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

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

  • J Nanobiotechnology. 2021 Sep 4;19(1):261. doi: 10.1186/s12951-021-00998-y.
Lulu Zhou  # 1,  Jinjin Chen  # 1 2,  Yunhao Sun 3,  Keke Chai 1,  Zhounan Zhu 1,  Chunhui Wang 1,  Mengyao Chen 1,  Wenmei Han 1,  Xiaochun Hu 1,  Ruihao Li 1,  Tianming Yao 1,  Hui Li 1,  Chunyan Dong 4,  Shuo Shi 5
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Breast Cancer Center, Shanghai East Hospital, Tongji University, Shanghai, 200092, People's Republic of China.
  • 2 Department of Oncology, The Fourth Affiliated Hospital of Nantong University, First People's Hospital of Yancheng, Yancheng, Jiangsu, People's Republic of China.
  • 3 Department of Thoracic Surgery, First People's Hospital of Yancheng, Affiliated to Medical College of Nanjing University, Yancheng, Jiangsu, People's Republic of China.
  • 4 Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Breast Cancer Center, Shanghai East Hospital, Tongji University, Shanghai, 200092, People's Republic of China. [email protected].
  • 5 Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Breast Cancer Center, Shanghai East Hospital, Tongji University, Shanghai, 200092, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 34481495 DOI: 10.1186/s12951-021-00998-y
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.

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