LY-2090314

Neuronal glycogen synthase kinase-3s (GSK-3α and the more abundant GSK-3β) are serine/threonine kinases that have been postulated to play roles in neuronal adaptations, including those that come from exposures to substances of abuse; however, there is only modest information about ways in which GSK-3 alters the effects of the widely abused psychostimulant, methamphetamine (METH). To evaluate the effects of GSK-3 inhibition on METH-induced symptoms, mice were treated with LY2090314, a potent and selective GSK-3 inhibitor, followed by METH. Horizontal locomotion, vertical rearing, and stereotyped behaviors were measured. Pretreatment with LY2090314 (2.5, 10, and 25 mg/kg) significantly inhibited stereotypic behavior induced by METH (10 mg/kg) in a dose-dependent fashion. Stereotyped biting was most robustly reduced by LY2090314. By contrast, LY2090314 had no significant effect on METH (3 mg/kg)-induced hyperlocomotion. GSK-3 signaling pathways appear to be differentially involved in acute METH effects on locomotion. GSK-3 appears essential for the expression of METH-induced stereotypy but not hyperlocomotion.

The low therapeutic index of hydrophilic drugs with potent pharmacological effects limits their effectiveness and clinical application. A common strategy to enhance hydrophilic drug delivery involves combining amphiphilic prodrugs with nanoparticle delivery systems; however, this approach often fails to overcome exclusion by stem cell-like circulating tumor cells (CTCs). This study introduces a fluorinated prodrug strategy designed to enhance intracellular protein interactions and reduce this exclusion. Danshensu (DAN), known to suppress metastasis by reducing cancer stemness, has limited clinical potential due to its hydrophilicity and resulting low bioavailability. Although aliphatic aromatic amphiphilic prodrug strategies improve hydrophilic drug bioavailability, efficient fluoroalkylation techniques are also useful for synthesizing bioactive fluorine-containing compounds. Inspired by these methods, we propose a novel amphiphilic prodrug approach that attaches aromatic aliphatic chains to enhance DAN's amphiphilicity and adds fluorinated aromatic rings to strengthen intracellular protein interactions, thereby improving DAN's intracellular effectiveness. Our studies showed that DAN reduces cancer stemness by inhibiting the β-catenin pathway, and that increasing the lipophilicity of DAN prodrugs enhances their regulatory effect on this pathway, with fluorinated aromatic prodrugs proving more effective than non-fluorinated ones. Additionally, these optimized prodrugs significantly amplified miriplatin's stemness-suppressing activity. Based on these findings, we designed a hyaluronic acid-based nanoparticle to co-encapsulate both the fluorinated aromatic prodrugs and miriplatin. This formulation exhibited targeted action against CTCs, effectively preventing postoperative metastasis in a breast cancer mouse model and significantly improving survival rates in treated mice. In conclusion, the fluorinated aromatic prodrug strategy offers a promising method for optimizing hydrophilic small-molecule drugs, enhancing their druggability, and preventing postoperative metastasis.