Metastatic cancers in bone are very difficult to treat and result in pain, bone fractures, nerve compression, morbidity, and often mortality. Current therapeutic modalities for bone-metastatic cancers are usually palliative in nature and there is a clear need for better treatment options, and this proposal addresses such an important public health need. The research project proposes to explore, develop and test a novel nanotherapeutic platform to improve the skeletal affinity, selectivity and efficacy of anti-cancer agents, in hopes of developing an effective therapeutic modality for bone metastases. The nanotherapeutics are based on a synthetic tri-block copolymers of peptide, poly(ethylene glycol) and poly(trimethylene carbonate) (Pep-b-PEG-b-PTMC). The functional peptide is designed to possess bone tropism octapeptide (Asp8) and cathepsin K (CTSK)-cleavable substrate (HPGGPQ). The amphiphilic copolymers can spontaneously form micellar nanoparticles with core-shell structures. Initially we will use doxorubicin (DOX), a FDA-approved anti-cancer therapeutics as a model anti-cancer agent. Amphiphilic copolymers are able to incorporate hydrophobic agents into the core of nanoparticles through a self-assembly process. Besides sharing common advantages of nanoparticles for delivery of anti-cancer therapeutics, our strategy offers an approach to differentiate healthy skeletons and osteolytic lesions and then elicit therapeutic actions to attack cancer cells within pathological skeletal domains, which is a substantial innovative feature in comparison with current available therapeutic approaches for bone metastases. The long-term goal of the project is to develop and validate an osteolytic stimuli-responsive drug delivery system and ultimately provide an effective therapeutic modality to improve the treatment of bone metastases. The proposed research project could lead to an effective therapeutic approach to attack invading cancer cells around bone metastatic microenvironments. In addition, the proposed therapeutic approach has considerable adaptability to accommodate different tissue-targeting moieties and therapeutic compounds. Once the nanotherapeutic system is established, it is easily adaptable for delivering other candidate therapeutics. This may lead to a new bone-targeted drug delivery platform for bone metastases and possibly other bone-related diseases.