This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Paclitaxel (Taxol) is a standard and effective chemotherapeutic for many cancer types, including breast cancer, ovarian cancer, small cell lung cancer and non-small cell lung cancer. Since paclitaxel (PTX) has very limited solubility in water, the formulation of this drug requires Cremophor EL which causes significant side effects, such as allergic reactions. Consequently, patients receiving PTX require premedication with histamine blockers and steroids. We proposed to use a novel water-soluble nanoparticle-based formulation to enable better drug delivery of PTX. This proprietary formulation has been demonstrated to be safer and more effective in preclinical studies compared to currently available formulations. For example, some tumor-bearing mice exposed to PTX-nanoparticles were cured of cancer, which was not observed for the Cremophor formulation. The goal of this study is to advance the use of PTX-nanoparticles into Phase 0 clinical studies by using 14C-paclitaxel to label the nanoparticles followed by absorption, distribution, metabolism and excretion (ADME) studies in nude mice with human tumor xenografts. The particles will be synthesized according to established protocols which includes addition of the 14C-paclitaxel in the final self-assemble step. Mice will be dosed with PTX-nanoparticles of sufficient specific activity to allow tracing by liquid scintillation counting (LSC). The LSC experiments will allow calculation of the specific activity needed for the studies to be repeated using AMS-based detection of the 14C-paclitaxel. AMS is needed as part of the project in order to predict dose formulations and develop methods for use in clinical studies (to be proposed later). It is anticipated that LSC has sufficient sensitivity for human phase 0 studies, but this needs to be established empirically with the proposed animal studies. If successful, the feasibility study data will be submitted to FDA for an exploratory IND application in order to determine the pharmacokinetics of PTX-nanoparticles in humans in order to justify subsequent Phase 1 studies.
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