Targ Oncol (2006) 1: 79–85 DOI 10.1007/s11523-006-0011-8 ORIGINAL RESEARCH Yoji Yamashita . Ryuta Saito . Michal T. Krauze . Tomohiro Kawaguchi . Charles Noble . Daryl C. Drummond . Dmitri B. Kirpotin . John W. Park . Mitchel S. Berger . Krystof S. Bankiewicz Convection-enhanced delivery of liposomal doxorubicin in intracranial brain tumor xenografts Received: 28 October 2005 / Revised: 19 January 2006 / Accepted: 24 January 2006 / Published online: 21 March 2006 # Springer-Verlag 2006 Abstract We previously reported that convection-en- hanced delivery (CED) of liposomes into brain tissue and intracranial brain tumor xenografts produced robust tissue distribution that can be detected by magnetic resonance imaging. Considering image-guided CED of therapeutic liposomes as a promising strategy for the treatment of brain tumors, we evaluated the efficacy of pegylated liposomal doxorubicin delivered by CED in an animal model. Distribution, toxicity, and efficacy of pegylated liposomal doxorubicin after CED were evaluated in a U251MG human glioblastoma intracranial xenograft model. CED of pegylated liposomal doxorubicin achieved good distribu- tion in brain tumor tissue and surrounding normal brain tissue. Distribution was not affected by the particle concentration of pegylated liposomal doxorubicin, but tissue toxicity increased at higher concentrations. CED of pegylated liposomal doxorubicin, at a dose not toxic to normal rat brain (0.1 mg/ml doxorubicin), was significantly more efficacious than systemic administration of pegylated liposomal doxorubicin at the maximum tolerated dose. CED of pegylated liposomal doxorubicin resulted in improved survival compared to CED of free doxorubicin at the same dose. Outcomes of this study suggest that CED of liposomal drugs is a promising approach for the treatment of glioblastoma. Keywords Convection-enhanced delivery . Liposomal doxorubicin . U251MG . Brain tumor Introduction Despite intensive multimodal treatment such as surgical resection, malignant glioma (e.g., glioblastoma multiforme) remains the most difficult neoplasm to treat. Poor penetration of most anticancer drugs across the blood–brain barrier (BBB) into the central nervous system (CNS), when systemically administered, is one of the major reasons why improvement of survival is limited. Even with drugs that penetrate the BBB, it is difficult to reach sufficient drug concentrations in brain tumor tissue without causing systemic side effects [1]. Convection-enhanced delivery (CED) is a promising local delivery technique. This technique uses bulk flow to deliver small or large molecules directly to targeted sites in clinically significant volumes of tissue and provides wider volumes of distribution compared with simple diffusion techniques [2]. CED of therapeutic agents bypasses the BBB, delivers a high concentration of therapeutic agents within target sites, and minimizes systemic exposure, resulting in fewer side effects. Many investigators are now applying this technique to brain tumors. BCNU [3], topotecan [4], carboplatin, gemcitabine [5], and paclitaxel [6] have been administered with this technique, all with promising outcomes. Liposomes are nanoscale lipid vesicles with a bilayered membrane structure and hollow core that can encapsulate a variety of small molecules. Liposomes have been shown to provide stable encapsulation for various anticancer drugs and have many advantages over the corresponding free drugs for the systemic treatment of cancer [7–9]. Liposomal formulations of doxorubicin (pegylated liposo- mal doxorubicin; ALZA/Johnson&Johnson) and daunoru- bicin (DaunoXome, Gilead) are already approved for the Y. Yamashita . R. Saito . M. T. Krauze . T. Kawaguchi . M. S. Berger . K. S. Bankiewicz (*) Department of Neurological Surgery, University of California, San Francisco, 1855 Folsom Street, Mission Center Building, Room 226, San Francisco, CA 94103, USA e-mail: kbank@itsa.ucsf.edu Tel.: +1-415-5023132 Fax: +1-415-5142177 C. Noble . J. W. Park Division of Hematology–Oncology, University of California, San Francisco, San Francisco, CA, USA D. C. Drummond . D. B. Kirpotin . J. W. Park Hermes Biosciences, Inc., South San Francisco, CA, USA