pH-sensitive prodrugs

The exploitation of prodrugs to overcome pharmacokinetic/pharmacodynamic limitations of an active compound is a validated approach in Medicinal Chemistry, with many successful examples found among the medications approved for clinical use. Among the different triggers that can be used to promote prodrug activation and liberation of the active moiety, pH variation is mostly exploited to ensure a selective delivery of the drug to the targeted biological systems. In this chapter, we report the main examples of pH-sensitive prodrugs reported in the literature and associated drugs currently approved in clinics or under clinical studies. Small molecule prodrugs have been considered along with few examples of macromolecular prodrugs. The main field in which this prodrug family is employed is the treatment of tumors, in which the altered metabolism and the peculiar environment can be therapeutically targeted and exploited. Although quite underrepresented when compared to prodrugs relying on enzymatic activation, pH-sensitive prodrugs are attracting a growing interest in the scientific community.