Nanoparticle STING Agonist Reprograms the Bone Marrow to an Antitumor Phenotype and Protects Against Bone Destruction

Abstract

When breast cancer metastasizes to bone, treatment options are limited. Failure to treat bone metastases is thought to be due to therapy-resistant features of the bone marrow microenvironment. Using a murine model of bone metastatic mammary carcinoma, we demonstrate that systemic delivery of polymer nanoparticles loaded with cyclic dinucleotide (CDN) agonists of stimulator of interferon genes (STING) inhibited tumor growth and bone destruction after 7 days of treatment. Each dose of STING-activating nanoparticles (STING-NPs) trafficked to the bone marrow compartment and was retained within the tumor microenvironment for over 24 h, enhancing antitumor immunity through proinflammatory cytokine production and early T cell activation. While acquired resistance mechanisms, including increased levels of immunosuppressive cytokines and the infiltration of regulatory T cells, ultimately limited antitumor efficacy after two weeks of treatment, bone protective effects remained. Overall, these studies demonstrate that STING pathway activation, here enabled using a nanomedicine approach to enhance CDN delivery to bone metastatic sites, can reprogram the immune contexture of the bone marrow to an antitumor phenotype that inhibits bone colonization of metastatic breast cancer cells and protects from tumor-mediated bone destruction.

Engineering endosomolytic nanocarriers of diverse morphologies using confined impingement jet mixing

“…A free cGAMP control group was not tested as we have previously demonstrated that free cGAMP does not improve therapeutic responses to B16.F10 melanoma when administered IV. 20 Notably, our previous formulation approach necessitated the IV administration of 10 μg of cGAMP within STANs to observe therapeutically significant results, 20,26,46–48 suggesting that STANs formulated via FNP may be more potent than our previous platform. This observation warrants further investigation.…”

“…4A and B), which is an innate immune agonist of the stimulator of interferon genes (STING) that we have previously loaded into PEG-DB nanocarriers. 20,22,26,[46][47][48] After impinging each polymer at 10 mg mL −1 in the organic stream five times against SRB dissolved at 1 mg mL −1 in the aqueous stream, unencapsulated SRB was removed via dialysis and SRB encapsulation was quantified via fluorescence spectroscopy. The encapsulation efficiency (EE) trended slightly upward with increasing second block MW, maintaining between 20-50% depending on polymer (Fig.…”

“…6,7,14,45 Previously, we found that PEG-DBP polymersomes enhanced the activity and pharmacological properties of cyclic dinucleotide (CDN) STING agonists to induce therapeutically relevant responses in models of melanoma, mammary carcinoma, and neuroblastoma when administered intratumorally (IT) or intravenously (IV). 20,26,46–48 Additionally, we found that subcutaneous (SC) administration of PEG-DBP nanocarriers that co-encapsulated CDNs and peptide neoantigens invoked therapeutically relevant, antigen-specific immune responses in models of melanoma and colon adenocarcinoma. 22 In all of these studies, we fabricated polymersomes using a modified direct hydration method in which an aqueous solution was slowly added to an ethanolic gel of PEG-DBP under sonication.…”