Chemotherapeutic bone-targeted bisphosphonate prodrugs with hydrolytic mode of activation.

Osseous tissues are considered to be limited as therapeutic target sites due to their biological properties. We have designed and synthesized two kinds of hydrolytically activated chemotherapeutic prodrugs containing bisphosphonate, a bone-targeting moiety. The first can be conjugated to drug molecules with an available hydroxy group; the drug is attached to the bisphosphonate component through an ester-labile linkage. The second is for use with drug molecules with amine functional group. In this case, a self-immolative linker is used to attach the drug to the bisphosphonate component through a carbonate-labile linkage. The concept was demonstrated using the drugs camptothecin, which has a hydroxy functional group, and tryptophan, which is a model molecule for a drug with amine functionality. Both prodrugs showed significant binding capability to hydroxyapatite, the major component of bone, and were hydrolytically activated under physiological conditions.