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• W2755795896 abstract "Diacylglycerol lipase-beta (DAGLβ) hydrolyzes arachidonic acid (AA)-containing diacylglycerols to produce bioactive lipids including endocannabinoids and AA-derived eicosanoids involved in regulation of inflammatory signaling. Previously, we demonstrated that DAGLβ inactivation using the triazole urea inhibitor KT109 blocked macrophage inflammatory signaling and reversed allodynic responses of mice in inflammatory and neuropathic pain models. Here, we tested whether we could exploit the phagocytic capacity of macrophages to localize delivery of DAGLβ inhibitors to these cells in vivo using liposome encapsulated KT109. We used DAGLβ-tailored activity-based probes and chemical proteomic methods to measure potency and selectivity of liposomal KT109 in macrophages and tissues from treated mice. Surprisingly, delivery of ∼5 μg of liposomal KT109 was sufficient to achieve ∼80% inactivation of DAGLβ in macrophages with no apparent activity in other tissues in vivo. Our macrophage-targeted delivery resulted in a >100-fold enhancement in antinociceptive potency compared with free compound in a mouse inflammatory pain model. Our studies describe a novel anti-inflammatory strategy that is achieved by targeted in vivo delivery of DAGLβ inhibitors to macrophages." @default.
• W2755795896 created "2017-09-25" @default.
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• W2755795896 date "2017-09-13" @default.
• W2755795896 modified "2023-10-18" @default.
• W2755795896 title "Liposomal Delivery of Diacylglycerol Lipase-Beta Inhibitors to Macrophages Dramatically Enhances Selectivity and Efficacy <i>in Vivo</i>" @default.
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• W2755795896 doi "https://doi.org/10.1021/acs.molpharmaceut.7b00657" @default.
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