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 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 to the targeted area of the liver only in groups receiving > or =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.
University of California Los Angeles Medical School, Department of Radiology, Los Angeles, California, USA. sgoodwin@mednet.ucla.edu
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SC
Goodwin
C A
CA
Bittner
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CL
Peterson
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G
Wong
D000792:Angiography; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D019963:Clinical Chemistry Tests; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D016503:Drug Delivery Systems / Q000009:adverse effects*; D004617:Embolism / Q000209:etiology / Q000473:pathology; D005260:Female; D006403:Hematologic Tests; D006499:Hepatic Artery / Q000000981:diagnostic imaging; D007269:Injections, Intra-Arterial; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008280:Magnetics; D023421:Models, Animal; D009336:Necrosis; D019055:No-Observed-Adverse-Effect Level; D011168:Portal System / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D013552:Swine
D000970:Antineoplastic Agents; D004317:Doxorubicin