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

Abstract

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.

Click Chemistry, A Powerful Tool for Pharmaceutical Sciences

“…As an example of a dendrimer used for drug delivery, Gopin et al (70) reported the synthesis and evaluation of a single-triggered disassemble dendrimer as a potential platform for a multi-prodrug. "These unique structural dendrimers can release all of their tail units through a selfimmolative chain fragmentation that is initiated by a single cleavage at the dendrimer's core" (70).…”

“…"These unique structural dendrimers can release all of their tail units through a selfimmolative chain fragmentation that is initiated by a single cleavage at the dendrimer's core" (70). To allow enzymatic activation of the second-generation of self-immolative dendrimers, azide-monoterminated PEG was conjugated to the dendritic platform via click chemistry, which prevented aggregate formation of the hydrophobic drugs.…”

New methodologies in the construction of dendritic materials

“…However, if a highly versatile reaction, such as the CuAAc reaction, is utilized in combination with convergent growth, the risk of partial coupling of the active sites in the dendritic core is diminished. For example, Shabat et al 43 reports on the convergent attachment of PEG-chains to a dendritic core via Click chemistry using only stoichiometric amounts of the linear polymer.…”

Dendrimers and miktoarm polymers based multivalent nanocarriers for efficient and targeted drug delivery

“…These results show that the incorporation of a specific enzyme substrate which would be cleaved by a protease overexpressed in tumor cells could be a suitable dendritic pro-drug system. 179 …”