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Development Of A Potential Protein Vector (NeuroTrans) To Deliver Drugs Across The Blood–brain Barrier

R. Gabathuler, G. Arthur, M. Kennard, Qingqi Chen, Sam S. Tsai, J. Yang, W. Schoorl, T. Z. Vitalis, W. Jefferies
Published 2005 · Medicine

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Abstract Purpose Delivery of chemotherapeutic drugs to the brain is limited by the capillary endothelial cells that form the blood–brain barrier (BBB). In this study, we investigate a novel transport mechanism based on the iron binding protein p97 (or melanotransferrin), which is able to cross the BBB. Methods The anticancer drug adriamycin (ADR), which is unable to cross the BBB, was conjugated to p97 to determine if it was possible to deliver a therapeutic dose of ADR to the brains of mice. Conjugates of p97-ADR were prepared and tested for efficacy against subcutaneous rat C6 glioma tumours in athymic mice. Results Conjugate and free ADR were shown to be equally effective in inhibiting the growth of these tumours. The ability of p97 to cross into the brain after conjugation to ADR was demonstrated in a mouse model using I125 labeled compounds. Transport of p97 and conjugate were shown to be 6–8 fold higher than BSA or lactoferrin. Conjugates were also tested for efficacy against intracranial rat C6 glioma and human ZR-75-1 mammary tumours in athymic mice. Conclusion The conjugate was shown to significantly increase the survival of mice compared to repeated injections of PBS or free ADR. These results demonstrate a marked improvement over existing chemotherapy strategies based on ADR alone. p97 may have significant potential as an effective vehicle for the delivery of therapeutic drugs across the BBB.
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