Single-dose toxicity study of hepatic intra-arterial infusion of doxorubicin coupled to a novel magnetically targeted drug carrier
Single-dose toxicity study of hepatic intra-arterial infusion of doxorubicin coupled to a novel magnetically targeted drug carrier
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DOI：
10.1093/toxsci/60.1.177
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发表时间：
2001-03-01
影响因子：
3.8
通讯作者：
Wong, G
中科院分区：
文献类型：
--
作者：
Goodwin, SC;Bittner, CA;Wong, G
在猪模型中评价了与磁靶向药物载体（MTC）偶联的阿霉素（DOX）的单次肝动脉内给药的毒性。MTC是元素铁和活性炭的微粒复合物。MTC-DOX是一种吸收到MTC的阿霉素的新制剂，并且被设计用于在外部施加的磁场存在下向实体瘤的位点特异性递送。磁场诱导MTC通过血管壁外渗，导致定位和保留在目标部位的组织中。将18只猪分配到6个治疗组，包括3个对照组（媒介物对照、阿霉素、MTC）和3个接受MTC-DOX制剂的实验组。对动物单次给予供试品，评价28天，然后处死。通过临床状态、总体重、大体和显微病理学以及血清化学监测毒性体征。使用血管造影术确定存在的任何栓塞的程度。在单独使用DOX组中未观察到不良反应。仅在接受大于或等于75 mg MTC（含或不含多柔比星）的组中，具有生物学意义的给药相关肉眼和显微镜病变仅限于肝脏靶向区域。肝坏死的严重程度与治疗后栓塞的严重程度相关。多柔比星在任何MTC-DOX组中都没有自由循环，表明成功定位于靶位点。以MTC-DOX低剂量组为无不良作用水平（NOAEL）。
The toxicity of a single hepatic intra-arterial administration of doxorubicin (DOX) coupled to a magnetically targeted drug carrier (MTC) was evaluated in a swine model. MTC is a microparticle composite of elemental iron and activated carbon. MTC-DOX is a new formulation of doxorubicin absorbed to the MTC and is designed for site-specific delivery to a solid tumor in the presence of an externally applied magnetic field. The magnetic field induces extravasation of MTCs through the vascular wall, leading to localization and retention in the tissue at the targeted site. Eighteen swine were assigned to 6 treatment groups, including 3 control groups (vehicle control, doxorubicin, MTC), and 3 experimental groups that received the MTC-DOX preparation. Animals were given a single administration of test article, evaluated over 28 days, and then sacrificed. Signs of toxicity were monitored via clinical status, total body weight, gross and microscopic pathology, and serum chemistries. Angiography was used to determine the extent of any embolization present. There were no adverse effects observed in the DOX-alone group. Biologically significant, treatment-related gross and microscopic lesions were limited tot the targeted area of the liver only in groups receiving greater than or equal to 75 mg of MTC (with or without doxorubicin). The severity of liver necrosis correlated to the severity of embolization following treatment. Doxorubicin was not freely circulating in any of the MTC-DOX groups, suggesting successful localization to the targeted site. The no adverse-effect level (NOAEL) was determined to be the MTC-DOX low-dose group.