Harnessing graphene oxide nanocarriers for siRNA delivery in a 3D spheroid model of lung cancer

Grilli, Francesca; Hassan, Eman; Variola, Fabio; Zou, Shan

doi:10.1039/d3bm00732d

Cited by 5 publications

(10 citation statements)

References 69 publications

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“…However, spheroids generated from fibroblast cell line (NIH 3T3) showed cell viability less than 80% at a GO treatment concentration of 4 μg/mL. 62 In contrast to previous reports, both enteroids and colonoids showed a loss of viability in a dose-dependent manner (Figure 3A,B). This is likely due to clonal nature of intestinal organoid culture, which promotes cellular homogeneity and increased sensitivity.…”

Section: ■ Results and Discussioncontrasting

confidence: 69%

“…For example, 3D spheroids generated from lung (A549) and leukemia (NB4) cancer cell lines showed noticeable toxicity only at 16 and 64 μg/mL but not at 1 and 4 μg/mL. However, spheroids generated from fibroblast cell line (NIH 3T3) showed cell viability less than 80% at a GO treatment concentration of 4 μg/mL . In contrast to previous reports, both enteroids and colonoids showed a loss of viability in a dose-dependent manner (Figure A,B).…”

Section: Resultsmentioning

confidence: 88%

“…Exposure time of 48 h was chosen as transfections with commercially available kits such as lipofectamine typically require 48 h, and the concentrations were selected based on our previous work. We and others , have previously reported that the cytotoxicity of GO formulations can vary based on cell lines. For example, 3D spheroids generated from lung (A549) and leukemia (NB4) cancer cell lines showed noticeable toxicity only at 16 and 64 μg/mL but not at 1 and 4 μg/mL.…”

Section: Resultsmentioning

confidence: 94%

“…In addition, the TNF-α_siRNA_smGO also showed a reduction in the number of apoptotic cells compared to the respective controls (Figure S3B,C), suggesting a positive therapeutic outcome following transfection. 62 To discount any anti-inflammatory effects of sGO and smGO, inflamed organoids were treated with sGO and smGO (without any siRNA) and the expression of TNF-α was evaluated. The mRNA expression of TNF-α in organoids treated with sGO and smGO showed no significant difference compared to untreated organoids (Figure S3D).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Our results are also in agreement with these in vivo models of IBD, where gene silencing of TNF-α has been shown to downregulate both the gene and protein expressions of TNF-α, IL-1β and IL-6. , Morphological scoring revealed a lower occurrence of organoids with morphological defects in those treated with TNF-α_siRNA_smGO compared to that of the untreated inflamed organoids (see Figure S3A). In addition, the TNF-α_siRNA_smGO also showed a reduction in the number of apoptotic cells compared to the respective controls (Figure S3B,C), suggesting a positive therapeutic outcome following transfection …”

Section: Resultsmentioning

confidence: 99%

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Attenuation of Chronic Inflammation in Intestinal Organoids with Graphene Oxide-Mediated Tumor Necrosis Factor-α_Small Interfering RNA Delivery

Sakib,

Zou

2024

Langmuir

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Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract with a complex and multifactorial etiology, making it challenging to treat. While recent advances in immunomodulatory biologics, such as antitumor necrosis factor-α (TNFα) antibodies, have shown moderate success, systemic administration of antibody therapeutics may lead to several adverse effects, including the risk of autoimmune disorders due to systemic cytokine depletion. Transient RNA interference using exogenous short interfering RNA (siRNA) to regulate target gene expression at the transcript level offers an alternative to systemic immunomodulation. However, siRNAs are susceptible to premature degradation and have poor cellular uptake. Graphene oxide (GO) nanoparticles have been shown to be effective nanocarriers for biologics due to their reduced cytotoxicity and enhanced bioavailability. In this study, we evaluate the therapeutic efficacy of GO mediated TNF-α_siRNA using in vitro models of chronic inflammation generated by treating murine small intestines (enteroids) and large intestines (colonoids) with inflammatory agents IL-1β, TNF-α, and LPS. The organotypic mouse enteroids and colonoids developed an inflammatory phenotype similar to that of IBD, characterized by impaired epithelial homeostasis and an increased production of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. We assessed siRNA delivery to these inflamed organoids using three different GO formulations. Out of the three, small-sized GO with polymer and dendrimer modifications (smGO) demonstrated the highest transfection efficiency, which led to the downregulation of inflammatory cytokines, indicating an attenuation of the inflammatory phenotype. Moreover, the transfection efficiency and inflammation-ameliorating effects could be further enhanced by increasing the TNF-α_siRNA/smGO ratio from 1:1 to 3:1. Overall, the results of this study demonstrate that ex vivo organoids with disease-specific phenotypes are invaluable models for assessing the therapeutic potential of nanocarrier-mediated drug and biologic delivery systems.

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Section: ■ Results and Discussioncontrasting

confidence: 69%

Section: Resultsmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 94%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

Attenuation of Chronic Inflammation in Intestinal Organoids with Graphene Oxide-Mediated Tumor Necrosis Factor-α_Small Interfering RNA Delivery

Sakib,

Zou

2024

Langmuir

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In Vivo Monitoring and Magnetically‐Enhanced Delivery of CAR T‐Cells to Solid Tumor

Chen,

Machado,

et al. 2024

Adv Funct Materials

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Chimeric antigen receptor (CAR) T‐cell therapy demonstrates efficacy for the treatment of hematologic cancers, but remains challenging in solid tumors because of the hostile tumor microenvironment and heterogeneity that restrict the infiltration and activity of CAR T‐cells. The lack of clinical imaging methods to monitor CAR T‐cell therapy in patients limits the potential to enhance the therapeutic approach and predict patient response. Here, a straightforward, non‐invasive method for Magnetic Resonance Imaging (MRI) tracking and magnetic targeting of CAR T‐cells to enhance T‐cell trafficking to solid tumors, in a setting that can be deployed in clinics, is reported. Iron oxide nanoparticles are loaded into T‐cells, allowing MRI detection and magnetic cell guidance, while preserving T‐cell viability, functions, and CAR specificity to target epidermal growth factor receptor (EGFR)‐expressing tumors. Longitudinal MRI monitoring of T‐cells over 14 days reveals differences in tumor infiltration rates and antitumor efficacy between EGFR‐targeted CAR T‐cells and non‐transduced T‐cell. Moreover, an external magnet placed over the tumor enhances the infiltration of CAR T‐cells and increases their antitumor effect. MRI monitoring and magnetic guidance represent a dual‐pronged clinically feasible therapeutic strategy to control and promote CAR T‐cells delivery into solid tumors, thereby improving the precision, efficacy, and safety of the treatment.

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Advancing cancer immunotherapy through siRNA-based gene silencing for immune checkpoint blockade

Choi,

Seok,

Yoon

et al. 2024

Advanced Drug Delivery Reviews

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Harnessing graphene oxide nanocarriers for siRNA delivery in a 3D spheroid model of lung cancer

Abstract: Gene therapy has been recently proposed as an effective strategy for cancer treatment. A significant body of literature proved the effectiveness of nanocarriers to deliver therapeutic agents to 2D tumour...

Cited by 5 publications

References 69 publications

Attenuation of Chronic Inflammation in Intestinal Organoids with Graphene Oxide-Mediated Tumor Necrosis Factor-α_Small Interfering RNA Delivery

Attenuation of Chronic Inflammation in Intestinal Organoids with Graphene Oxide-Mediated Tumor Necrosis Factor-α_Small Interfering RNA Delivery

In Vivo Monitoring and Magnetically‐Enhanced Delivery of CAR T‐Cells to Solid Tumor

Advancing cancer immunotherapy through siRNA-based gene silencing for immune checkpoint blockade

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