Enhanced cancer therapy of celastrol in vitro and in vivo by smart dendrimers delivery with specificity and biosafety

Celastrol, a pentacyclic triterpene extracted from the roots of Tripterygium Wilfordi (thunder god vine) plant, has shown promising antitumor activities in various preclinical studies. However, its clinical application is limited largely due to the significant toxic side effects. PAMAM dendrimers by virtue of its excellent "multivalent effect", combined with biocompatible components, were usually used as outstanding vehicles to overcome the in vivo application limitations of chemotherapeutics. This work aimed at developing bioconjugates composed of EpCAM aptamer, polyethylene glycol, and dendrimers for specifically delivering celastrol into EpCAM-abundant tumors to improve the antitumor efficacy and mitigate the toxicity. The measurements of cancer cell targeting and apoptosis-inducing effects were conducted in SW620 colorectal cancer cells both in vitro and in nude mice, and the biosafety was evaluated in mice and zebrafish models. Our results showed that the bioconjugates (40 nm) possessed a spherical morphology with a negative surface charge, which maintained the great biostability in physiological environment. When exposed to bioconjugates, SW620 not AD293 cells underwent extensive apoptosis. The bioconjugates were superior to free celastrol in inducing apoptosis of SW620 cells in vitro and in nude mice. Moreover, they exhibited much reduced local and systemic toxicity both in xenograft mice and zebrafish models. Taken together, these data indicate that the integrated strategy-designed dendrimer delivery system represents a promising application of celastrol in targeted cancer treatment with great biosafety and specificity.