| This year, 189,000 new cases of prostate cancer will be diagnosed in the United States. The survival benefit of late stage patients due to current treatment options is minimal. Fortunately, 80% of newly diagnosed cases are confined within the prostate. Current treatment options for localized prostate cancer are accompanied by side effects including impotence and incontinence. The work presented in this dissertation reflects a multidisciplinary approach towards the development and study of regional prostate cancer chemotherapy. Formulation studies were performed using biodegradable polymers. A Poly(lactide-co-glycolide) cylindrical matrix containing doxorubicin was selected as the optimal drug delivery device. Distribution and penetration kinetics of doxorubicin from these devices were studied in dog prostates. Doxorubicin cylinders were implanted into prostates under ultrasonic guidance and harvested at varying time points. Using laser confocal microscopy and image analysis, pixel intensity profiles were generated. From these data, it was determined that doxorubicin distribution was localized within the implanted lobules. Doxorubicin distribution within the implanted lobules was incomplete prior to 24 hours and characterized by a mean w½ of 250 μm. Doxorubicin tissue concentrations within the implanted lobule ranged from 31–585 μg/g, while plasma and lymph node concentrations were below the HPLC detection limit. Histopathologic changes induced by the intra-prostatic implants were also studied. Prostates containing doxorubicin implants were harvested between 2.5 hours–3 months after implantation. Results indicated that the implants produced localized tissue necrosis. Necrosis was limited to the implanted lobules and was not evident until 24 hours. The implants produced a mild inflammatory response lasting approximately one week. Twenty eight days after implantation, there was no evidence of tissue necrosis. There was no damage caused to neither the prostatic urethra, nor the peri-prostatic neurovascular bundles at any time. Finally, the efficacy of these implants was studied using dog patients diagnosed with spontaneously arising tonsillar and prostate tumors. The implants were shown to reduce, or inhibit tumor volume growth for several weeks. While these implants did not show a benefit for the treatment of metastatic diseases, they have shown promising results for the treatment of localized primary tumors. |
