A self-amplified nanocatalytic system for achieving \u201c1\u2009+\u20091\u2009+\u20091\u2009>\u20093\u201d chemodynamic therapy on triple negative breast cancer

Lulu Zhou,Keke Chai,Yunhao Sun,Mengyao Chen,Xiaochun Hu,Ruihao Li,Jinjin Chen,Chunhui Wang,Chunyan Dong,Tianming Yao,Shuo Shi,Zhounan Zhu,Hui Li,Wenmei Han

doi:10.1186/s12951-021-00998-y

Lulu Zhou, Keke Chai + Show 12 more

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https://doi.org/10.1186/s12951-021-00998-y

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BackgroundChemodynamic 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”).ResultsThe 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.ConclusionsThis 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.Graphic

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As a newly developed reactive oxygen species (ROS)mediated therapeutic model, chemodynamic therapy (CDT) that can transform intratumoral overexpressed hydrogen peroxide (H2O2) into highly cytotoxic ·OHZhou et al J Nanobiotechnol (2021) 19:261 of H2O2 in cancer cells undoubtedly confers a large chemical barrier for effective Chemodynamic therapy (CDT) [18,19,20,21]
Preparation and characterizations of the ZIF67/Ola/Lapa nanoparticles In this study, poly(ADP-ribose) polymerase (PARP) inhibitor Ola and anticancer drug Lapa were encapsulated in ZIF67 via co-precipitation to prepare the ZIF67/Ola/Lapa nanoparticles
According to transmission electron microscopy (TEM) images, the obtained ZIF67/Ola/Lapa nanocomposites are monodispersed with defined spherical structure and mean diameter of 138.5 ± 15.9 nm (Fig. 1a and Additional file 1: Fig. S1), in line with the size of 132.2 ± 13.3 nm revealed by scanning electron microscope (SEM) images (Additional file 1: Fig. S2)

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As a newly developed reactive oxygen species (ROS)mediated therapeutic model, chemodynamic therapy (CDT) that can transform intratumoral overexpressed hydrogen peroxide (H2O2) into highly cytotoxic ·OHZhou et al J Nanobiotechnol (2021) 19:261 of H2O2 in cancer cells undoubtedly confers a large chemical barrier for effective CDT [18,19,20,21]. It is difficult to completely deliver the wrapped H 2O2 to the tumor site, and the leakage of H2O2 from nanocarriers can induce non-specific toxicity In this regard, in situ production of H 2O2-supplementing functionality into CDT agents may be a better choice to improve the anticancer efficacy. Since the NAD(P)H: NQO1 is constitutively overexpressed at levels 5- to 200-fold greater in breast [29], non-small cell lung [28], pancreas [27, 30], and prostate cancer [31] compared with the associated normal tissues, selecting Lapa for tumor-specific H 2O2 level amplification seems to hold great promise for enhanced CDT efficacy. 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 2O2 production and augmented CDT (“1 + 1 + 1 > 3”)

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