In‐Gel Generated Palladium Nanostructures as Bioorthogonal Uncaging Reactors

In the quest to alleviate the severe side effects of chemotherapy, a promising approach is through prodrugs, an inactivate form of the drug that is administered systemically but activated locally. Bioorthogonal chemistry has the potential to generate high doses of drug at the tumor site with minimal off‐target exposure. To harness the potential of bioorthogonal prodrugs, implantable heterogenous catalysts consisting of biocompatible polymers with immobilized metal nanoparticles are required. Polymers based on poly(2‐hydroxyethyl methacrylate) with different levels of hydrophilicity are functionalized with either palladium nanocubes (≈10 nm) or palladium nanosheets (<200 nm). Using a palladium‐sensitive fluorogenic model compound, propargylated resorufin, the nanosheets show higher catalytic activity than the nanocubes, as well as better metal retainment within the hydrogels. The more hydrophilic polymers show improved diffusion, conversion, and release and better recyclability. Converted product is sequestered by the polymer and released with delay, establishing a potential route to sustained release. These heterogenous catalysts can facilitate the clinical translation of bioorthogonal prodrugs.