Convection-enhanced delivery (CED) of highly stable PEGylated liposomes encapsulating chemotherapeutic drugs has previously been effective against malignant glioma xenografts. We have developed a novel, convectable non-PEGylated liposomal formulation that can be used to encapsulate both the topoisomerase I inhibitor topotecan (topoCED™) and paramagnetic gadodiamide (gadoCED™), providing an ideal basis for real-time monitoring of drug distribution. Tissue retention of topoCED following single CED administration was significantly improved relative to free topotecan. At a dose of 10 μg (0.5 mg/ml), topoCED had a half-life in brain of approximately 1 day and increased the area under the concentration–time curve (AUC) by 28-fold over free topotecan (153.8 vs. 5.5 μg day/g). The combination of topoCED and gadoCED was found to co-convect well in both naïve rat brain and malignant glioma xenografts (correlation coefficients 0.97–0.99). In a U87MG cell assay, the 50% inhibitory concentration (IC50) of topoCED was approximately 0.8 μM at 48 and 72 h; its concentration–time curves were similar to free topotecan and unaffected by gadoCED. In a U87MG intracranial rat xenograft model, a two-dose CED regimen of topoCED co-infused with gadoCED greatly increased median overall survival at dose levels of 0.5 mg/ml (29.5 days) and 1.0 mg/ml (33.0 days) vs. control (20.0 days; P < 0.0001 for both comparisons). TopoCED at higher concentrations (1.6 mg/ml) co-infused with gadoCED showed no evidence of histopathological changes attributable to either agent. The positive results of tissue pharmacokinetics, co-convection, cytotoxicity, efficacy, and lack of toxicity of topoCED in a clinically meaningful dose range, combined with an ideal matched-liposome paramagnetic agent, gadoCED, implicates further clinical applications of this therapy in the treatment of malignant glioma.
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Wong ET, Hess KR, Gleason MJ et al (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578CrossRefPubMedGoogle Scholar
Rapisarda A, Zalek J, Hollingshead M et al (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1α protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 64:6845–6848. doi:10.1158/0008-5472.CAN-04-2116CrossRefPubMedGoogle Scholar
Mainwaring MG, Gomez SP, Marsh RD, Chen S (2001) Sequential temozolomide followed by topotecan in the treatment of glioblastoma multiforme. Proc Am Soc Clin Oncol 20:245 (abstract)Google Scholar
Fisher BJ, Scott C, Macdonald DR, Coughlin C, Curran WJ (2001) Phase I study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group Trial 9507. J Clin Oncol 19:1111–1117CrossRefPubMedGoogle Scholar
Fisher B, Won M, MacDonald D, Johnson DW, Roa W (2002) Phase II study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group 9513. Int J Radiat Oncol Biol Phys 53:980–986. doi:10.1016/S0360-3016(02)02817-1CrossRefPubMedGoogle Scholar
Grabenbauer GG, Anders K, Fietkau RJ et al (2002) Prolonged infusional topotecan and accelerated hyperfractionated 3d-conformal radiation in patients with newly diagnosed glioblastoma-a phase I study. J Neurooncol 60:269–275. doi:10.1023/A:1021100413142CrossRefPubMedGoogle Scholar
Pipas JM, Meyer LP, Rhodes CH, Cromwell LD, McDonnell CE, Kingman LS, Rigas JR, Fadul CE (2005) A phase II trial of paclitaxel and topotecan with filgrastim in patients with recurrent or refractory glioblastoma multiforme or anaplastic astrocytoma. J Neurooncol 71:301–305. doi:10.1007/s11060-004-2026-2CrossRefPubMedGoogle Scholar
Lieberman DM, Laske DW, Morrison PF et al (1995) Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J Neurosurg 82:1021–1029CrossRefPubMedGoogle Scholar
Croteau D, Walbridge S, Morrison PF et al (2005) Real-time in vivo imaging of the convective distribution of a low-molecular-weight tracer. J Neurosurg 102:90–97CrossRefPubMedGoogle Scholar
Lonser RR, Walbridge S, Garmestani K et al (2002) Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg 97:905–913CrossRefPubMedGoogle Scholar
Moog R, Burger AM, Brandl M et al (2002) Change in pharmacokinetics and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels. Cancer Chemother Pharmacol 49:356–366. doi:10.1007/s00280-002-0428-4CrossRefPubMedGoogle Scholar
Szebeni J, Baranyi L, Savay S et al (2002) Role of complement activation in hypersensitivity reactions to doxil and hynic PEG liposomes: experimental and clinical studies. J Liposome Res 12:165–172. doi:10.1081/LPR-120004790CrossRefPubMedGoogle Scholar
Saito R, Krauze MT, Noble CO et al (2006) Tissue affinity of the infusate affects the distribution volume during convection-enhanced delivery into rodent brains: implications for local drug delivery. J Neurosci Methods 154:225–232. doi:10.1016/j.jneumeth.2005.12.027CrossRefPubMedGoogle Scholar
Kunwar S, Westphal M, Medhorn M et al (2007) Results from PRECISE: a randomized phase 3 study in patients with first recurrent glioblastoma multiforme (GBM) comparing cintredekin besudotox (CB) administered via convection-enhanced delivery (CED) with Gliadel Wafers (GW). Neuro-oncology 9:531 (abstract)Google Scholar
Nakashio A, Fujita N, Tsuruo T (2002) Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K-Akt signaling pathway. Int J Cancer 98:36–41. doi:10.1002/ijc.10166CrossRefPubMedGoogle Scholar
Dickensen PJ, LeCouteur RA, Higgins RJ et al (2008) Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging. J Neurosurg 108:989–998. doi:10.3171/JNS/2008/108/5/0989CrossRefGoogle Scholar
Yamashita Y, Krauze MT, Kawaguchi T et al (2007) Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts. Neuro-oncology 9:20–28. doi:10.1215/15228517-2006-016CrossRefPubMedPubMedCentralGoogle Scholar