Liposomal Delivery of MIW815 (ADU-S100) for Potentiated STING Activation

Abstract

Stimulator of interferon genes (STING) agonists can improve the anticancer efficacy of immune checkpoint blockade by amplifying tumor immunogenicity. However, the clinical translation of cyclic dinucleotides (CDNs) as STING agonists is hindered by their poor drug-like properties. In this study, we investigated the design criteria for DOTAP/cholesterol liposomes for the systemic delivery of ADU-S100 and delineated the impact of key formulation factors on the loading efficiency, serum stability, and STING agonistic activity of ADU-S100. Our findings demonstrate that the cationic liposomal formulation of ADU-S100 can be optimized to greatly potentiate STING activation in antigen-presenting cells.

Design of Liposome Formulations for CRISPR/Cas9 Enzyme Immobilization: Evaluation of 5-Alpha-Reductase Enzyme Knockout for Androgenic Disorders

“…Optimization studies by Haghiralsadat et al found that the liposomal cationic lipid, DOTAP, in combination with stearoyl phosphoethanolamine-polyethylene glycol, produced stable round-shaped particles without the aggregate formation and an average diameter of 71 nm . DOTAP/cholesterol liposomes could also resist destabilizing effects from serum proteins. , The protein delivery efficiency of liposomal formulations would depend on the average diameter and the cellular uptake. Yan and Huang demonstrated that 20 μg of ovalbumin (OVA) formulated in 200 nmol DOTAP with a particle size range of 350–550 nm, protein loading capacity of 95–90%, and zeta potential of 29–38 mV had the best OVA-specific antibody response, suggesting both Th1 and Th2 immune responses were generated by this formulation .…”

“…43 DOTAP/cholesterol liposomes could also resist destabilizing effects from serum proteins. 44,45 The protein delivery efficiency of liposomal formulations would depend on the average diameter and the cellular uptake. Yan and Huang demonstrated that 20 μg of ovalbumin (OVA) formulated in 200 nmol DOTAP with a particle size range of 350−550 nm, protein loading capacity of 95−90%, and zeta potential of 29− 38 mV had the best OVA-specific antibody response, suggesting both Th1 and Th2 immune responses were generated by this formulation.…”

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

“…Optimization of liposome composition allowed researchers to obtain CDNs stably incorporated into the liposomes, protect CDNs from spontaneous degradation in the blood, and retain the activity of ADU-100 [216], and diABZI [217] and various CDNs in extracellular vesicles [218]. Moreover, virus-like particles containing long DNA strands encapsulated in cationic liposomes showed some promise in inducing the liquid-phase condensation of cGAS, thereby activating STING [219].…”

Mn-phenolic networks as synergistic carrier for STING agonists in tumor immunotherapy

“…Presently, ADU-S100 is undergoing phase I/II clinical trials for treating advanced metastatic solid tumors and lymphomas [ [26] , [27] , [28] ]. Nonetheless, ADU-S100 confronts several challenges, including issues related to stability, negative charge-associated impediments to effective cellular targeting, inefficient cytoplasmic transport, and heightened hydrophilicity [ 18 , 23 , [29] , [30] , [31] ]. Consequently, the predominant mode of ADU-S100 administration remains intratumoral delivery.…”