Carrier-Free Triterpene Prodrugs with Glutathione Response and Biosafety for Synergistically Enhanced Photochemotherapy

Carrier-free pure drug self-assembled nanosystems have been proposed as a promising strategy for synergetic anticancer therapy. Herein, we purposefully designed and synthesized disulfide-modified glutathione (GSH)-responsive natural pentacyclic triterpene betulinic acid (BA) with better biodegradability and biocompatibility to construct carrier-free photosensitive prodrugs BA-S-S/Ce6 NPs for synergistically enhanced and biosafe photochemotherapy. The molecular dynamics simulation elucidates the possible coassembly mechanism that the coplanar arrangement of BA-S-S dimeric may be primarily responsible for the formation of a long lamella-like or spherical morphology. The density functional theory calculations demonstrate that the reduced energy gap (Delta E-ST) of Ce6 facilitates the improved singlet oxygen generation of BA-S-S/Ce6 nanoparticles (NPs). The assembled prodrugs exhibited remarkable GSH-responsive property and multiple favorable therapeutic features, leading to enhanced synergistic antitumor efficacy without noticeable toxicity. Additionally, evaluation of the antitumor efficacy of another tetracyclic triterpene stigmasterol (ST)-mediated ST-S-S/Ce6 NPs further confirmed the effectiveness of this rational design. This work provides a promising insight for exploring the pure drug self-assembly behavior and construction of GSH-responsive carrierfree triterpenoid prodrugs toward improved multiple combination antitumor therapies.