© Copyright 2007 by the Society for Neuro-Oncology
Received August 31, 2006
Accepted December 18, 2006
Basic and Translational Investigations
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Convection-enhanced delivery of nanoliposomal CPT-11 (Irinotecan) and PEGylated liposomal doxorubicin (Doxil) in rodent intracranial brain tumor xenografts
Michal T. Krauze 1,
Charles O. Noble 2,
Tomohiro Kawaguchi 1,
Daryl Drummond 3,
Dmitri B. Kirpotin 3,
Yoji Yamashita 1,
Erika Kullberg 4,
John Forsayeth 1,
John W. Park 5,
Krystof S. Bankiewicz 1*
1 Department of Neurological Surgery, Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA, USA
2 Division of Hematology-Oncology, University of California, San Francisco, San Francisco, CA; and Hermes Biosciences, Inc., South San Francisco, CA, USA
3 Hermes Biosciences, Inc., South San Francisco, CA, USA
4 Division of Hematology-Oncology, University of California, San Francisco, San Francisco, CA, USA
5 Division of Hematology-Oncology, University of California San Francisco, San Francisco, CA, USA
* To whom correspondence should be addressed. E-mail: krystof.bankiewicz{at}ucsf.edu.
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Abstract |
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We have previously shown that convection-enhanced delivery (CED) of highly stable nanoparticle/liposome agents encapsulating chemotherapeutic drugs is effective against intracranial rodent brain tumor xenografts. In this study, we have evaluated the combination of a newly developed nanoparticle/liposome containing the topoisomerase I inhibitor CPT-11 (nanoliposomal CPT-11 [nLs-CPT-11]), and PEGylated liposomal doxorubicin (Doxil) containing the topoisomerase II inhibitor doxorubicin. Both drugs were detectable in the CNS for more than 36 days after a single CED application. Tissue half-life was 16.7 days for nLs-CPT-11 and 10.9 days for Doxil. The combination of the two agents produced synergistic cytotoxicity in vitro. In vivo in U251MG and U87MG intracranial rodent xenograft models, CED of the combination was also more efficacious than either agent used singly. Analysis of the parameters involved in this approach indicated that tissue pharmacokinetics, tumor microanatomy, and biochemical interactions of the drugs all contributed to the therapeutic efficacy observed. These findings have implications for further clinical applications of CED-based treatment of brain tumors.
Key Words:
brain tumor, CED, CPT-11, Doxil, Irinotecan, liposome, xenograft
