Glutaminolysis inhibitors have shown early promise in
cancer therapeutics. Specifically, kidney-type
glutaminase (KGA) has been a long-standing anti-
tumor drug target; KGA allosteric inhibitors have attracted great attention due to their superior
enzyme specificity and good drug safety profiles. However, the main issue with allosteric inhibitors-including BPTES,
CB-839, and the recently developed KGA allosteric and
glutamate dehydrogenase (GDH) dual inhibitor, Hexylselen (CPD-3B)-is their low solubility; it leads to limited in vivo efficacy. To optimize their formulation, various delivery carriers were screened in the present study. Soluplus® (
SOL), an amphiphilic graft
polymer, showed an interesting structure-solubility/activity relationship with Selen molecules containing different middle chain sizes. Among these molecules, the long chain molecule CPD-3B showed 3000-fold increased solubility with
SOL, forming well-dispersed and stable
micelles 60-80 nm in size. Moreover, CPD-3B@
SOL micelles exhibited good metabolic stability in both blood and liver microsomes. These advantages significantly enhanced the bioavailability and in vivo antitumor efficacy of CPD-3B@
SOL micelles in the H22 hepatocarcinoma xenograft mouse model. Thus, the current study provided a practical delivery system for allosteric inhibitors of
glutaminase, which is one of the bottlenecks of targeting
tumor glutaminolysis.