Establishing bioactive serum and toxicity levels for Nanolipolee-007

DESCRIPTION (provided by applicant): Better therapies are needed to treat malignant melanoma, the most deadly form of skin cancer. Multiple pathways such as STAT, MAP and PI3 kinase are deregulated in the development of melanoma, and targeting these pathways in melanoma cells, could be used as a better strategy to effectively treat this deadly disease. Many natural products are used to treat cancer; therefore, to identify a natural product that would simultaneously target the STAT, MAP and PI3 kinase pathways; a natural product library was screened to identify those performing this function. A natural product called leelamine, derived from the bark of pine trees, was identified as a potent potential regulator of these pathways. Leelamine decreased tumor development in mice but was not bio-available and had to be administered in DMSO. To overcome this limitation, a nanoliposomal formulation called Nanolipolee-007, has been developed for intravenous administration, which is as effective as leelamine administered in DMSO. Therefore, the objective of this phase I SBIR proposal is to undertake IND enabling studies to develop an assay to measure the levels of leelamine in serum and tissues, which would subsequently be used for establishing the concentration required for cancer therapeutic efficacy, toxicity and to undertake preliminary pharmacokinetic/pharmacodynamic studies. Thus, the innovative and novel central hypothesis for these studies is that leelamine contained in liposomes will be released into the serum and taken into tissues to levels that will be detectable by LC-MS/MS enabling an optimal dose of leelamine to be established for dosing, therapeutic efficacy, toxicity and used for pharmacokinetic as well as pharmacodynamic studies. An agent of this type does not currently exist for melanoma, making this product highly innovative and thereby constituting a unique commercial market. This hypothesis will be tested and objective accomplished by: (1) establishing an LC-MS/MS method for measuring levels of leelamine contained in Nanolipolee-007 in the serum or tissues of animals over time following intravenous administration to establish dosing for therapeutic efficacy, toxicokinetics, pharmacokinetic and pharmacokinetic studies of the agent; and (2) undertaking escalating dose and 10-day repeated intravenous dosing studies in rats and dogs followed by measurement of leelamine levels present in the serum and tissues of the animals. Collectively, these discoveries are expected to form a crucial portion of the foundation to obtain IND status for systemic Nanolipolee-007 treatment from the FDA to enable evaluation in a phase I clinical trial.