Abstract
Paclitaxel is anti-neoplastic agent shown to be extremely potent against glioblastoma in-vitro; however, it has yet to demonstrate antitumor activity in the clinic due to its inadequate brain penetration. Ultrasound-mediated drug delivery is an emerging new technology that transiently disrupts the blood-brain barrier to allow the passage of larger molecules that under physiological conditions would not reach the brain tissue. In this preclinical study, we investigated the ability of low intensity pulsed ultrasound (LIPU), delivered with the SonoCloud System (CarThera), to increase brain paclitaxel concentrations in a murine model. LIPU increased paclitaxel concentrations in the brain 300–500% after systemic administration of two different commercially available formulations of paclitaxel; paclitaxel dissolved in Cremophor (Taxol®) and albumin-bound paclitaxel (Abraxane®). The two formulations differed in their toxicity and biodistribution profiles with albumin-bound paclitaxel exhibiting increased tolerability and brain penetration. After sonication, albumin-bound paclitaxel increased survival in an orthotropic glioma model, whereas cremophor-paclitaxel induced central nervous system toxicity. Our experiments suggest that increased paclitaxel drug delivery by opening the BBB is feasible, and an effective anti-glioma treatment. Albumin-bound paclitaxel is the preferred formulation for further investigation with the SonoCloud system in the clinical setting.