Numerous treatment modalities have been used for brain tumor patients, however, none have significantly altered the course of the disease. Anticancer drug therapy of brain tumors is less than adequate due to the production of low and variable brain tumor concentrations, inability to selectively deliver anticancer agents to tumors often resulting in toxicity, and the development of drug resistance. This investigation examines a new targeted drug delivery approach that may be able to maintain substantial anticancer drug brain tumor concentrations, and selectively achieve these concentrations. The targeted drug delivery system is magnetic aminodextran microspheres (MADM), representative of magnetic cationic polysaccharide microspheres. It is proposed that MADM can be retained at the blood-brain barrier (BBB) and blood-tumor barrier (BTB) by combined magnetic and biochemical forces. The biochemical forces result from binding interactions between the cationic MADM and the anionic glycosaminoglycans (GAG) on the luminal surface of the BBB and BTB. MADM retained at the BTB may be endocytized, pass intact through a morphologically altered BTB, and release entrapped drug maintaining a high blood to tumor concentration gradient. MADM transported across the BTB may also bind to the tumor cell (i.e. rat glioma-2, RG-2) surface increasing the drugs residence time in the tumor. Retention and transport of drug- containing MADM by these mechanisms at the BTB would result in high brain tumor drug concentrations. A key aspect of this investigation is to characterize the mechanisms of MADM brain capillary retention and uptake. Normal and predominantly brain tumor (i.e. RG2) animals will be examined to elucidate the disposition of MADM and the disposition of the anticancer drug oxantrazole (OX), administered as a solution (OX-S) and entrapped int he MADM (i.e. MADM-OX). Further, the effects of magnetic field parameters and dose on MADM transport and OX uptake will be determined. This analysis will allow optimal drug delivery regiments to be designed, and future modifications to the delivery system planned.
The final aims of athe project will be to quantitatively demonstrate the ability of the MADM-OX system to enhance brain tumor OX deliverly and animal survival compared to a conventional treatment regimen of intraarterial OX in solution. The information gained from this project will clearly establish the role of magnetic cationic polysaccharide carriers to deliver therapeutic agents to brain tumor
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