Development of Novel Bisphosphonate
Prodrugs of Doxorubicin
for Targeting Bone Metastases That Are Cleaved pH Dependently or by
Cathepsin B: Synthesis, Cleavage Properties, and Binding Properties
to Hydroxyapatite As Well As Bone Matrix
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Abstract
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 (<b>1</b>) or a cathepsin B cleavable bond (<b>3</b>) 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 <b>1</b> and <b>3</b> was
demonstrated with hydroxyapatite and with native bone. In orientating
toxicity studies in nude mice, the MTD of <b>1</b> was 3-fold
higher compared to conventional doxorubicin, whereas <b>3</b> showed essentially the same MTD as doxorubicin