Bone metastases are a frequent cause of morbidity in cancer patients. The present palliative therapeutic options are chemotherapy, hormone therapy, and the administration of bisphosphonates. The affinity between bisphosphonates and the apatite structure of bone metastases is strong. Thus, we designed two low-molecular-weight and water-soluble prodrugs which incorporate a bisphosphonate group as a bone targeting ligand, doxorubicin as the anticancer agent, and either an acid-sensitive bond (1) or a cathepsin B cleavable bond (3) for ensuring an effective release of doxorubicin at the site of action. Cleavage studies of both prodrugs showed a fast release of doxorubicin but sufficient stability over several hours in human plasma. Effective binding of prodrug 1 and 3 was demonstrated with hydroxyapatite and with native bone. In orientating toxicity studies in nude mice, the MTD of 1 was 3-fold higher compared to conventional doxorubicin, whereas 3 showed essentially the same MTD as doxorubicin.