Functional recovery of natural killer cell activity by nanoparticle‐mediated delivery of transforming growth factor beta 2 small interfering RNA

Adjei, Isaac M.; Jordan, Jahnelle C.; Tu, Nhan; Trinh, Thu Le; Kandell, Wendy; Wei, Sheng; Bk, Sharma

doi:10.1002/jin2.63

Cited by 14 publications

(19 citation statements)

References 52 publications

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“…Formulation of MnO 2 NPs, PEG-MnO 2 NPs, and PLGA-MnO 2 NPs. Manganese dioxide (MnO 2 ) NPs were synthesized by reducing potassium permanganate with polyallylamine hydrochloride (PAH), as previously described 38. In a typical reaction, 60 mg of KMnO 4 was dissolved in 18 mL of ultrapure water (DiH 2 O), after which 60 mg of PAH in 2 mL of DiH 2 O was added with continuous mixing.…”

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confidence: 99%

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

et al. 2021

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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.

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

et al. 2021

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“…They show that the nanoparticles were taken up by around 92% of the NK cell population and yielded 90% knockdown reduction of TGFBR2 mRNA levels (without cell selection). [95] Nanoparticles have also found great utility in modulating the immune system for cancer immunotherapy such as drug delivery to tumors and we refer readers to excellent reviews elsewhere. [96,97] We will focus specifically on nanoparticles for CAR-T cell transfection and engineering.…”

Section: Transfection With Nanoparticlesmentioning

confidence: 99%

Materials for Improving Immune Cell Transfection

et al. 2021

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recognize and bind to tumor-associated antigens such as CD19 and epidermal growth factor receptor (EGFR) before releasing cytotoxic granules and effector cytokines to destroy cancer cells. [3] CAR-T therapy has shown remarkable success against CD19 expressing B cell hematological malignancies and, thus far, five products (Kymriah from Novartis; Yescarta and Tecartus from Kite Pharma/Gilead Sciences; and Breyanzi and Abecma from Bristol-Myers Squibb) have been approved by the US Food and Drug Administration (FDA) for clinical use. [4,5] Currently, there are at least 500 clinical trials registered on ClinicalTrials.gov database using engineered immune cells to treat various cancers including that of the brain, lungs, and skin.Despite the clinical success of CAR-T cells against B cell leukemia, CAR-T therapy still face tremendous challenges in manufacturing, safety, and affordability before it can become a viable clinical option. [6] One of the biggest technical difficulties is to transfect sensitive, primary T cells whereby biomolecules like oligonucleotides and proteins have to be delivered intracellularly and into the nuclei of cells. FDA-approved gold standard viruses and bulk electroporation suffer from low transfection efficiency while also perturbing the critical biological attributes of cells such as proliferation, metabolism, and gene expression. [7] This increases the time and costs for cell expansion, and without an efficient and cost-friendly transfection technology, the price (between USD 0.4-0.5 million per patient) for FDA-approved CAR treatments (Kymriah and Yescarta) will remain unaffordable and untimely. [8] The limitations in conventional transfection techniques have motivated the development of micro-and nanoplatforms such as microfluidics, nanoparticles, and high-aspect-ratio nanostructures to improve immune cell viability and throughput during transfection.Herein, we first provide an overview of CAR-T cell manufacturing, with emphasis on the science of transfection and limitations of traditional technology using viruses and bulk electroporation. There will also be discussion of other cell-based cancer immunotherapy using other types of promising immune cell types. Next, we describe emerging transfection platforms and companies that have been established to overcome gaps in CAR-T transfection. We then provide a list of assays constituting the polyfunctionalities of immune cells that we believe will help the field better assess the robustness and suitability of their transfection methods. Finally, we end off with existing challenges in CAR-T transfection and how overcoming these challenges can significantly enhance the clinical impact of CAR-T therapy.Chimeric antigen receptor T cell (CAR-T) therapy holds great promise for preventing and treating deadly diseases such as cancer. However, it remains challenging to transfect and engineer primary immune cells for clinical cell manufacturing. Conventional tools using viral vectors and bulk electroporation suffer from low efficiency while posing risks ...

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“…In addition to activating the targeting ligand, size is also an important factor in NK cell-targeting NPs. Adjei et al showed the effect of the size of polystyrene NPs on uptake by NK cells [ 57 ]. They incubated NK92 cells with fluorescently labeled polystyrene NPs that were 20, 30, 40, and 100 nm in diameter.…”

Section: Immune Cells Targeting Nanoparticlesmentioning

confidence: 99%

Immune cell targeting nanoparticles: a review

2021

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Immune cells are attractive targets for therapy as they are direct participants in a variety of diseases. Delivering a therapeutic agent only to cells that act on a disease by distinguishing them from other cells has the advantage of concentrating the therapeutic effect and lowering systemic side effects. Distinguishing each immune cell from other immune cells to deliver substances, including drugs and genes, can be achieved using nanotechnology. And also nanoparticles can ensure in vivo stability and sustained drug release. In addition, there is an ease of surface modification, which is an important characteristic that can be utilized in targeted drug delivery systems. This characteristic allows us to utilize various properties that are specifically expressed in each immune cell. A number of studies have delivered various substances specifically to immune cells through surface engineering with active target ligands that can target each immune cell and enzyme-responsive coating, and demonstrated high therapeutic effects compared to conventional treatments. Progress in research on target delivery has been suggested to be a breakthrough for the treatments of various diseases, including cancer treatment.

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Functional recovery of natural killer cell activity by nanoparticle‐mediated delivery of transforming growth factor beta 2 small interfering RNA

Cited by 14 publications

References 52 publications

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

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

Materials for Improving Immune Cell Transfection

Immune cell targeting nanoparticles: a review

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