Journal
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
Volume 14, Issue 2, Pages 237-246Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.nano.2017.10.013
Keywords
STING agonist; PBAE nanoparticle formulation; Cancer immunotherapy
Funding
- NIH [NIH R01EB016721, R01EB022148, R01CA195503, S10 OD016374, R01CA178613]
- Wilmer Core Grant [5P30EY001765]
- Bloomberg-Kimmel Institute for Cancer Immunotherapy
- Johns Hopkins University
- NSF [DGE-0707427]
- Baker Lab
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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 N100-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. (c) 2017 Elsevier Inc. All rights reserved.
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