Multifunctional albumin-MnO₂ nanoparticles modulate solid tumor microenvironment by attenuating hypoxia, acidosis, vascular endothelial growth factor and enhance radiation response.
Insufficient oxygenation (hypoxia), acidic pH (acidosis), and elevated levels of reactive oxygen species (ROS), such as H2O2, are characteristic abnormalities of the tumor microenvironment (TME). These abnormalities promote tumor aggressiveness, metastasis, and resistance to therapies. To date, there is no treatment available for comprehensive modulation of the TME. Approaches so far have been limited to regulating hypoxia, acidosis, or ROS individually, without accounting for their interdependent effects on tumor progression and response to treatments. Hence we have engineered multifunctional and colloidally stable bioinorganic nanoparticles composed of polyelectrolyte-albumin complex and MnO2 nanoparticles (A-MnO2 NPs) and utilized the reactivity of MnO2 toward peroxides for regulation of the TME with simultaneous oxygen generation and pH increase. In vitro studies showed that these NPs can generate oxygen by reacting with H2O2 produced by cancer cells under hypoxic conditions. A-MnO2 NPs simultaneously increased tumor oxygenation by 45% while increasing tumor pH from pH 6.7 to pH 7.2 by reacting with endogenous H2O2 produced within the tumor in a murine breast tumor model. Intratumoral treatment with NPs also led to the downregulation of two major regulators in tumor progression and aggressiveness, that is, hypoxia-inducible factor-1 alpha and vascular endothelial growth factor in the tumor. Combination treatment of the tumors with NPs and ionizing radiation significantly inhibited breast tumor growth, increased DNA double strand breaks and cancer cell death as compared to radiation therapy alone. These results suggest great potential of A-MnO2 NPs for modulation of the TME and enhancement of radiation response in the treatment of cancer.
Department of Pharmaceutical Sciences, Leslie L. Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario M5S 3M2, Canada.
Preethy
P
Prasad
Claudia R
CR
Gordijo
Azhar Z
AZ
Abbasi
Azusa
A
Maeda
Angela
A
Ip
Andrew Michael
AM
Rauth
Ralph S
RS
DaCosta
Xiao Yu
XY
Wu
D000138:Acidosis / Q000188:drug therapy*; D000818:Animals; D001692:Biological Transport; D002417:Cattle; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D004355:Drug Stability; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D017895:Manganese Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008958:Models, Molecular; D053758:Nanoparticles / Q000737:chemistry*; D010087:Oxides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D010100:Oxygen / Q000378:metabolism; D011487:Protein Conformation; D011836:Radiation Tolerance / Q000187:drug effects*; D012710:Serum Albumin, Bovine / Q000737:chemistry*; D059016:Tumor Microenvironment / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017895:Manganese Compounds; D010087:Oxides; D042461:Vascular Endothelial Growth Factor A; D012710:Serum Albumin, Bovine; D006861:Hydrogen Peroxide; D010100:Oxygen; C016552:manganese dioxide