Direct delivery of
chemotherapy agents to the brain via degradable
polymer delivery systems-such as Gliadel®-is a clinically proven method for treatment of
glioblastoma multiforme, but there are important limitations with the current technology-including the requirement for surgery, profound local tissue toxicity, and limitations in diffusional penetration of agents-that limit its application and effectiveness. Here, we demonstrate another technique for direct, controlled delivery of
chemotherapy to the brain that provides therapeutic benefit with fewer limitations. In our new approach,
camptothecin (
CPT)-loaded poly(lacticco-
glycolic acid) (PLGA) nanoparticles are infused via convection-enhanced delivery (CED) to a stereotactically defined location in the brain, allowing simultaneous control of location, spread, and duration of drug release. To test this approach,
CPT-PLGA nanoparticles (~100 nm in diameter) were synthesized with 25%
drug loading. When these nanoparticles were incubated in culture with 9L
gliosarcoma cells, the IC50 of
CPT-PLGA nanoparticles was 0.04 µM, compared to 0.3 µM for
CPT alone.
CPT-PLGA nanoparticles stereotactically delivered by CED improved survival in rats with intracranial 9L
tumors: the median survival for rats treated with
CPT-PLGA nanoparticles (22 days) was significantly longer than unloaded nanoparticles (15 days) and free
CPT infusion (17 days).
CPT-PLGA nanoparticle treatment also produced significantly more long-term survivors (30% of animals were free of disease at 60 days) than any other treatment.
CPT was present in tissues harvested up to 53 days post-infusion, indicating prolonged residence at the local site of administration. These are the first results to demonstrate the effectiveness of combining
polymer-controlled release nanoparticles with CED in treating fatal intracranial
tumors.