Remarkable drug-release enhancement with an elimination-based AB3 self-immolative dendritic amplifier

Abstract: Self-immolative dendritic prodrugs, activated through a single catalytic reaction by a specific enzyme, could offer significant advantages in inhibition of tumor growth relative to monomeric prodrug, especially if the targeted or secreted enzyme exists at relatively low levels in the malignant tissue. We have designed and synthesized new AB3 self-immolative dendritic prodrug system that releases three active drugs by a single cleavage of the enzyme penicillin-G-amidase. The cleavage signal is transferred from the dendron focal point to its periphery through fast elimination reactions and the design leads to three-fold signal amplification. In cell-growth inhibition assays, the elimination-based AB3 self-immolative dendritic prodrug was significantly more effective than a cyclization-based AB3 dendritic prodrug. [Copyright &y& Elsevier]