Comparison of the uptake of untargeted and targeted immunostimulatory nanoparticles by immune cells in the microenvironment of metastatic breast cancer
| Autor: | Mayura P Umapathy, Gil Covarrubias, Morgan E Lorkowski, Taylor J. Moon, Prabhani U. Atukorale, Georgia Loutrianakis, Haley M. Sims, Michelle L. Wiese, Efstathios Karathanasis, Peter Bielecki |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Agonist
1 2-Dipalmitoylphosphatidylcholine medicine.drug_class T-Lymphocytes Biomedical Engineering Breast Neoplasms Ligands Article Metastasis Polyethylene Glycols Immune system Cell Line Tumor medicine Tumor Microenvironment Cytotoxic T cell Animals Immunologic Factors General Materials Science Cyclic GMP Tumor microenvironment Mice Inbred BALB C biology Chemistry Macrophages Phosphatidylethanolamines General Chemistry General Medicine Dendritic Cells medicine.disease Metastatic breast cancer Primary tumor Immunity Innate Fibronectin Cancer research biology.protein Phosphatidylcholines Nanoparticles Peptides |
| Zdroj: | J Mater Chem B |
| Popis: | To alter the immunosuppressive tumor microenvironment (TME), we developed an immunostimulatory nanoparticle (NP) to reprogram a tumor’s dysfunctional and inhibitory antigen-presenting cells (APCs) into properly activated APCs that stimulate tumor-reactive cytotoxic T cells. Importantly, systemic delivery allowed NPs to efficiently utilize the entire microvasculature and gain access into the majority of the perivascular TME, which coincided with the APC-rich tumor areas leading to uptake of the NPs predominantly by APCs. In this work, a 60-nm NP was loaded with a STING agonist, which triggered a robust production of interferon β, resulting in activation of APCs. In addition to untargeted NPs, we employed ‘mainstream’ ligands targeting fibronectin, α(v)β(3) integrin and P-selectin that are commonly used to direct nanoparticles to tumors. Using the 4T1 mouse model, we assessed the microdistribution of the four NP variants in the tumor immune microenvironment in three different breast cancer landscapes, including primary tumor, early metastasis, and late metastasis. The different NP variants resulted in variable uptake by immune cell subsets depending on the organ and tumor stage. Among the NP variants, therapeutic studies indicated that the untargeted NPs and the integrin-targeting NPs exhibited a remarkable short- and long-term immune response and long-lasting antitumor effect. |
| Databáze: | OpenAIRE |
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