(T1230-09-49) Complex of Paclitaxel Mesoporous Silica Nanoparticles with Curcumin, TPGS Exerts Higher Anticancer Potency in B16F10 Melanoma

Purpose: Paclitaxel, is renown among chemotherapy drugs for solid tumor. It operates by stabilizing microtubule polymers, thereby preventing their disassembly, and is extensively employed in the treatment of various solid tumors. However, its utility is impeded by low bioavailability, primarily due to the extensive expression of P-glycoprotein (P-gp) on intestinal epithelial cells, necessitating administration via intravenous injection and leading to numerous side effects during therapeutic regimens. To effectively reverse MDR in tumor treatments, a new pH-sensitive nano drug delivery system composed of mesoporous silica nanoparticles (SMB7DPP), curcumin(CUR) and D-a-tocopheryl poly-ethylene glycol 1000 succinate (TPGS) copolymers was synthesized to deliver paclitaxel into drug-resistant melanoma cancer cell line B16F10. In our approach, we encapsulated paclitaxel within SMB7DPP to facilitate sustained release and co-administered it with CUR to reinforce efficacy of paclitaxel. Furthermore, to counteract P-gp, we employed TPGS as an inhibitor.

Methods: In our anticancer study, we investigated the efficacy of a combination therapy consisting of SMB7DPP-PTX (2.5 mg/kg) with CUR (20 mg/kg) and TPGS (60 mg/kg) [SDPCT], compared to SMB7DPP-PTX (2.5 mg/kg) with CUR (20 mg/kg) [SDPC], and PTX (2.5 mg/kg) with CUR (20 mg/kg) [PC]. These formulations were administered subcutaneously to B16F10 tumor-bearing C57BL/6 mice in a twice-daily 12-hour cycle for 7 days. Subsequently, a 8hr of pharmacokinetic study was conducted, including harvesting organs and tumors to quantify paclitaxel levels by LC-MS/MS.

Results: The results demonstrated a significant reduction in tumor size in the SDPCT group compared to the SDPC, PC, and control groups. Despite no difference in pharmacokinetic parameters, there was a 7,20-fold increase in paclitaxel accumulation within the tumors of the SDPCT group compared to the SDPC and PC groups 2 hours post-administration with no difference on organs. Additionally, 8 hours after administration, only trace amounts of paclitaxel were detectable in the body.

Conclusion: A new pH-sensitive nano drug delivery system composed of mesoporous silica nanoparticles (SMB7DPP), curcumin(CUR) and D-a-tocopheryl poly-ethylene glycol 1000 succinate (TPGS) copolymers, delivering paclitaxel optimizes paclitaxel's ADME profile.

References: Collnot, E. M., Baldes, C., Wempe, M. F., Kappl, R., Hüttermann, J., Hyatt, J. A., ... & Lehr, C. M. (2007). Mechanism of inhibition of P-glycoprotein mediated efflux by vitamin E TPGS: influence on ATPase activity and membrane fluidity. Molecular pharmaceutics, 4(3), 465-474.
Wei, Y., Pu, X., & Zhao, L. (2017). Preclinical studies for the combination of paclitaxel and curcumin in cancer therapy. Oncology reports, 37(6), 3159-3166.
Lin, J., Cai, Q., Tang, Y., Xu, Y., Wang, Q., Li, T., ... & Lin, D. (2018). PEGylated Lipid bilayer coated mesoporous silica nanoparticles for co-delivery of paclitaxel and curcumin: Design, characterization and its cytotoxic effect. International Journal of Pharmaceutics, 536(1), 272-282.

Plasma concentration vs time profile of paclitaxel in three different drug-loaded paclitaxel complex and combination

Anticancer effect of paclitaxel and drug-loaded paclitaxel complex on tumor growth of B16F10 melanoma tumor-bearing mice (n=6)

Uptake study of B16F10 melanoma cells to paclitaxel was determined using cell uptake study after treatment of various concentrations of three different drug-loaded paclitaxel complex and combination (1µM of paclitaxel for each complex and combination) for 1hr (n=6)