Abstract
Therapeutic cancer vaccines require adjuvants leading to robust type I interferon and proinflammatory cytokine responses in the tumor microenvironment to induce an anti-tumor response. Cyclic dinucleotides (CDNs), a potent Stimulator of Interferon Receptor (STING) agonist, are currently in phase I trials. However, their efficacy may be limited to micromolar concentrations due to the cytosolic residence of STING in the ER membrane. Here we utilized biodegradable, poly(beta-amino ester) (PBAE) nanoparticles to deliver CDNs to the cytosol leading to robust immune response at >100-fold lower extracellular CDN concentrations in vitro. The leading CDN PBAE nanoparticle formulation induced a log-fold improvement in potency in treating established B16 melanoma tumors in vivo when combined with PD-1 blocking antibody in comparison to free CDN without nanoparticles. This nanoparticle-mediated cytosolic delivery method for STING agonists synergizes with checkpoint inhibitors and has strong potential for enhanced cancer immunotherapy.
Original language | English (US) |
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Pages (from-to) | 237-246 |
Number of pages | 10 |
Journal | Nanomedicine: Nanotechnology, Biology, and Medicine |
Volume | 14 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2018 |
Keywords
- Cancer immunotherapy
- PBAE nanoparticle formulation
- STING agonist
ASJC Scopus subject areas
- Bioengineering
- Medicine (miscellaneous)
- Molecular Medicine
- Biomedical Engineering
- General Materials Science
- Pharmaceutical Science