A novel "carrier-free" nanofiber co-delivery system with synergistic antitumor effect of Paclitaxel and Tetrandrine through the enhancement of mitochondria apoptosis.

Paclitaxel (Ptx), a type of microtubule depolymerization inhibitor, is one of the main components in gastric cancer chemotherapy. Some studies have demonstrated that Tetrandrine (Tet), a bisbenzylisoquinoline alkaloids, has potential anti-tumor effect in several cancers. Aside from the direct anticancer effect, Tet is proved to synergistically enhance the antitumor effect of Ptx in gastric cancer. However, the application of the combinational strategy is limited by the poor solubility of both drugs. Nano-drug delivery systems including polymeric nanoparticles, self-assembled nanofibers or hydrogels, etc., hold the potential to meet the need. Here, a novel supramolecular nanomaterial, based on the concept of "Carrier free", is reported as feasible platforms for synergistic drug delivery. Ptx-SA-RGD is obtained through the conjugation of Ptx and tumor specific peptide RGD (arginine-glycine-aspartic acid peptide) with succinic acid (SA) as a linker. Ptx-SA-RGD could self-assembled into Ptx nanofibers (P-NFs) with a high drug loading efficiency. Tet was then encapsulated into P-NFs to acquire novel Ptx and Tet co-loaded self-assembled nanofibers (P/T-NFs). The uptake study shows the dynamic internalization of P/T-NFs by gastric cancer cell line MGC-803. P/T-NFs significantly triggered the accumulation of ROS in gastric cancer cells MGC803 and further decreased the mitochondrial membrane potential, which led to the induction of mitochondrial apoptosis with superior cytotoxicity against free drugs. Moreover, P/T-NFs suppressed the expressions of p-STAT3 and p-JAK, initiated Cytochrome-C release and promoted caspase-proteins expression. Furthermore, P/T-NFs demonstrated the strongest tumor delaying effect as well as the lowest toxicity. Therefore, self-assembled nanofibers of P/T-NFs demonstrated a raise of mitochondrial apoptosis level and a stronger antitumor effect both in vitro and in vivo, which could be a potential way to enhance the clinical efficacy and reduce the side-effect of Ptx in gastric cancer.