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Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and a topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts¹

Department of Neurological Surgery, Brain Tumor Research Center (Y.Y., M.T.K., T.K., K.S.B.), and Division of Hematology-Oncology (C.O.N., J.W.P.), University of California, San Francisco, San Francisco, CA 94103; and Hermes Biosciences, Inc., South San Francisco, CA 94080 (D.C.D., J.W.P.); USA

³ Address correspondence to Krystof S. Bankiewicz, Department of neurological Surgery, University of California, San Francisco, 1855 Folsom Street, Mission Center Building room 226, San Francisco, CA 94103, USA (Krystof.Bankiewicz{at}ucsf.edu).

Despite multimodal treatment options, the response and survival rates for patients with malignant gliomas remain dismal. Clinical trials with convection-enhanced delivery (CED) have recently opened a new window in neuro-oncology to the direct delivery of chemotherapeutics to the CNS, circumventing the blood-brain barrier and reducing systemic side effects. Our previous CED studies with liposomal chemotherapeutics have shown promising antitumor activity in rodent brain tumor models. In this study, we evaluated a combination of nanoliposomal topotecan (nLs-TPT) and pegylated liposomal doxorubicin (PLD) to enhance efficacy in our brain tumor models, and to establish a CED treatment capable of improving survival from malignant brain tumors. Both liposomal drugs decreased key enzymes involved in tumor cell replication in vitro. Synergistic effects of nLs-TPT and PLD on U87MG cell death were found. The combination displayed excellent efficacy in a CED-based survival study 10 days after tumor cell implantation. Animals in the control group and those in singleagent groups had a median survival of less than 30 days, whereas the combination group experienced a median survival of more than 90 days. We conclude that CED of two liposomal chemotherapeutics (nLs-TPT and PLD) may be an effective treatment option for malignant gliomas.

Key Words: brain tumor • CED • convection-enhanced delivery • glioma • liposome • topotecan

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