68P Dendritic polylysine with paclitaxel and triptolide codelivery for enhanced NSCLC ferroptosis through the accumulation of ROS

The clinical application of Paclitaxel (PTX), a first-line chemotherapeutic for NSCLC, is severely limited because of its developed resistance and insolubility. It is reported by our previous studies that the resistance to PTX is closely related to intracellular redox balance in cancer cells. Moreover, our preliminary data demonstrated that Triptolide (TPL) could improve the cytotoxicity of PTX through inducing ROS production. Most importantly, the synergistic anticancer effect between PTX and TPL is mainly through the induction of ferroptosis in NSCLC cell lines. To improve the delivery efficiency of both drugs, we constructed a novel nano-drug delivery system NDDS chemosynthesis by PEGylated generation 3 (G3) dendritic polylysine co-loaded with PTX and TPL (PTX-TPL-PEG-PLL, PTPP), which was endowed with the ability of tumor targeting and favorable solubility. this is the first report on the dendritic polylysine loaded with PTX and TPL for NSCLC treatment. In addition, the enhanced ferroptosis-inducing effect of PTPP was mediated through ROS level, which illustrated the possible mechanism underlying the synergistic effect of PTX and TPL. First, the PTPP was characterized by 1H NMR analysis, mass spectra, and HPLC. the in vitro synergetic effect and mechanism of PTX and TPL were explored by MTT assay and western blot. In vivo evaluation was performed in a xenograft mice model of NSCLC cell lines. The PTPP was synthesized successfully through covalent bonding and the MTT assay indicated the synergetic effect of PTX and TPL. Besides, regarding the mechanism, the TPL could promote the generation of ROS by inhibiting the NF-κB signaling pathway, which synergistically increased ROS level with PTX, inducing NSCLC cells ferroptosis. In the end, in vivo experiments suggested the outstanding tumor-inhibiting ability of PTPP. Overall, the current study suggested that PTPP exerted an excellent antitumor effect than PTX, TPL, or PTX combined with TPL through ferroptosis induction. PTPP may be a potential treatment system for NSCLC treatment.