Role of Caveolae Mediated Transport for Abraxane Uptake in vivo
thesisposted on 15.04.2014, 00:00 by Maricela Castellon
An in vivo study was conducted to determine whether the chemotherapeutic drug Abraxane is taken up by tissues and tumors via caveolae-mediated endocytosis and transcytosis. Cancer is one of the leading causes of death worldwide and a global health concern due to the increase in global death rates reported each year. A major focus of basic and clinical research is to find new drug delivery systems that increase the therapeutic efficacy of chemotherapeutic agents while reducing the associated toxicity in normal tissues. In the present study, we focused on the mechanism of tissue uptake of the chemotherapeutic drug Abraxane, a newly developed drug currently used for treatment for breast cancer. Abraxane is an albumin-bound paclitaxel conjugate specifically designed to replace the commonly used paclitaxel formulation, Taxol, which is delivered in a cremophor-ethanol solution. Taxol requires long infusion cycles and is associated with highly toxic side effects that have been associated with this drug formulation. The creators of Abraxane proposed internalization into the tissue and tumors is via a caveolin-1 mediated transport pathway. Our experimental design included the use of murine models, wild-type B6/129 female mice as compared to female caveolin-1 knockout mice, which were intravenously injected with either paclitaxel suspended in 1% albumin-saline solution or Abraxane suspended in saline. Blood and tissues were collected and processed for analysis of paclitaxel by liquid chromatography and mass spectrometry. The results obtained showed a higher accumulation of Abraxane in the liver, kidney, and breast tissues while paclitaxel uptake was greater in the lung and liver tissues. Plasma levels were higher for Abraxane, suggesting it has a longer circulation time in the blood. Both Abraxane and paclitaxel accumulated at low levels in the brain suggesting neither is able to cross the blood-brain barrier. Finally, there were no significant differences in the accumulation of either paclitaxel formulation between wild type and knockout mice. We conclude from this study that the uptake and transport of Abraxane in normal tissues is not mediated by caveolae-dependent mechanisms and that the beneficial effects of the albumin-paclitaxel conjugation of Abraxane may have more to do with its greater bioavailability.