Women have a 1 in 8 lifetime risk of breast cancer making it their second highest oncogenic cause of mortality behind lung cancer. Thirty percent of patients with stage I to III disease have silent bone marrow (BM) micro-metastases, which increase their likelihood of cancer recurrence as well as complications, such as pathological fractures, and related to the osteolytic nature of the disease. Even patients with limited early-stage disease, who responded well to chemo- or hormonal therapy at the primary site, may relapse years later when dormant bone marrow micro-metastases, previously protected within the bone marrow niche, recrudesce. Our research has recently revealed that breast cancer metastasis in the presence of bone marrow stromal cells, in vitro and in vivo, up-regulated αvβ3-integrin expression, leading to marked diminished sensitivity to systemic chemotherapy. Moreover, these data indicated that TGF-β3 sequestered in the bone microstroma was liberated to induce αvβ3-integrin up-regulation. Utilizing this bone BC target, αvβ3-targeted mixed micelles (~15nm) incorporating Sn2 lipase-labile docetaxel (DTX) prodrug (DTX-PD) (αvβ3-DTX-PD MP) were developed to rapidly and homogeneously penetrate into the tumor shown and deliver DTX therapy directly into the cell through a novel approach, termed "Contact Facilitated Drug Delivery" (CFDD). αvβ3-DTX-PD MP markedly reduced bone marrow BC tumor burden and osteolytic damage with negligible off-target effects, whereas systemic DTX at up to 4-fold higher doses had no impact on tumor progression yet elicited hepatic and hematologic toxicity. However, many patients with bone BC likely will have previously received DTX. From this perspective and recognizing the "stem cell" nature of breast cancer bone metastases, a camptothecin (CPT) Sn2 lipase-labile prodrug (CPT-PD) was developed to offer a new patient-naive treatment. CPT is a topoisomerase 1 (TOPO 1) inhibitor with powerful hypoxia-inducible factor 1-alpha (HIF-1α) inhibitor that is cytotoxic to cancer stem cells. This proposal investigates the efficacy and safety the αvβ3-CPT-PD-MP or αvβ3-DTX-PD MP nanosystems against the bone BC tumors, micro-metastases, dormant tumor cells to provide potent therapy to bone and to reduce the risk of breast cancer relapse from micrometastases. This proposal addresses the unmet therapeutic challenge and medical need posed by BC bone metastases. This project will delineate the bone BC efficacy and safety of αvβ3-Sn2-prodrug micelles and also elucidate the impact of key bone microstroma constituents such as TGF-β and αvβ3+ tumor associated macrophages (M2 TAMS) and αvβ3+ osteoclasts on treatment responses. The translational overarching goals are to more effectively treat patients with Stage 4 breast cancer in bone (Aims 1& 2), and to increase the enduring cure rate for Stage 1 to 3 BC patients by treating occult breast cancer micro-metastases to diminish disease relapse (Aim 3).