Iron oxide nanoparticles are novel agents for the delivery of high concentrations of therapeutics to areas with leaky blood vessels. The focus of this initial proposal is the nanoparticle mediated delivery of a novel therapeutic agent, Tris DBA Palladium for the prevention and treatment of genetically diverse melanoma. We propose to assess the efficacy of IGF-1 targeted nanoparticles containing Tris DBA Palladium to mice carrying genetically diverse melanoma xenografts. This will be followed by studies on transgenic mice that develop melanoma due to expression of mutant Braf and loss of the tumor suppressor gene PTEN. Finally, we will perform pharmacokinetic and toxicology studies on optimized Tris DBA Palladium containing nanoparticles in anticipation of discussions with the FDA. Our innovation has been awarded US Patent 8,030,299. Hypothesis: The novel chemotherapeutic agent Tris DBA Palladium encapsulated in IGF-1R targeted theranostic IONPs can be selectively delivered to primary and metastatic melanoma, leading to improved therapeutic efficacy and overcome drug resistance in genetically diverse melanomas and enabling non- invasive imaging of targeted drug delivery and monitoring tumor responses to the therapy. In our initial studies with Tris DBA Palladium, we noted a significant therapeutic effect even though absorption of drug was incomplete. Thus, our initial studies likely underestimated the potential efficacy of the drug. By enhancing the delivery using novel nanoparticle carriers, it is likely that we can increase efficacy of the drug.In addition, our studies will determine when in tumor progression vessels become leaky and retain nanoparticles. This has important implications for future therapies.
Specific Aims :
Aim 1 : We will develop of IGF-1R1 targeted theranostic IONPs carrying Tris DBA Palladium and examine the effects of targeted drug delivery and tumor growth inhibition using human melanoma xenograft models in nude mice.
Aim 2 : We will evaluate and compare of the effects of image-guided and targeted therapy using IGF-1R- targeted theranostic IONPs on tumor growth and development of metastases in a transgenic Braf/PTEN melanoma model.
Aim 3 : We will perform Pre-IND development studies including systemic toxicity, dose, and PK/PD in normal and tumor-bearing mice.
In this proposal, we are targeting melanoma, which is one of the most common and deadly malignancies afflicting US veterans. My laboratory has discovered and patented a novel drug, Tris DBA Palladium, which inhibits an enzyme called N-myristoyltransferase 1, required for melanoma growth. We have already demonstrated that Tris DBA Palladium by itself has activity against melanoma in mice. However, we believe that we can make Tris DBA Palladium into an even more powerful drug by adding it to nanoparticles that are guided to the tumor because the particles contain IGF-1, a factor that guides particles to tumors. We believe that by targeting Tri DBA Palladium to IGF-1 expressing particles, we can build a 'guided missile' that will selectively deliver a lethal payload to tumors. In this way, we can deliver high doses of drug directly to the tumor without causing harm to normal tissues. We believe that the impact of this proposal goes far beyond melanoma, as many other solid tumors have high level expression of IGF-1 receptor and leaky blood vessels.