Prostate cancer is the most commonly occurring malignancy and the second-leading cause of cancer-related death in men in the US. The resistance of the advanced (androgen-independent) prostate cancer phenotype to conventional treatments such as chemo- and radiation therapies is the major cause of death and currently there is no therapy that significantly increases survival in these cases. There is an urgent medical need for treatments that specifically target advanced prostate cancer disease while sparing normal tissue in advanced prostate cancer disease. Mitochondria play a key role in regulating survival and apoptosis (cellular suicide) pathways in cells and therefore, mitochondrial integrity is linked to cell survival. Upon cellular uptake, cationic amphipathic peptides preferentially localize in the mitochondria leading to membrane depolarization, release of apoptosis-inducing proteins, and ultimately, cell death.

The Prostate Specific Membrane Antigen (PSMA) is over-expressed on the surface of malignant prostate cells and is therefore an appropriate receptor for targeting MDPs to the malignant prostate tissue. We describe the design, generation, characterization, and in vitro evaluation of targeted prostate cancer therapeutics using PSMA-mediated delivery of MDPs. The first effort involved the design and evaluation of a PSMA Targeting Peptide (PTP)-MDP fusion. In parallel, we explored the display of PTPs on the surface of nanoscale quantum dots using molecular self-assembly as means to develop QD-PTP assemblies capable of targeting prostate cancer cells. In addition to the display of multiple PTPs, fluorescent QDs facilitate visualization of targeted cells. A third approach is directed towards the development of multi-functional QD-PTP/MDP conjugates that possess imaging, targeting, and apoptotic functionalities on a single platform. Finally, in addition to PTP based constructs, we are developing monoclonal antibody (mAb)-MDP immunoconjugates capable of inducing apoptosis in prostate cancer cells. Current research involves the optimization of these constructs with an eye toward generating immunoconjugates and QD-peptide assemblies with higher efficacies and selectivities. It is expected that this research will significantly expand the toolbox of targeted therapies against advanced prostate cancer disease.