Enzymatic Activation of Second-Generation Dendritic Prodrugs:Conjugation of Self-Immolative Dendrimers with Poly(ethylene glycol)via Click Chemistry

摘要

Single-triggered disassemble dendrimers were recently developed and introduced as a potential platform for a multi-prodrug.These unique structural dendrimers can release all of their tail units through a self-immolative chain fragmentation initiated by a single cleavage at the dendrimer's core.There are several examples for the bioactivation of first-generation self-immolative dendritic prodrugs.However,enzymatic activation failed for second-generation self-immolative dendrimers.The hydrophobic large molecular structure of the dendritic prodrugs results in aggregation under aqueous conditions and prevented the enzyme from reaching the triggering substrate.Here we show a simple solution for the enzymatic activation of second-generation self-immolative dendrimers.Poly(ethylene glycol)(PEG)was conjugated to the dendritic platform via click chemistry.The poly(ethylene glycol)tails significantly decreased the hydrophobic properties of the dendrimers and thereby prevented aggregate formation.We designed and synthesized a dendritic prodrug with four molecules of the anticancer agent camptothecin and a trigger that can be activated by penicillin-G-amidase.The PEG5000-conjugated,self-immolative dendritic prodrug was effectively activated by penicillin-G-amidase under physiological conditions and free camptothecin was released to the reaction media.Cell-growth inhibition assays demonstrated increased toxicity of the dendritic prodrug upon incubation with the enzyme.