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

Abstract

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 (ΔE 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.

Triterpenoids as Reactive Oxygen Species Modulators of Cell Fate

“…To overcome this problem, a novel molecular design based on the natural product betulinic acid was developed (compound 17f , Figure 8 ). 58 The synthesis of this chemical probe began with the addition of 3,3′-dithiodipropionic acid to 17 under mild esterification conditions to provide the resultant product in good yield. The glutathione-responsive carrier-free triterpenoid prodrug nano-coassembly of compound 17f with Ce6 was developed.…”

“…Therefore, it offers a promising therapeutic strategy. 58 An alternative approach uses a derivative of natural product compound 17 in coassembly with glucose oxidase to generate a novel nanoparticle, which provides a dual attack on the cancer cells. 59 This study takes advantage of self-encapsulation of organic compounds, 17g and glucose oxidase, and it also utilizes guest−host interactions between the ferrocene functionality of compound 17g and the water-soluble pillar [6]arene.…”

“…This self-assembly system can serve as a GSH-responsive prodrug nano-coassembly to deliver the chemical cargo at the appropriate subcellular site and improve the antitumor efficacy by reducing excess glutathione. Therefore, it offers a promising therapeutic strategy …”

Bioactive small-molecule constituents of Lao plants

“…A carrier-free disulfide-modified glutathione (GSH)responsive 3b has been prepared, and a photosensitive prodrug, BA-S-S/Ce6 nanoparticles (NPs), has been constructed. Under irradiation, BA-S-S/Ce6 NPs exhibited more potent cytotoxicity than Ce6 against 4T1 musculus breast cancer cells, and it improved the antitumor efficacy of Ce6 (Cheng et al, 2021).…”

A nanomedicine enables synergistic chemo/photodynamic therapy for pancreatic cancer treatment

“…As expected for hydrogen bonds, the intermolecular interactions among GVS, Ce6, and solvents, such as steric effect and van der Waals force, had an effect on the molecular self-assembly as well. [40][41][42] Therefore, the average noncovalent interaction (aNCI) among GVS, Ce6, and solvent molecules was investigated and is visualized in Fig. 2D.…”