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Catalase-Gold Nanoaggregates Manipulate the Tumor Microenvironment and Enhance the Effect of Low-Dose Radiation Therapy by Reducing Hypoxia Publisher Pubmed



Najafi A1, 2 ; Keykhaee M3 ; Kazemi MH1, 2 ; Karimi MY4 ; Khorramdelazad H1, 5 ; Aghamohamadi N1, 2 ; Bolouri MR1, 2 ; Ghaffarinazari H6 ; Mirsharif ES7 ; Karimi M1, 2 ; Dehghan Manshadi HR8 ; Mahdavi SR9 ; Safari E1, 2 ; Jalali SA10 Show All Authors
Authors
  1. Najafi A1, 2
  2. Keykhaee M3
  3. Kazemi MH1, 2
  4. Karimi MY4
  5. Khorramdelazad H1, 5
  6. Aghamohamadi N1, 2
  7. Bolouri MR1, 2
  8. Ghaffarinazari H6
  9. Mirsharif ES7
  10. Karimi M1, 2
  11. Dehghan Manshadi HR8
  12. Mahdavi SR9
  13. Safari E1, 2
  14. Jalali SA10
  15. Falak R1, 2
  16. Khoobi M11, 12

Source: Biomedicine and Pharmacotherapy Published:2023


Abstract

Radiotherapy as a standard method for cancer treatment faces tumor recurrence and antitumoral unresponsiveness. Suppressive tumor microenvironment (TME) and hypoxia are significant challenges affecting efficacy of radiotherapy. Herein, a versatile method is introduced for the preparation of pH-sensitive catalase-gold cross-linked nanoaggregate (Au@CAT) having acceptable stability and selective activity in tumor microenvironment. Combining Au@CAT with low-dose radiotherapy enhanced radiotherapy effects via polarizing protumoral immune cells to the antitumoral landscape. This therapeutic approach also attenuated hypoxia, confirmed by downregulating hypoxia hallmarks, such as hypoxia-inducible factor α-subunits (HIF-α), vascular endothelial growth factor (VEGF), and EGF. Catalase stability against protease digestion was improved significantly in Au@CAT compared to the free catalase. Moreover, minimal toxicity of Au@CAT on normal cells and increased reactive oxygen species (ROS) were confirmed in vitro compared with radiotherapy. Using the nanoaggregates combined with radiotherapy led to a significant reduction of immunosuppressive infiltrating cells such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells (T-regs) compared to the other groups. While, this combined therapy could significantly increase the frequency of CD8+ cells as well as M1 to M2 macrophages (MQs) ratio. The combination therapy also reduced the tumor size and increased survival rate in mice models of colorectal cancer (CRC). Our results indicate that this innovative nanocomposite could be an excellent system for catalase delivery, manipulating the TME and providing a potential therapeutic strategy for treating CRC. © 2023
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