Click-unclick

In recent years, tremendous efforts have been focused on the design of novel ways to target drugs to specific cells or organs. One highly promising strategy is the design of efficient delivery systems for which the drug release can be triggered by a photochemical event. The drug can be linked covalently to a carrier, or encapsulated within a porous nano-delivery system. Irradiation of the prodrug system within the organ to treat must lead to the rapid cleavage of the bond between the drug and the carrier, for carrier-based prodrugs, or to the “opening” of nano-delivery systems. The chemical bonds involved in the assembly of the delivery systems determine the complexity of the synthetic work and the fragmentation properties upon irradiation. To date, different linkers have been designed for this purpose. Usually, they require complex protection schemes for the assembly or lead to suboptimal fragmentation rates. Recently, the IBL team has designed a novel strategy named click-unclick (CC) allowing both the site-specific assembly of prodrugs and the subsequent rapid release of the active substance at the delivery site. The CC strategy involves first a novel click-type reaction which leads to the chemoselective assembly of the prodrug. Because the bond is formed chemoselectively, the assembly of the prodrug is considerably simplified compared to known strategies. Importantly, the bond formed in this process for assembling the constituents of the prodrug is used in the second step to unclick the drug at the site of delivery. For the moment, the unclick process was triggered by a biochemical (proteolytic enzyme) or a chemical (pH change). The aim of this project is to trigger the unclick process using a photochemical event, and to use the CC strategy for assembling novel peptide-based prodrugs and nano-delivery systems. The nano-delivery systems will be assembled by closing the pores of porous nanoparticles with dendrimers. Here, the CC strategy is used for closing/opening the nanoparticles filled with model anticancer drugs. The project includes also novel synthetic developments to facilitate the introduction of key functional groups for the click-unclick strategy.