Breast cancer affects up to one in 10 women in Western and industrialized countries and the total number of cases diagnosed are about 190,000 each year in the United States alone, with a considerable mortality rate of 40,000. This strongly motivates the development of more effective treatments. Results from recent epidemiological and experimental studies have revealed significant beneficial association between breast cancer and hydrophobic statin therapy. Nanoemulsions offer exciting new possibilities for better treatment strategies of hydrophobic compounds by improving the biodistribution, the circulation half-life, and by diminishing interactions with plasma proteins or other plasma constituents. In addition, they also offer the possibility for target-specific delivery and, importantly, the integration of multiple properties, e.g. to allow therapy and diagnostics with the same agent. In this project we propose to develop a unique theranostic and surface activatable nanoparticle platform, which can be applied for target-specific MRI and anti-tumor therapy of breast cancer. The nanoparticles are targeted to 1v23-expressing breast cancer cells via RGD-peptides, but are prevented from targeting 1v23-expressing cells in the circulation through the following strategy: When the nanoparticles circulate, the RGD-peptides are actively shielded by long PEG-chains to minimize their exposure to the angiogenic vasculature and the cells of the reticulo-endothelial system. Once the particles accumulate in the tumor interstitial space, the PEG-chains are cleaved off by matrix metalloproteinase-2 activity inside the tumor and the RGD-moieties become available to facilitate uptake by tumor cells. Full in vitro targeting and efficacy studies will be performed. In vivo, biodistribution and molecular imaging studies will be performed on mouse breast cancer models in order to evaluate targeting efficiency. Lastly, therapeutic efficacy will be investigated in the same mouse models. Extensive immunofluorescent, histological, and molecular biological techniques will be applied to evaluate the in vivo findings and to unravel the mechanism of action.
The specific aims are:
Aim 1 : To synthesize and characterize a surface-switching nanoemulsion platform for targeting, visualizing and treating breast cancer.
Aim 2 : To test the targeting efficacy and therapeutic potential of nanoemulsions in vitro on different cell types.
Aim 3 : To study the biodistribution and targeted 'trapping'of surface-switching nanoemulsions in a breast cancer mouse model via in vivo imaging.
Aim 4 : To conduct a therapy study where surface-switching nanoemulsions, that carry statins, are applied to a breast cancer mouse model.
In this project we propose the development of a surface activatable nanoemulsion platform for the diagnosis and treatment of breast cancer. We will test the platform on breast cancer cells in vitro and mouse models in vivo, use magnetic resonance imaging and optical imaging to determine endpoints, and thoroughly investigate and validate targeting and therapeutic efficacy using traditional molecular biology and histological techniques. We expect that our overall approach will improve the diagnosis and treatment of breast cancer.
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