RqGem

RqGem is a self-assembling trimeric mutual prodrug designed for the treatment of pancreatic cancer. It consists of gemcitabine (GEM) and all-trans retinoic acid (atRA) covalently linked via a glutathione (GSH)-depleting linker. This architecture enables excipient-free nanoassembly, achieving 100% drug loading and ensuring the simultaneous delivery of both therapeutic agents. Upon entering the intracellular environment, RqGem nanoassemblies are activated by esterases, releasing GEM, atRA, and a quinone methide intermediate. The quinone methide rapidly depletes intracellular GSH, inducing a redox imbalance that elevates oxidative stress and sensitizes cancer cells to GEM-induced DNA damage and atRA-mediated differentiation cues. Furthermore, the released atRA targets and downregulates Pin1, a peptidyl-prolyl isomerase associated with oncogenic signaling and poor prognosis in pancreatic cancer. Preclinical studies in cell culture and orthotopic mouse models have demonstrated that RqGem nanoassemblies exhibit superior cytotoxicity, cellular uptake, and apoptosis induction compared to free drug mixtures.