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Physical laws underlying the intravascular magnetic guidance of a novel drug carrier are discussed. The drug carrier is a magnetically responsive drug-bearing microsphere measuring approximately 1 μm in diameter. The microspheres consist of an albumin matrix in which a prototype drug (adriamycin HCl) and ultrafine Fe3O4 particles are entrapped. An in vitro analog of the human circulatory system is used to test both bipolar and unipolar magnetic arrangements which can retain microspheres flowing in aqueous suspension in the area of applied magnetic field. Retention of the microspheres by the magnetic field is shown to vary with the linear velocity of the viscous suspending medium and to be dependent on the magnitude of the applied magnetic force. This system permits extracorporeal control over the distribution of intravascular soluble chemotherapeutic agents and allows their concentration at specified body sites.

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Magnetically responsive albumin microspheres containing doxorubicin and magnetite (Fe3O,) were selectively targeted to Yoshida sarcoma tumors in rats by utilizing an extracorporeal magnet. Tumor cells were inoculated subcutaneously in the tail ofrats, and the tumors were allowed to grow to an average size of 9 X 45 mm prior to initiating treatment. Drug-bearing microspheres (0.5 mg ofdoxorubicin per kg ofbody weight) were infused proximal to the tumor through the ventral caudal artery while the tumor was exposed to an external magnetic field of 5500 Oe for 30 min. Control animals received free doxorubicin administered either intravenously (5 mg/kg) or infused intraarterially (5 and 0.5 mg/kg), drug-bearing microspheres infused intraarterially (0.5 mg/kg) without the external magnet, or placebo microspheres with magetic localization. Ofthe 12 animals treated with a single dose in the experimental group, 9 exhibited total remission of the tumor, representing a disappearance of tumors as large as 60 mm in length. Marked tumor regression was observed in the remaining three rats, and no deaths or metastases occurred in the experimental group. In contrast, significant increases in tumor size with widespread metastases occurred in all control groups and most rats died. These experiments indicate that targeting of oncolytic agents to solid neoplasms by magnetic microspheres may be a means of increasing the efficacy and decreasing the toxicity of antitumor agents.The ability to selectively target and restrict activity of antineoplastic agents to known foci of tumors has been a continuous challenge in cancer chemotherapy. Encapsulation carriers such as liposomes (1, 2) and albumin microspheres (3, 4) offer promise for attaining target-site specificity. However, the unrestricted circulation of liposomes and other carriers results in their rapid clearance by the, reticuloendothelial system if injected intravascularly. Moreover, neither modality has demonstrated a significant degree oftarget-site specificity. The various modalities for the targeting of drugs have recently been extensively reviewed (5) and will not be discussed here.With the goal of circumventing the reticuloendothelial system and achieving high target-area concentrations of drug carrier, we designed small (1-,m average diameter) magnetically responsive albumin microspheres capable of responding to extracorporeal magnetic fields (6). Virtually any water-soluble drug can be entrapped in these microspheres. By varying magnetic parameters, we have shown in vitro that the microspheres could be selectively retained at capillary-level flow rates (7). Retention ofthe drug carrier in capillaries is important, as maximum drug diffusion occurs at this level ofthe circulation. In addition, one ideally would like to remove the carrier from the vascular system into the extravascular compartment, producing a depot for sustained release ofantineoplastic agents. We have demonstrated that as early as 30 min after drug-carrier lo-

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