Morgan Department of Radiology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Cardiovasc Intervent Radiol. 2010 Jun;33(3):576-82. doi: 10.1007/s00270-010-9794-1. Epub 2010 Jan 20.
The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.
本研究旨在评估多柔比星负载的聚乙烯醇-丙烯酸钠共聚物微球[QuadraSphere 微球（QSMs）]在肝癌动物模型中的经导管动脉递送的体内外疗效。首先在体外测试多柔比星的载药效率和释放曲线。在体内，将 15 只植入肝脏 Vx-2 肿瘤的兔子，根据安乐死时间分为每组 5 只的 3 组。将 25 毫克 QSMs 稀释于 10ml10mg/ml 多柔比星溶液和 10ml 非离子型对比剂中，总容量为 20ml。将 1ml 载药 QSM 溶液（含 5mg 多柔比星）注入肿瘤供养动脉。测量血浆多柔比星和多柔比星醇浓度，以及肿瘤内和肿瘤周围的多柔比星组织浓度。对肿瘤标本进行病理评估以记录肿瘤坏死情况。作为对照，每组各有 1 只动物用单纯 QSM 进行盲目栓塞。QSM 载多柔比星能力和随时间释放的体外测试表明，2 小时内多柔比星载药率为 82-94%，负载后前 6 小时内释放 6%，随后呈缓慢释放模式。在体内，多柔比星的血浆浓度在 40 分钟时下降。多柔比星肿瘤内浓度的峰值在第 3 天出现，并可在研究终点（第 7 天）检测到。多柔比星 QSM 组的肿瘤细胞死亡百分比平均值在第 7 天为 90%，在单纯 QSM 栓塞组为 60%。总之，QSM 可以有效地负载多柔比星。载多柔比星 QSMs 的初步实验在肝癌动物模型中显示出安全的药代动力学特征和有效的肿瘤杀伤作用。
