Prostate cancer is a heterogeneous disease in which initial treatments are usually successful, but the percent of relapse is high and there are few efficient treatments for advanced local and metastatic disease. We propose to develop new approaches to prostate cancer therapy by developing nanocomposites that can be used for treatment of advanced prostate cancer and for imaging of disseminated prostate cancer cells. In our laboratory, we are working with titanium dioxide based nanocomposites (TiNCs) that belong to the category of bio-nanocomposites?nanometer-sized particles created by the conjugation of inorganic and """"""""traditionally"""""""" biological molecules. These nanocomposites are prepared from metal oxide (TiO2) nanoparticles (4.5 nm in size, surface-coated with glycidyl isopropyl ether) and DNA oligonucleotides covalently bound to the nanoparticles via dopamine. Within the TiNCs, the DNA oligonucleotides retain their base-pairing specificity, while the Ti02 nanoparticles exhibit a semiconductor characteristic photoreactivity. In particular, excitation of TiO2 (induced by exposure to electromagnetic radiation of energy above 3.2 eV) results in charge separation, ultimately resulting in scission of the DNA phosphodiester backbone in an adjacent DNA double helix. This endonuclease-like activity is therefore: (a) excitable by a factor not naturally encountered by cells in vivo (electromagnetic radiation of energy higher than 3.2 eV);and (b) highly sequence specific. This cleavage can be directed toward a single target gene in a whole genome (due to the high specificity of long oligonucleotide base-pairing);consequently, TiNCs behave as inducible genespecific endonucleases with allele-differentiating sequence specificity. In this proposal, we describe experiments designed to develop TiNCs for two main purposes. First, we propose to use TiNCs to cleave specific DNA targets involved in prostate cancer cell growth. Secondly, we propose to use TiNCs coupled with gadolinium (Gd) compounds to image disseminated prostate cancer cells in mice using magnetic resonance (MRI). Eventually, we hope to combine imaging and treatment capabilities into a single nanocomposite.
SPECIFIC AIM 1 : Develop TiNCs that use aberrant androgen receptor activity in hormone refractory prostate cancer cells to enter cell nuclei and cleave genes required for prostate cancer cell growth.
SPECIFIC AIM 2 : Develop TiNCs loaded with Gd that use aberrant androgen receptor activity in hormone refractory prostate cancer cells to accumulate both in situ arid in disseminated prostate cancer cells.
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