This proposal describes a new inter-institutional collaboration between Assistant Professor Jason H. Hafner (Department of Physics and Astronomy, Rice University) and Assistant Professor Liana Adam (Department of Urology, M.D. Anderson Cancer Center) and two collaborators covering other important areas and expertise: (1) clinical aspects of bladder cancer therapy, Dr. Colin Dinney (Professor and Chair, Department of Urology and (2) Transmission Electron Microscopy imaging: Dr. Corazon Bucana (Professor, Department of Cancer Biology).

Using a multifaceted approach of simplified in vitro and in vivo models, we propose to investigate a new technique of gene delivery using nanoscale particles. In the proposed study, Dr. Hafner and I will work together to design proof of concept studies that will determine the efficacy of using the gold Nanorods (NRs) as targeted delivery vehicles for gene therapy. The unique structural and optical properties of gold NRs may facilitate the programmed delivery to the superficial tumor of a DNA-based siRNA construct for gene silencing. To achieve targeted cellular integration into the bladder cancer cells we will use epidermal growth factor (EGF) peptide bioconjugates to the PEGylated NRs and EGF receptor as "port of entry" into the bladder cancer cells. The bladder is an optimal site for gene therapy of superficial disease for several reasons. First, the therapeutic agent can be instilled transurethrally into the bladder and, at least theoretically, establish contact with the urothelium and tumor. The bladder is isolated from most vital organs, and the safety of gene therapy has been established in previous studies using BCG, the most extensive type of gene therapy used for superficial bladder cancer. Although most patients will initially respond to BCG, given time most will eventually fail and require second-line therapy, which unfortunately is ineffective. For many of these patients, the cancer has already metastasized by the time intravesical approaches are abandoned because of the resistance of both patients and surgeons to proceed to radical cystectomy for the treatment of only "superficial disease." Clearly, new approaches need to be developed unless we are willing to proceed to radical cystectomy earlier. If we are successful to deliver highly efficient quantities in a clinical setting of one type of gene delivery, we could expand the list of targets in a more patient-tailored, personalized manner, depending on expressed molecular markers. Thus, a scenario could be envisaged in which a cocktail of NRs containing various siRNA targets (against growth factors, signal molecules, etc.) may be released at different time intervals through specific manipulation of the NRs optical properties and cell targets through specific peptide bioconjugatate addition.