Cyclic monochalcogen bonds enable improved stability and fine-tuned activation of dimeric prodrug nanoassemblies for potent cancer therapy

Abstract

Homodimeric prodrug nanoassemblies (HPNs) have attracted attention as an effective approach to enhance the delivery efficiency of chemotherapeutic drugs. The chemical linkages are critical determinants of the therapeutic performance and safety profile of the HPNs. Previous studies have shown that the linear monochalcogen bonds (including monosulfide and monoselenide bond) exhibit excessively high oxidative responsiveness, causing premature drug leakage during systemic circulation. To address the paradox of systemic circulation stability and site-specific drug release, five-membered cyclic monochalcogen bond based HPNs have been developed, in which the molecular structures were engineered to introduce relatively high steric hindrance and strained tension, as indicated by molecular mechanics calculations. These structural features enhance both chemical and assembly stability of prodrugs with the cyclic monochalcogen bonds, thereby conferring the HPNs with improved systemic circulation stability while maintaining on-demand site-specific activation. In vivo studies further demonstrate that the HPNs modified with cyclic monochalcogen bonds exhibit prolonged blood circulation, enhanced tumor accumulation, and ultimately improved therapeutic outcomes. This is the first case that employs cyclic monochalcogen bonds in establishing intelligent prodrug nanoassemblies. Moreover, the ring-forming engineering technology may serve as a general strategy to optimize intelligent medicines and advance the precision and safety of cancer chemotherapy.

Keywords: Cyclic chalcogen bonds; Prodrug nanoassemblies; Redox responsive; cancer therapy.