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

Abstract

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.

One-Step Fabrication of Multifunctional PLGA-HMME-DTX@MnO2 Nanoparticles for Enhanced Chemo-Sonodynamic Antitumor Treatment

“…Recently, metal oxides have been demonstrated to have potential as oxygen-generating materials. Tetravalent manganese [Mn(IV)], which exists in the form of MnO 2 , can be used in nanoparticles as a convenient and straightforward way to construct a nanosystem with GSH-depletion ability 27 , 29 , 40 to overcome hypoxia and improve PDT/SDT efficiency. Hence, the role of MnO 2 in PHD@MnO 2 nanosystems was further explored in subsequent cellular and in vivo therapeutic effect experiments.…”

Reprogramming Mitochondrial Metabolism in Synovial Macrophages of Early Osteoarthritis by a Camouflaged Meta‐Defensome

“…Preparation of PLGA-MnO 2 /STM NPs (MSP): MnO 2 NPs were synthesized by reducing potassium permanganate with polyallylamine hydrochloride (PAH). [57] Briefly, KMnO4 (30 mg mL −1 ) was mixed with PAH (30 mg mL −1 ). After reacting for 30 min, MnO 2 NPs were obtained after purification.…”

Recent Advances in Multicellular Tumor Spheroid Generation for Drug Screening

“…Since LDH released from damaging cells, the amount of LDH release correlated to drug efficacy of preussin. In addition, Murphy et al, (2021) suggested a drug delivery model incorporating with manganese dioxide nanoparticles (MnO 2 NPs) to design controlled oxygen production and promote nature killer cell function [120]. To increase biocompatibility, MnO2 nanoparticles were encapsulated to poly(lactic-co-glytic), forming PLGA-MnO 2 NPs.…”