Reversing Hypoxia with PLGA-Encapsulated Manganese Dioxide Nanoparticles Improves Natural Killer Cell Response to Tumor Spheroids

Autor: Tingyuan Yang, Heyong Cheng, David A Murphy, Isaac M. Adjei, Xin Yan
Rok vydání: 2021
Předmět:
Adoptive cell transfer
Adenosine
medicine.medical_treatment
Metal Nanoparticles
Pharmaceutical Science
Breast Neoplasms
02 engineering and technology
Adaptive Immunity
030226 pharmacology & pharmacy
Natural killer cell
Cell therapy
03 medical and health sciences
0302 clinical medicine
Nanocapsules
Polylactic Acid-Polyglycolic Acid Copolymer
Spheroids
Cellular
Drug Discovery
Immune Tolerance
Tumor Microenvironment
medicine
Humans
Cytotoxic T cell
Lactic Acid
Particle Size
Cytotoxicity
Tumor microenvironment
Chemistry
technology
industry
and agriculture
Oxides
Hydrogen Peroxide
Immunotherapy
021001 nanoscience & nanotechnology
Adoptive Transfer
Cell Hypoxia
Killer Cells
Natural
medicine.anatomical_structure
Manganese Compounds
Cancer cell
MCF-7 Cells
Cancer research
Molecular Medicine
Female
0210 nano-technology
Signal Transduction
Zdroj: Molecular Pharmaceutics. 18:2935-2946
ISSN: 1543-8392
1543-8384
DOI: 10.1021/acs.molpharmaceut.1c00085
Popis: The adoptive transfer of natural killer (NK) cells, which can recognize and obliterate cancer cells, provides a practical alternative to current treatment modalities to improve cancer patients' survival. However, translating NK cell therapies to treat solid tumors has proven challenging due to the tumor microenvironment (TME). Hypoxia in the TME induces immunosuppression that inhibits the cytotoxic function of NK cells. Thus, reversing hypoxia-induced immunosuppression is critical for effective adoptive NK cell immunotherapy. In this study, we use manganese dioxide nanoparticles (MnO2 NPs) to catalyze the degradation of tumor-produced hydrogen peroxide, thereby generating oxygen. For improved biocompatibility and modulation of oxygen production, the MnO2 NPs were encapsulated into poly(lactic-co-glycolic) to produce particles that are 116 nm in size and with a ζ-potential of +17 mV (PLGA-MnO2 NPs). The PLGA-MnO2 NPs showed first-order oxygen production and sustained high oxygen tension compared to equivalent amounts of bare MnO2 NPs in the presence of H2O2. The PLGA-MnO2 NPs were biocompatible, reduced hypoxia after penetration into the core of cancer spheroids, and decreased hypoxia-induced factor 1 α expression. Reducing hypoxia in the spheroid resulted in a decrease in the potent immunosuppressors, adenosine, and lactate, which was confirmed by electrospray ionization mass spectroscopy (ESI-MS). ESI-MS also showed a change in the metabolism of the amino acids aspartate, glutamine, and glutamate after hypoxia reduction in the cancer cells. Notably, the spheroids' microenvironment changes enhanced NK cells' cytotoxicity, which obliterated the spheroids. These results demonstrate that reducing hypoxia-induced immunosuppression in tumors is a potent strategy to increase the potency of cytotoxic immune cells in the TME. The developed NPs are promising new tools to improve adoptive NK cell therapy.
Databáze: OpenAIRE
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