Designer Anticancer Nanoprodrugs with Self-Toxification Activity Realized by Acid-triggered Biodegradation and...

Prodrugs that allow in situ chemical conversion of less toxic precursors into active drugs in response to certain stimuli are promising anticancer candidates. Herein, we present a novel design of nanoprodrugs with a "degradation-mediated self-toxification" strategy, which realizes intracellular synthesis of anticancer agents using the nanoparticles' own degradation fragments as the precursors. To fulfill this concept, a metal complexing dicyclohexylphosphine (DCP) organosilane is carefully screened out from various ligands to conjugate onto Pd(OH)₂ nanodots confined hollow silica nanospheres (PD-HSN). This constructed nanoprodrug shows acid-triggered degradation in lysosomes and neutralizes protons to induce lysosomes rupturing, generating predesigned less toxic fragments (Pd²⁺ and DCP-silicates) that complex into DCP/Pd complex in situ for inducing DNA damage, leading to enhanced anticancer activity against various cancer cell lines as well as in a xenograft tumour model.