Biodegradable self-assembly micelles significantly enhanced the solubility, biological stability and in vivo antitumor efficacy of Hexylselen

• Published in: RSC chemical biology 2021-12, Vol.2 (6), p.1669-1681
• Main Authors: Fang, Jinzhang, Chen, Zhao, Song, Jun, Li, Jinxiu, Han, Yunying, Hou, Wei, Wang, Wenxi, Ruan, Benfang H
• Format: Article
• Language: English
• Subjects: Chemistry
• ISSN: 2633-0679; 2633-0679
• DOI: 10.1039/d1cb00089f

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 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 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.