Novel nanofibers for co-delivery of Paclitaxel and Tetrandrine with synergistic anticancer efficiency for gastric cancer

[Speaker] Xiaolin Li:1
[Co-author] Na Yu:1, Weihao Sun:1
1:Department of Geriatric Gastroenterology, the First Affiliated Hospital with Nanjing Medical University, China

Background: Paclitaxel (Ptx), a type of microtubule depolymerization inhibitor, has been recommended as a main component of first line chemotherapy regimen for gastric cancer. Its clinical application has been greatly limited by its emerging resistance developed by tumor cells. Previous reports from our group has demonstrated that Tetrandrine (Tet) is effective to enhance the anticancer effect of Ptx as a chemosensitizer. However, the insolubility of Ptx and Tet, together with the hypersensitivity from the Cremophor EL (solvent of clinical Ptx solution), bring great difficulty in administration. Here we report a nano-drug delivery system to co-deliver Ptx and Tet to achieve synergistic antitumor efficiency.
Methods: Ptx was conjugated with a tumor targeting peptide (RGD) by the link of succinic acid (SA) to form Ptx-SA-RGD, which can self-assemble into nanofibers. Then Tet was physically loaded into the self-assembled Ptx-SA-RGD nanofibers to obtain Ptx/Tet-co-loaded nanofbiers (P/T-NFs). P/T-NFs were characterized for physiochemical property by Transmission Electric Microscopy and HPLC. Cytotoxicity test were evaluated by XTT assay. Possible mechanisms under the synergistic anticancer effect of P/T-NFs were examined by western blotting. Intracellular reactive oxygen species (ROS) level and mitochondria membrane potential were also studied.
Results: The cellular uptake study shows the dynamic internalization of P/T-NFs by gastric cancer cell line MGC803. MTT assay shows the superior cytotoxicity of P/T-NFs in MGC803 cells, particularly in a low concentration (Figure). Apoptosis analyzes indicate an obviously up-regulation of apoptotic cell numbers after incubated with P/T-NFs (Figure). Intracellular ROS levels and calcium accumulation are significantly increased in P/T-NFs group, while mitochondrial membrane potential is decreased, indicating that P/T-NFs enhances mitochondrial apoptosis in MGC803 cells. Moreover, western blot proved that P/T-NFs simultaneously advances Cytochrome-C release, promote caspase-proteins expression and suppress the expressions of p-STAT3 and p-JAK in vitro.
Conclusion: Therefore, self-assembled nanofibers of P/T-NFs demonstrated a raise of mitochondrial apoptosis level and a stronger antitumor effect, which could be a potential method to improve the therapeutic efficacy and reduce the side-effect of Ptx in gastric cancer.

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