Alendronate-functionalized hypoxia-responsive polymeric micelles for targeted therapy of bone metastatic prostate cancer.

Bone metastasis is one of the leading causes of cancer-related death and remains incurable in spite of great efforts. Bone-targeted nanoparticle-based drug carriers can overcome the difficulties in delivering therapeutic agents to metastatic bone and endowing them with a stimuli-responsive feature for controllable drug release can further maximize their therapeutic outcome. In light of hypoxic microenvironment of bone metastasis, we herein reported a bone-targeted and hypoxia-responsive polymeric micelle system for effective treatment of bone metastatic prostate cancer. The micelles were self-assembled from a polyethylene glycol and poly-l-lysine based copolymer using alendronate as a bone-targeted moiety and azobenzene as a hypoxia-responsive linker, showing a high affinity to metastatic bone and a high sensitivity in responding to hypoxia in vitro. In vivo studies further showed that after a selective accumulation in metastatic bone, the micelles could respond to hypoxic bone metastasis for rapid drug release to an effective therapeutic dosage. As a result, the micelles could suppress tumor growth in bone and inhibit bone destruction by inhibiting osteoclast activity and promoting osteoblast activity, achieving an enhanced therapeutic outcome with relieved bone pain and prolonged survival time. Bone-targeted and hypoxia-responsive nanocarriers therefore represent a promising advancement for treating bone metastasis. To our best knowledge, it might be the first example of the application of hypoxia-responsive nanocarriers in treating bone metastasis.