Formulation of Fenretinide Nanoparticles for Enhanced Bioavailability

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DESCRIPTION (provided by applicant): Neuroblastoma, a neoplasm of the sympathetic nervous system, is the second most common malignant tumor in childhood. In recent years, prognosis for patients with this neoplasm has improved, but the overall 5- year survival is still less than 60% because of fatal relapses of the disease. However, the incidence of fatal relapses can be reduced by adding innovative therapy to eradicate the residual disease. Complete eradication of the residual disease requires long-term treatment during the early stages. Fenretinide, a synthetic retinoid, is the focus of long-term treatment for complete eradication of the disease. The drug has been successfully tested for antitumor activity in vitro and in vivo. However, the potential of fenretinide as a long-term treatment for childhood neuroblastoma is limited by its poor water solubility and poor bioavailability following oral administration. The overall objective of this project is to develop fenretinide nanoparticles. The central hypothesis i that the bioavailability of fenretinide will be significantly enhanced due to the small size of the nanoparticles and their enhanced ability to penetrate cell membranes. The following four specific aims delineate the step-wise approach towards the testing of the central hypothesis. Specific Aim 1. Preparation of nanoparticle formulations. Two different nanoparticle formulations will be prepared using a laboratory nanospray dryer and a high pressure homogenizer, respectively. Specific Aim 2. Characterization of the nanoparticles. Specific Aim 3. Evaluation of the in vitro drug release. Specific Aim 4. Evaluation of the intestinal permeability of fenretinide using a Caco-2 cell model. The proposed research is innovative, in our opinion, because there are no reports in the literature of using the Nano Spray Dryer or high pressure homogenizer to produce nanoparticles of fenretinide. We expect that the bioavailability of fenretinide will be enhanced by its formulation in the form of nanoparticles, and as a result, lower doses of the drug will be needed to achieve therapeutic plasma concentrations. Lowering the drug dose will also reduce the incidence of adverse side effects and enhance patient compliance. The proposed project will help the principal investigator develop his skills in nanotechnology and the formulation of nanoparticles of drug substances. It will help him enhance his publication record and, therefore, strengthen his ability to submit competitive grant applications. The proposed project will also increase the exposure of minority students to research by working in conjunction with a training program funded by the Center of Excellence program at the university, which requires the mentor to be a faculty member involved in research.