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

BACKGROUND: Chemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H(2)O(2)) 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 H(2)O(2) level in tumor cells. Fortunately, β-Lapachone (Lapa) that can exert H(2)O(2)-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 H(2)O(2) 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 H(2)O(2) production and augmented CDT (“1 + 1 + 1 > 3”). RESULTS: The effective inhibition of PARP by Ola can synergize Lapa to enhance H(2)O(2) formation due to the continuous NQO1 redox cycling. In turn, the high levels of H(2)O(2) further react with Co(2+) 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 H(2)O(2) generation for tumor-specific self-amplified CDT. GRAPHIC ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12951-021-00998-y.