Treatment of
malignant gliomas represents one of the most formidable challenges in oncology. The combination of surgery, radiation, and
chemotherapy yields median survivals of less than one year. Here we demonstrate the use of a minimally invasive surgical technique, convection-enhanced delivery (CED), for local administration of a novel nanoparticle
liposome containing
topotecan. CED of this liposomal
topotecan (Ls-
TPT) resulted in extended brain tissue retention (t1/2 = 1.5 days), whereas free
topotecan was rapidly cleared (t1/2 = 0.1 days) after CED. The favorable pharmacokinetic profile of extended
topotecan release for about seven days, along with biodistribution featuring perivascular accumulation of the nanoparticles, provided, in addition to the known
topoisomerase I inhibition, an effective antiangiogenic
therapy. In the rat intracranial U87MG
tumor model, vascular targeting of Ls-
TPT with CED was associated with reductions in
laminin expression and vascular density compared to free
topotecan or control treatments. A single CED treatment on day 7 showed that free
topotecan conferred no survival benefit versus control. However, Ls-
TPT produced a significant (P = 0.0002) survival benefit, with six of seven complete cures. Larger U87MG
tumors, where CED of Ls-
TPT on day 12 resulted in one of six cures, indicated the necessity to cover the entire
tumor with the infused therapeutic agent. CED of Ls-
TPT was also efficacious in the intracranial U251MG
tumor model (P = 0.0005 versus control). We conclude that the combination of a novel nanoparticle Ls-
TPT and CED administration was very effective in treating experimental
brain tumors.