? The principal objective of this research plan is to evaluate the effectiveness of the combination use of liposomal encapsulated fenretinide and safingol for the therapeutic treatment of neuroblastoma and other cancers. Neuroblastoma is a leading cause of brain cancer in children and therapy for these tumors are inefficient. The administration of oral fenretinide in clinical trials has shown promising results, yet the bioavailability is low for this hydrophobic compound. Safingol has been shown to synergize with antineoplastic agents (i.e. doxorubicin and cisplatin); however, administered as a single agent, safingol has no significant anticancer activity. Pre-clinical intravenous co-administration of 4HPR with safingol significantly decreases tumor growth in mice. Attempts to solubilize fenretinide with standard excipients (e.g. Cremophor-EL) have lead to toxic side effects in rodents and dogs. Using a proprietary liposome matrix method that allows us to quickly and efficiently identify commercially viable liposome formulations, we intend to formulate fenretinide and safingol liposomal formulations, and based upon physical/chemical criteria, select potential commercial viable candidates for further in vitro and in vivo testing. Positive formulations that pass these criteria and considered potential candidates for large-scale commercial manufacturing will be tested for toxicity. Formulations possessing low toxicity profiles will be radiolabeled and their in vivo biodistribution and pharmacokinetics determined. Various formulations consisting of different lipid ratios corresponding to different transition temperatures and drug retention times will be tested. To correlate biodistribution and tissue localization of liposomal fenretinide and liposomal safingol with efficacy, candidate formulations will be tested in a neuroblastoma animal model. We will use this model to test the liposome formulations and compare our best liposomal drug formulations. If successful, the formulation would allow for the safe intravenous administration of the broad-spectrum anticancer agents, fenretinide and safingol. This will allow: (1) safe intravenous administration of the drugs, thereby increasing the bioavailability and improving the tumor distribution; (2) elimination of side effects associated with the use of the solvents, such as oils and alcohols necessary for the solubilization of hydrophobic compounds; and (3) a fundamental understanding of the biodistribution of these anticancer liposomes. ? ?
