Self-Assembling and Self-Immolative Three-in-One Prodrug Nanoassemblies for Self-Synergistic Combinational Anticancer Therapy

Therapeutic efficacy of combination therapy could be markedly enhanced when two or more drugs are codelivered to targeted cancer cells, exerting synergistic therapeutic actions. However, codelivering individual drugs to the same target cells, while minimizing off-target effects, remains challenging. We report here the synthesis and synergistic anticancer actions of a trimeric prodrug (RqGem), which is rationally designed by leveraging the advantages of self-assembling hybrid prodrugs and cancer redox biology. RqGem is a self-assembling trimeric prodrug of gemcitabine (GEM), all-<i>trans</i> retinoic acid (atRA), and glutathione-depleting quinone methide (QM). In design, GEM and atRA are conjugated via a QM precursor-containing linker that not only serves as a self-immolative moiety but also boosts the anticancer actions of atRA and GEM by elevating oxidative stress in cancer cells. RqGem self-assembles into homogeneous nanoassemblies with 100% drug loading and undergoes esterase-triggered self-immolation, resulting in the release of atRA, GEM, and QM, which together exert self-synergistic combinatorial therapeutic effects. In mouse xenograft models, RqGem nanoassemblies exhibit superior anticancer efficacy compared with the simple mixture of atRA and GEM, underscoring the potential of antioxidant depletion-mediated synergistic combinational therapy. We believe that the rational design of RqGem offers valuable insight into the development of efficient strategies for self-synergistic combination therapy.