Prostate cancer is the most frequently diagnosed cancer and the second leading cause of cancer related death in Western men. In prostate intraepithelial neoplasia annexin A2 expression is absent however upon loss of androgen dependence annexin A2 is subsequently over-expressed. Regaining regulatory control of annexin A2 presents a means of therapy in the treatment of hormone refractory prostate cancers. In an effort to regain control of aberrant annexin A2 expression we have formulated poly lactide-co-glycolide (PLGA) nanoparticles loaded with pDrive-sh AnxA2 plasmid DNA. These nanoparticles are capable of sustained intracellular delivery of pDrive-sh AnxA2 plasmid DNA vector for long-term siRNA mediated down-regulation of annexin A2. Intra-tumoral administration of pDrive-sh AnxA2 loaded nanoparticles to xenograft prostate tumors in nude mice demonstrates an overall decrease in tumor growth. The decrease in tumor growth is through a reduction of annexin A2 and VEGF mRNA and protein levels within the tumor mass. Administration of blank nanoparticles demonstrated no alteration in tumor growth or annexin A2 and VEGF at either the mRNA or protein levels. Our findings suggest that the use of sustained-release polymeric nanoparticles for down-regulation of annexin A2 expression may serve as an effective adjuvant treatment option for prostate cancer.