Palladium nanoparticle loaded polymers for the bioorthogonal catalytic activation of chemotherapy prodrugs in vivo

Severe side effects arising from systemic administration of potent anticancer drugs has prompted the ongoing search for new ways to deliver chemotherapeutics to a target site in a spatially controlled manner. The last decade has seen increasing interest in the use of bioorthogonal organometallic (BOOM) reactions for the metal-catalysed activation of prodrugs in situ. The development of a series of prodrugs containing the palladium (Pd)-cleavable propargyl moiety has necessitated the need for a suitable method to deliver the palladium nanoparticle (PdNP) catalyst to a desired location. Immobilisation of PdNPs within a non-degradable, biocompatible polymer matrix would allow for the implantation of the catalyst, e.g. intratumourally. Subsequent systemic administration of a harmless Pd-sensitive prodrug would result in the synthesis of high concentrations of the active drug where the implant is located.

Loading of polymeric materials with PdNPs can be done through infusion with Pd(II)-precursor followed by subsequent in situ reduction to generate PdNPs. Here we present the synthesis of poly(N-isopropylacrylamide-co­-4-vinylpyridine) (poly(NIPAM-co-4VP)) hydrogel and the subsequent Pd-functionalisation of both it, and commercially available poly(ethylene glycol) (PEG) microbeads. These Pd-laden polymeric materials were shown to successfully cleave the propargyl ether protecting group from a fluorogenic probe, propargylated resorufin, as shown in the figure. "