Acetalated Dextran Microparticles for Codelivery of STING and TLR7/8 Agonists

Oct 4, 2018Molecular pharmaceutics

Biodegradable Microparticles for Delivering STING and TLR7/8 Immune Activators Together

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Abstract

Codelivery of STING and TLR7/8 agonists using Ace-DEX microparticles induced a stronger immune response than separate delivery.

Subunit vaccines generally require adjuvants to enhance their immune response.
Pathogen-associated molecular patterns (PAMPs) can stimulate the immune system through specific receptors.
The combination of cGAMP and TLR7/8 agonist R848 yielded the broadest cytokine response in immune cells.
Coencapsulation of cGAMP and R848 within Ace-DEX microparticles resulted in enhanced antigen-specific cellular immunity.
This approach produced a balanced Th1/Th2 humoral response that surpassed the effects of cGAMP alone or separate PAMPs.

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Vaccines are the most effective tool for preventing infectious diseases; however, subunit vaccines, considered the safest type, suffer from poor immunogenicity and require adjuvants to create a strong and sustained immune response. As adjuvants, pathogen-associated molecular patterns (PAMPs) offer potent immunostimulatory properties and defined mechanisms of action through their cognate pattern recognition receptors (PRRs). Their activity can be further enhanced through combining two or more PAMPs, particularly those that activate multiple immune signaling pathways. However, the cytosolic localization of many PRRs requires intracellular delivery of PAMPs for optimal biological activity, which is particularly true of the stimulator of interferon genes (STING) PRR. Using acetalated dextran (Ace-DEX) microparticles (MPs) encapsulating STING agonist 3'3'-cyclic GMP-AMP (cGAMP) combined with soluble PAMPS, we screened the effect of codelivery of adjuvants using primary mouse bone marrow derived dendritic cells (BMDCs). We identified that codelivery of cGAMP MPs and soluble Toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) elicited the broadest cytokine response. cGAMP and R848 were then coencapsulated within Ace-DEX MPs via electrospray. Using the model antigen ovalbumin, we observed that Ace-DEX MPs coencapsulating cGAMP and R848 (cGAMP/R848 Ace-DEX MPs) induced antigen-specific cellular immunity, and a balanced Th1/Th2 humoral response that was greater than cGAMP Ace-DEX MPs alone and PAMPs delivered in separate MPs. These data indicate that polymeric Ace-DEX MPs loaded with STING and TLR7/8 agonists represent a potent cellular and humoral vaccine adjuvant.

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