Biomimetic Brain-Targeted Delivery of Esterified XAV939 for Treating Autism-Associated Social Deficits

Background/Objectives: Autism spectrum disorder (ASD) is a group of developmental disorders featured by social dysfunction, for which there still lacks effective treatments. Our previous study demonstrated that XAV939, a tankyrase inhibitor, could alleviate social dysfunction in two ASD mouse models via suppressing Wnt and glycolytic signaling. However, its further application is limited by poor brain-blood barrier penetration and low bioavailability. Methods: XAV939 was structurally optimized by esterification. The effects of XAV939-derivatives on Wnt/glycolysis were assessed by Western blotting, Topflash luciferase assay, lactate levels and the extracellular acidification rate. Social behaviors were evaluated by a three-chamber test, a resident-intruder test and ultrasonic vocalization. Biomimetic brain targeting was achieved by neuron-astrocyte hybrid cell membrane encapsulation. Periphery toxicities were examined by biochemical and histological analysis. Results: Three esterified XAV939 were synthesized. Data from both 293FT cells and primary Shank3b^-/- neurons revealed that an alkyl ester prodrug of XAV939 (named XAV939-L1) exhibited dual inhibition of Wnt/glycolysis. Intravenous injection of XAV939-L1 effectively improved the social function of Shank3b^-/- mice but showed hepatic side effects. Further, we made brain-targeting XAV939-L1 (XAV939-L1-BT) by neuron-astrocyte hybrid cell membrane encapsulation, which greatly enhanced the accumulation of XAV939-L1-BT in the brain and reduced its distribution in peripheral tissues (liver and intestine). At a half-dose of XAV939-L1, XAV939-L1-BT exhibited significant social improvement effects without obvious hepatic and intestinal toxicity. Conclusions: Our data demonstrated an esterified XAV939 and its biomimetic brain-targeted formula as a potential drug candidate for treating ASD-associated social dysfunction.