Angiogenesis a major contributor to tumor development and metastases. Formation of new blood vessels supports tumor proliferation and disease progression and is often associated with poor clinical prognosis. Recent advances targeting angiogenesis and inhibition of tumor neovascularization has led to the approval of several new antiangiogenic drugs for clinical use in many types of cancers. Yet despite promising potential, the efficacy of these treatments has been relatively limited. Additionally, as with chemotherapeutics, over time these therapies are associated with tumor resistance and escape. Antiangiogenic therapy (target-specific or broad spectrum) aims to eradicate the tumor by damaging its blood supply; as a result tumor tissue becomes hypoxic and, consequently, necrotic. By current clinical measure, this tissue death is considered a positive outcome; however it is recently discovered that the necrotic tissue in turn releases signals contributing to inflammation and angiogenesis, eventually initiating aggressive revascularization, overriding the foreseen beneficial effects of the antiangiogenic drug. For this grant, we propose to design a novel drug-delivery system based on multifunctional polymer nanomicelles which combine two small molecule drugs: one a potent antiangiogenic drug, and second which is an antagonist of these necrotic signals, combating the feed-back loop which can undermine the positive effects of therapy. Using this innovative approach, we intend to significantly improve cancer treatment by minimizing resistance to antiangiogenic drugs. This technology is based on our previous development of the PEG-PLA polymer conjugate of a small molecule angiostatic compound, TNP-470, which form nanomicelle with improved pharmacological properties compared with the free drug. By combining a second drug with distinct mechanism of action we will provide an important, clinically relevant tool, and a future platform for antiangiogenic or other drugs.