Antitumor and toxicity study of mitochondria-targeted triptolide derivatives using triphenylphosphine (TPP+) as a carrier

Based on the higher mitochondrial membrane potential (Delta psi(m)) of tumor cells than normal cells, a mitochondria-targeting strategy using delocalized lipophilic cations as carriers is a promising way to improve the antitumor effect of small molecules and to reduce toxicity. Triptolide (TP) has a strong antitumor effect but is limited in the clinic due to high systemic toxicity. Mitochondria-targeted TP derivatives were designed and synthesized using triphenylphosphine cations as carriers. The optimal derivative not only maintained the antitumor activity of TP but also showed a tumor cell selectivity trend. Moreover, the optimal derivative increased the release of lactate dehydrogenase and the production of ROS, decreased Delta psi(m), and arrested HepG2 cells in G0/G1 phase. In a zebrafish HepG2 xenograft tumor model, the inhibitory effect of the optimal derivative was comparable to that of TP, while it had no obvious toxic effect on multiple indicators in zebrafish at the test concentrations. This work provided some evidence to support the mitochondria-targeting strategy.

Automated summary

By using delocalized lipophilic cations as carriers, mitochondria-targeted derivatives of TP were designed and synthesized, maintaining strong antitumor activity with tumor cell selectivity. These derivatives also increased the release of lactate dehydrogenase and production of ROS, reduced mitochondrial membrane potential, and arrested HepG2 cells in the G0/G1 phase.