Nanoparticle Encapsulation of Synergistic Immune Agonists Enables Systemic Codelivery to Tumor Sites and IFNβ-Driven Antitumor Immunity

Autor: S. Raghunathan, Gil Covarrubias, Efstathios Karathanasis, Taylor J. Moon, Carolyn Zheng, Peter Bielecki, Vanitha Raguveer, Christopher J. Hoimes, Amy Goldberg, Michelle L. Wiese, Prabhani U. Atukorale
Rok vydání: 2019
Předmět:
0301 basic medicine
Agonist
Cancer Research
medicine.drug_class
medicine.medical_treatment
Melanoma
Experimental
Antigen-Presenting Cells
Monophosphoryl Lipid A
Triple Negative Breast Neoplasms
Article
Mice
03 medical and health sciences
Drug Delivery Systems
Lymphocytes
Tumor-Infiltrating
0302 clinical medicine
Immune system
Nanocapsules
Cancer immunotherapy
medicine
Animals
Cyclic GMP
Mice
Inbred BALB C
business.industry
Microcirculation
Melanoma
Mammary Neoplasms
Experimental
Drug Synergism
Interferon-beta
Immunotherapy
medicine.disease
Killer Cells
Natural
Mice
Inbred C57BL
Toll-Like Receptor 4
Lipid A
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Stimulator of interferon genes
Cancer research
Systemic administration
Female
Drug Screening Assays
Antitumor
business
Zdroj: Cancer Research. 79:5394-5406
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.can-19-0381
Popis: Effective cancer immunotherapy depends on the robust activation of tumor-specific antigen-presenting cells (APC). Immune agonists encapsulated within nanoparticles (NP) can be delivered to tumor sites to generate powerful antitumor immune responses with minimal off-target dissemination. Systemic delivery enables widespread access to the microvasculature and draining to the APC-rich perivasculature. We developed an immuno-nanoparticle (immuno-NP) coloaded with cyclic diguanylate monophosphate, an agonist of the stimulator of interferon genes pathway, and monophosphoryl lipid A, and a Toll-like receptor 4 agonist, which synergize to produce high levels of type I IFNβ. Using a murine model of metastatic triple-negative breast cancer, systemic delivery of these immuno-NPs resulted in significant therapeutic outcomes due to extensive upregulation of APCs and natural killer cells in the blood and tumor compared with control treatments. These results indicate that NPs can facilitate systemic delivery of multiple immune-potentiating cargoes for effective APC-driven local and systemic antitumor immunity. Significance: Systemic administration of an immuno-nanoparticle in a murine breast tumor model drives a robust tumor site–specific APC response by delivering two synergistic immune-potentiating molecules, highlighting the potential of nanoparticles for immunotherapy.
Databáze: OpenAIRE
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