Acid-sensitive prodrugs of Doxorubicin.

The endosomal and/or lysosomal pathway of macromolecules, as well as the slightly acidic extracellularenvironment in solid tumors, form the rationale for designing carrier-linked prodrugs with pH-dependentlinkers. In the past 20 years, a spectrum of acid-sensitive doxorubicin prodrugs has been developedwith antibodies, serum proteins, and synthetic polymers. For a number of these, a convincingproof of concept has been obtained preclinically, showing an enhanced therapeutic efficacy of theprodrugs compared to free doxorubicin in tumor models. Clinically, the (6-maleimidocaproyl)-hydrazonederivative of doxorubicin, which binds either to the monoclonal antibody BR96 or to endogenous albumin,has been evaluated in clinical trials.