Glycogen kinase 3 inhibitor nanoformulation as an alternative strategy to inhibit PD-1 immune checkpoint
Date
2022
Authors
Badiee, P.
Maritz, M.F.
Thierry, B.
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Journal article
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International Journal of Pharmaceutics, 2022; 622(121845):1-9
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Abstract
Immune checkpoint inhibition with antibodies targeting the programmed cell death-1 (PD-1) pathway is a frontline cancer immunotherapy. Driven by the limited response rates and high off-target toxicity associated to monoclonal antibodies, small molecule inhibitors of PD-1 are under active investigation. Glycogen synthase kinase 3 (GSK3) is an up-stream regulator of PD-1 and small molecule GSK3 inhibitors have been shown to effectively reduce T-cell expression of PD-1 receptors. Towards harnessing the potent anticancer effects of GSK3 inhibition, we report here on the development of a nanoformulation within PEG-PLGA nanoparticles of the small molecule GSK3 inhibitor SB415286. The formulation physicochemical properties were optimised using a novel 3D printed microfluidic nanoprecipitation device and a hydrophobic ion pairing approach was used to increase the loading of the drug. The SB415286 nanoformulation efficiently inhibited PD-1 expression in chimeric antigen receptor (CAR)-T cells co-cultured with tumour cells expressing the CAR target, and improved their survival and proliferation. Treatment of the CAR-T cells with nanoformulation also increased the population of memory T-cells. The nanoformulation of small molecule inhibitor of the GSK3 pathway is a promising alternative to antibody-based checkpoint inhibition that warrants further studies.
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Data source: Supplementary data, https://doi.org/10.1016/j.ijpharm.2022.121845
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Copyright 2022 Elsevier B.V.