bis(3--5-)-cyclic-diguanylic-acid and Glioblastoma

The high mortality associated with glioblastoma multiforme (GBM) is attributed to its invasive nature, hypoxic core, resistant cell subpopulations and a highly immunosuppressive tumor microenvironment (TME). To support adaptive immune function and establish a more robust antitumor immune response, we boosted the local innate immune compartment of GBM using an immunostimulatory mesoporous silica nanoparticle, termed immuno-MSN. The immuno-MSN was specifically designed for systemic and proficient delivery of a potent innate immune agonist to dysfunctional antigen-presenting cells (APCs) in the brain TME. The cargo of the immuno-MSN was cyclic diguanylate monophosphate (cdGMP), a Stimulator of Interferon Gene (STING) agonist. Studies showed the immuno-MSN promoted the uptake of STING agonist by APCs in vitro and the subsequent release of the pro-inflammatory cytokine interferon β, 6-fold greater than free agonist. In an orthotopic GBM mouse model, systemically administered immuno-MSN particles were taken up by APCs in the near-perivascular regions of the brain tumor with striking efficiency. The immuno-MSNs facilitated the recruitment of dendritic cells and macrophages to the TME while sparing healthy brain tissue and peripheral organs, resulting in elevated circulating CD8

Topics: Animals; Antigen-Presenting Cells; Antineoplastic Agents; Brain Neoplasms; CD8-Positive T-Lymphocytes; Cyclic GMP; Dendritic Cells; Female; Glioblastoma; Immunity, Innate; Immunologic Factors; Immunotherapy; Interferon Type I; Macrophages; Mice; Mice, Inbred C57BL; Nanoparticles; Porosity; RAW 264.7 Cells; Silicon Dioxide; Tumor Microenvironment