Recent advances in polysulfide-based prodrug nanomedicines for cancer therapy

Abstract

Polysulfide bonds, particularly trisulfide and tetrasulfide bonds, are prevalent in the fields of medicine, pharmacy, and materials science. Polysulfide-based prodrug nanomedicines exhibit exceptional properties and hold significant potential as drug delivery carriers. These bonds can remain stable in the extracellular environment; however, upon entering cancer cells, they undergo a sulfhydryl-polysulfide bond exchange reaction with glutathione in the cytoplasm, leading to cleavage of the polysulfide bond. In comparison to sulfur bonds such as thioether and disulfide bonds, polysulfide bonds confer prodrug nanomedicines with superior self-assembly stability, prolonged blood circulation, and enhanced tumour accumulation. Importantly, the ultra-high reduction responsivity of polysulfide bonds renders prodrug nanomedicines highly selective “tumour bombs” that can be activated by endogenous reducing agents within tumour cells. Hence, polysulfide-based prodrug nanomedicines show great promise in the treatment of cancer. Recently, there has been a focus on advanced polysulfide-based prodrug nanomedicines to enhance their effectiveness in vivo. These advanced prodrug nanomedicines have the ability to address the undesirable physicochemical characteristics found in traditional sulfur-based prodrug nanomedicines, thereby improving their targeting capability and reducing off-target side-effects. In this review, we provide a comprehensive summary of recent advances made in these cutting-edge prodrug nanomedicines, explain their underlying design principles, discuss current challenges, and provide insight into the future prospects of this evolving field.