Amplification of Tumor Oxidative Stresses with Liposomal Fenton Catalyst and Glutathione Inhibitor for Enhanced Cancer Chemotherapy and Radiotherapy

Nano Lett. 2019 Feb 13;19(2):805-815. doi: 10.1021/acs.nanolett.8b03905. Epub 2019 Jan 2.


Amplification of intracellular oxidative stress has been found to be an effective strategy to induce cancer cell death. To this end, we prepare a unique type of ultrasmall gallic acid-ferrous (GA-Fe(II)) nanocomplexes as the catalyst of Fenton reaction to enable persistent conversion of H2O2 to highly cytotoxic hydroxyl radicals (•OH). Then, both GA-Fe(II) and l-buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, are coencapsulated within a stealth liposomal nanocarrier. Interestingly, the obtained BSO/GA-Fe(II)@liposome is able to efficiently amplify intracellular oxidative stress via increasing •OH generation and reducing GSH biosynthesis. After chelating with 99mTc4+ radioisotope, such BSO/GA-Fe(II)@liposome could be tracked under in vivo single-photon-emission-computed-tomography (SPECT) imaging, which illustrates the time-dependent tumor homing of such liposomal nanoparticles after intravenous injection. With GA-Fe(II)-mediated •OH production and BSO-mediated GSH depletion, treatment with such BSO/GA-Fe(II)@liposome would lead to dramatically enhanced intratumoral oxidative stresses, which then result in remarkably improved therapeutic efficacies of concurrently applied chemotherapy or radiotherapy. This work thus presents the concise fabrication of biocompatible BSO/GA-Fe(II)@liposome as an effective adjuvant nanomedicine to promote clinically used conventional cancer chemotherapy and radiotherapy, by greatly amplifying the intratumoral oxidative stress.

Keywords: Fenton reaction; GA−Fe(II) nanocomplexes; GSH depletion; cancer combination therapy; disruption of redox homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Buthionine Sulfoximine / administration & dosage
  • Buthionine Sulfoximine / therapeutic use*
  • Cell Line, Tumor
  • Female
  • Ferrous Compounds / administration & dosage
  • Ferrous Compounds / therapeutic use*
  • Gallic Acid / administration & dosage
  • Gallic Acid / therapeutic use*
  • Glutathione / antagonists & inhibitors*
  • Glutathione / metabolism
  • Hydroxyl Radical / metabolism
  • Liposomes / chemistry
  • Mammary Neoplasms, Animal / metabolism
  • Mammary Neoplasms, Animal / pathology
  • Mammary Neoplasms, Animal / radiotherapy
  • Mammary Neoplasms, Animal / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Oxidative Stress / drug effects*
  • Tomography, Emission-Computed, Single-Photon


  • Ferrous Compounds
  • Liposomes
  • Hydroxyl Radical
  • Buthionine Sulfoximine
  • Gallic Acid
  • Glutathione