The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment
| Autor: | Gil Covarrubias, Yahan Zhang, Morgan E Lorkowski, Efstathios Karathanasis, Prabhani U. Atukorale, Taylor J. Moon, Wyatt M. Becicka, Peter Bielecki |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Agonist Tumor microenvironment Innate immune system medicine.diagnostic_test Chemistry medicine.drug_class General Engineering Bioengineering General Chemistry Atomic and Molecular Physics and Optics Flow cytometry 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Immune system Interferon 030220 oncology & carcinogenesis medicine PEGylation Cancer research General Materials Science Secretion medicine.drug |
| Zdroj: | Nanoscale Advances |
| ISSN: | 2516-0230 |
| Popis: | The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed immunostimulatory silica mesoporous nanoparticles (immuno-MSN). The cargo of immuno-MSN is a Stimulator of Interferon Gene (STING) agonist, which activates innate immune cells leading to production of interferon (IFN) β. By proficiently trafficking its cargo into immune cells, the immuno-MSN induced a 9-fold increase of IFN-β secretion compared to free agonist. While an external PEG shield has historically been used to protect nanoparticles from immune recognition, a PEGylated immunostimulatory nanoparticle needs to strike a balance between immune evasion to avoid off-site accumulation and uptake by target immune cells in tumors. Using the 4T1 mouse model of metastatic breast cancer and flow cytometry, it was determined that the degree of PEGylation significantly influenced the uptake of ‘empty’ MSNs by tumor-resident innate immune cells. This was not the case for the agonist-loaded immuno-MSN variants. It should be noted the surface charge of the ‘empty’ MSNs was positive rather than neutral for the agonist-loaded immuno-MSNs. However, even though the cellular uptake was similar at 24 h after injection for the three immuno-MSN variants, we observed a significant beneficial effect on the activation and expansion of APCs especially in lung metastasis using the lightly PEGylated immuno-MSN variant. The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. |
| Databáze: | OpenAIRE |
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