||It is estimated that in 2016, more than 848,000 new cases of cancer will be diagnosed in men with more than a quarter being prostate cancer and more than 26,000 deaths attributed to this disease. Prostate cancer poses a limited risk when detected at an early stage and treatment of stages II-III has a 5-year survival rate of almost 100%. However, these early-stage cancers can eventually progress and develop into stage IV, dramatically dropping the 5-year survival rate to 28%. Thus, development of a new therapy is needed to fully eliminate these tumors. Combination of heat and chemotherapy improves therapeutic efficacy while allowing for reduced dosing of drugs and limiting side effects. Localized hyperthermia has been used to enhance the delivery of polymer therapeutics to prostate tumors through increased blood flow, vascular permeability, and incorporation of heat shock targeting. This strategy has been shown to increase the delivery and retention of polymer-drug conjugates leading to enhanced efficacy. Although much work has been done using this strategy, the effects of different thermal dosing on polymer accumulation are unknown. The first aim of this research is to examine how altering heating parameters influences polymer tumor accumulation. The hypothesis for this aim is that there is an optimal thermal treatment that leads to the maximal amount of polymer accumulation in the tumors. Additionally, the previously used heating method of plasmonic photothermal therapy (PPTT) can result in long-term accumulation of gold nanoparticles in healthy organs, potentially limiting clinical applicability. The second aim of this proposal will be focused on investigating the alternative method of high intensity focused ultrasound (HIFU) for selective heating of tumors and enhancing macromolecular delivery. HIFU has shown the capability for precise, noninvasive heating of specific regions within the prostate through magnetic resonance imaging (MRI) guidance. The hypothesis to be tested in this aim is that mild hyperthermia produced with HIFU will have the same effect as that produced by PPTT in improving the delivery of macromolecular systems to solid tumors. Finally, in the third aim, the enhanced delivery of targeted polymer therapeutics to prostate tumors in mice models will be investigated using mild hyperthermia produced with HIFU. In the long term, it is anticipated that HIFU can be used in conjunction with delivery of polymer-drug conjugates for enhanced efficacy and reduced toxicity of chemotherapy to produce a clinically relevant treatment of advanced prostate cancer.