Bisphosphonate-Functionalized Imaging Agents, Anti-Tumor Agents and Nanocarriers for Treatment of Bone Cancer.

Bone metastases result from the invasion of primary tumors to bone. Current treatment modalities include local treatments such as surgery and radiotherapy, while systemic treatments include chemotherapy and (palliative) treatment of skeletal metastases. Nevertheless, once bone metastases have been established they remain incurable leading to morbidity and mortality. Bisphosphonates are a well-established class of drugs, which are increasingly applied in the treatment of bone cancers owing to their effective inhibition of tumor cells and suppression of bone metastases. The increased understanding of the mechanism of action of bisphosphonates on bone and tumor cells has prompted the development of novel bisphosphonate-functionalized imaging and therapeutic agents. This review provides an update on the preclinical efficacy of bisphosphonate-functionalized fluorophore, anti-tumor agents and nanocarriers for the treatment of bone metastases. After an overview of the general characteristics of bisphosphonates and their mechanisms of action, an outline is provided on the various conjugation strategies that have become available to functionalize imaging agents, anti-tumor agents and nanocarriers with bisphosphonates. Finally, the efficacy of these bisphosphonate-modified agents and carriers in preclinical studies is evaluated by reviewing their potential to target tumors and inhibit tumor growth in clinically relevant animal models for the treatment of bone cancer.