Development of nanocarriers for the encapsulation of STING agonists
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Date
2024-07-04
Authors
Mendez López, Sandra Guadalupe
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Abstract
STING (Stimulator of Interferon Genes) agonists are molecules used for the regulation of the cGAS-STING pathway involved in the activation of an immune response producing and anti-infectious or anti-oncogenic effect. Therefore, in recent years there has been an interest in using them for therapeutic purposes. Albeit degradation and low bioavailability are challenges that can be overcome with the use of nano vehicles. In the present project, a liposomal platform was tested for the encapsulation of different STING agonists: 3’3’-cGAMP, c-di-AMP, c-di-GMP, c-di-AMP, cAIMP, cAIMP-difluor, ADU-S100, MSA-2, and SR-717. The liposomes were prepared by the Thin-Film Hydration (TFH) Method and were composed of DPPC, DOTAP, Cholesterol, and DSPE-PEG-Mannose (3, 1.5, 1, 0.05 equivalent respectively in reference to cholesterol). This platform allowed the encapsulation of the different agonists and improved their stimulation of THP-1 cells in vitro. Formulations entrapping different agonists showed different stability profiles where non-nucleotidic agonists were more stable compared to the nucleotidic ones. Therefore, the presence of DOTAP was investigated for the entrapment of non-nucleotidic agonists. The results showed that DOTAP-free liposomes allowed a better encapsulation of MSA-2. Finally, the formulation functionalization was optimized by a DoE to find the optimal conditions between DSPE-PEG and DSPE-PEG-Mannose ratio and the chain length of DSPE-PEG.
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Keywords
STING agonists, Liposomes, DOTAP