A self-amplified nanocatalytic system for achieving "1 + 1 + 1 > 3" chemodynamic therapy on triple negative breast cancer

Abstract

Background: Chemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H₂O₂) into toxic hydroxyl radicals (·OH) to kill cancer cells, holds great promise in tumor therapy due to its high selectivity. However, the therapeutic effect is significantly limited by insufficient intracellular H₂O₂ level in tumor cells. Fortunately, β-Lapachone (Lapa) that can exert H₂O₂-supplementing functionality under the catalysis of nicotinamide adenine dinucleotide (phosphate) NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme offers a new idea to solve this problem. However, extensive DNA damage caused by high levels of reactive oxygen species can trigger the "hyperactivation" of poly(ADP-ribose) polymerase (PARP), which results in the severe interruption of H₂O₂ supply and further the reduced efficacy of CDT. Herein, we report a self-amplified nanocatalytic system (ZIF67/Ola/Lapa) to co-deliver the PARP inhibitor Olaparib (Ola) and NQO1-bioactivatable drug Lapa for sustainable H₂O₂ production and augmented CDT ("1 + 1 + 1 > 3").

Results: The effective inhibition of PARP by Ola can synergize Lapa to enhance H₂O₂ formation due to the continuous NQO1 redox cycling. In turn, the high levels of H₂O₂ further react with Co²⁺ to produce the highly toxic ·OH by Fenton-like reaction, dramatically improving CDT. Both in vitro and in vivo studies demonstrate the excellent antitumor activity of ZIF67/Ola/Lapa in NQO1 overexpressed MDA-MB-231 tumor cells. Importantly, the nanocomposite presents minimal systemic toxicity in normal tissues due to the low NQO1 expression.

Conclusions: This design of nanocatalytic system offers a new paradigm for combing PARP inhibitor, NQO1-bioactivatable drug and Fenton-reagents to obtain sustained H₂O₂ generation for tumor-specific self-amplified CDT.