Intraperitoneal Nanoparticulate Paclitaxel

DESCRIPTION (provided by applicant): Paclitaxel has shown promise in the treatment of several types of cancers, including ovarian cancer. The long-term goals of this research are to design a formulation of paclitaxel that is effective in the treatment of cancer and exhibits no formulation related toxicity. The present set of studies utilizes the techniques of precipitation with compressed antisolvent to produce nanoparticulate paclitaxel. The effects of nanoparticulate paclitaxel on the progression of ovarian cancer in a surgically debulked and non-debulked mouse model will be assessed. The first Aim will focus on production of the nanoparticulate paclitaxel. The second part of Aim 1 will assess the effects of nanoparticulate paclitaxel on the progression of ovarian cancer in a syngeneic mouse model. The effects of nanoparticulate paclitaxel delivered intravenoussly or intraperitoneally will be compared to the effects of Taxol(R), the current commercial formulation delivered intravenously or intrapedtoneally. We hypothesize nanoparticulate paclitaxel functions, at least in part, by acting as a reservoir providing a slow release of paclitaxel. This hypothesis will be examined in the studies described in the second Aim. The pharmacokinetics and tissue distribution of nanoparticulate paclitaxel and Taxol(R) will be measured in a time dependent manner following intravenous or intraperitoneal delivery in normal non-tumor bearing, tumor debulked, and non-debulked mice. Paclitaxel will be measured by mass spectrometry in the ascites fluid, plasma, organs, tumors, peritoneal immune cells and peritoneal tumor cells. Nanoparticulate paclitaxel within cells will further be visualized by transmission electron microscopy. The information gained by completion of the proposed studies will not be limited to paclitaxel but can be extended to other drugs. This information will have the potential to improve the efficacy of several drugs, as many have limited water solubility and exhibit toxicity related to formulation, and ultimately provide safer treatments to cancer patients. In addition novel insights will be gained by completion of the comparitive studies in debulked and nondebulked animals related to the effects of adhesions on treatment outcomes and drug pharmacokinetics and disposition. These studies will assess the potential of nanoparticulate paclitaxel delivered intraperitoneally as a means to improve on the current treatment of women with ovarian cancer.