Targeted Polymer Micelles for Treatment of Metastatic Melanoma

DESCRIPTION (provided by applicant): According to the American Cancer Society, half of all men and one-third of all women in the United States will develop cancer in their lifetime. While chemotherapy has dramatically improved the survival rate of cancer patients, it comes at the cost of severe toxicities and in some cases poor response rates. In order to address these shortcomings, equal investments in drug delivery innovations are necessary to improve the success rate of these treatments and improve the quality of life for these patients. In order to accomplish these goals, drug delivery vehicles are needed which are stable to post-administration dilution, can avoid biological barriers (e.g. reticuloendothelial system (RES) uptake), and deliver drugs in response to a physiological stimuli encountered in solid tumor environment, i.e. change in the pH level. Furthermore, drug delivery systems that employ active targeting strategies will gain an additional advantage in the ability to target tumor cells in vivoand in turn increase the exposure of the chemotherapeutic locally at the tumor site. Polymer micelles formed by the assembly of amphiphilic block copolymers are a particular type of nanocarrier that are attractive due to their ability to confer water solubility to hydrophobic drug by encapsulating them within the core of the micelle. While the use of polymer micelles equipped with cancer-specific targeting groups is particularly promising for chemotherapy, their current clinical utility is limited due to their instability in biologically relevant environments.In an effort to address this instability problem, a polymer micelle-based drug delivery system was developed that utilizes novel stabilizing technology. This stabilizing technology utilizes reversible,pH-dependent crosslinking chemistry that stabilizes the micelle at physiological pH, but releases the drug in response to lower pH environments, such as areas surrounding a tumor or within endosomes. Taxanes are a widely prescribed family of chemotherapeutic agents, but their efficacy is limited by systemic toxicity. Herein, we propose the encapsulation of taxanes in a stabilized micelle delivery system with the goal of widening the therapeutic index of taxanes by increasing the amount of drug delivered tothe tumor and reducing exposure to healthy cells. Melanoma is an example of a specific indication that has shown a preclinical response to taxanes. Because there is no effective treatment for metastatic melanoma, patients diagnosed with this lethal disease would benefit from a taxane loaded drug delivery system equipped with melanoma specific targeting group. Accordingly, we have attached a MC1R specific targeting peptide to the surface of the micelle to enhance tumor uptake and retention. MC1R is a bona fide melanoma marker with high and broad expression among metastases. Specific aim 1 will investigate the physiochemical properties of the stable; taxane loaded micelle as well as the binding affinity of the MC1R targeted micelles on live cells. Specific aim 2 will focus on the in vivo behavior of the MC1R targeted micelle in comparison to the untargeted; drug loaded micelle as well as free drug. Key experiments will include maximum tolerated dose, pharmacokinetics, biodistribution and efficacy. Completion of these aims will provide essential preclinical data for the further advancement of a taxane loaded, MC1R targeted micelle formulation into IND-enabling Phase 2 studies. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The goal of this project entitled Targeted Polymer Micelles for Treatment of Metastatic Melanoma is to develop a safer, more effective treatment for metastatic melanoma by utilizing polymer micelle drug delivery technology. The use of a melanoma specific targeting group helps increase the amount of drug that accumulates in the tumor environment, while decreasing the amount of drug in healthy tissues. Completion of the proposed research will lead to a safer, more effective treatment for metastatic melanoma, which has the potentialfor a significant global impact.