Single-dose toxicity study of hepatic intra-arterial infusion of doxorubicin coupled to a novel magnetically targeted drug carrier

The toxicity of a single hepatic intra-arterial administration of doxorubic in (DOX) coupled to a magnetically targeted drug carrier (MTC) was evaluate d 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 t he MTC and is designed for site-specific delivery to a solid tumor in the p resence of an externally applied magnetic field. The magnetic field induces extravasation of MTCs through the vascular wall, leading to localization a nd retention in the tissue at the targeted site. Eighteen swine were assign ed to 6 treatment groups, including 3 control groups (vehicle control, doxo rubicin, MTC), and 3 experimental groups that received the MTC-DOX preparat ion. Animals were given a single administration of test article, evaluated over 28 days, and then sacrificed. Signs of toxicity were monitored via cli nical status, total body weight, gross and microscopic pathology, and serum chemistries. Angiography was used to determine the extent of any embolizat ion 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 gr eater than or equal to 75 mg of MTC (with or without doxorubicin). The seve rity of liver necrosis correlated to the severity of embolization following treatment. Doxorubicin was not freely circulating in any of the MTC-DOX gr oups, suggesting successful localization to the targeted site. The no adver se-effect level (NOAEL) was determined to be the MTC-DOX low-dose group.