Despite rapid advances in early diagnostics and treatments, cancer remains one of the deadliest diseases killing over 1500 Americans each day. These are the driving forces for new cancer therapies and early diagnostics to enhance the clinical outcome of cancer patients. Of significant interest to the cancer community are image-guided drug delivery (IGGD) agents that probe tumor-drug interactions as well as track delivery and distribution of drugs and imaging agents. Such IGGD agents would replace chemotherapies whose administration affects the whole body systematically leading to toxicity. Recent nanotechnology advances have led to the development of nanocarriers/nanoimaging agents for tracking site-directed drug delivery and therapeutic response. These IGDD platforms hold tremendous potential but have translational limitations that must be overcome for clinical implementation including in vivo stability, localization in the body, and toxicity. Our focus is the optimization IGDD design to improve site-directed delivery, biodistribution, and reduce toxicity to normal cells.