Experimental Design of D-α-tocopherol polyethylene glycol 1000 succinate Stabilized Bile Salt Based Nano-vesicles for Improved Cytotoxicity and Bioavailability of Colchicine Binding Site Inhibitor Candidates: In Vitro, In silico, and Pharmacokinetic Studies

Nowadays, conventional anticancer therapy suffers many pitfalls, including drastic side effects and limited therapeutic efficacy resulting from diminished oral bioavailability. So, in an attempt to enhance their poor solubility and oral bioavailability along with the cytotoxic activity, the developed lead compounds (C1 and C2) were loaded in D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) modified vesicles adopting thin film hydration technique. The formulations of the aforementioned candidates (F1 and F2, respectively) were elected as the optimum formula with desirability values of 0.701 and 0.618, respectively. Furthermore, an outstanding enhancement in the drug’s cytotoxic activity against different cancer cell lines (MCF-7, HepG-2, MDA-MB-321, A375, and MGC-803) after being included in the nano-TPGS-modified optimum formula was noticed relative to the unformulated compounds. The formula F1 showed the best cytotoxic activities against HepG-2 with an IC₅₀ = 3 µM.

Furthermore, regarding MCF-7, F1 was shown to be the most potent and protective among all the tested formulations with an IC₅₀ = 6 µM. Besides, F1 exerted the best caspase 3/7 activity stimulation (around a 5-folds increase) compared to control in the MCF-7 cell line. Notably, it was disclosed that both C1 and C2 induced cell cycle arrest at the resting S growth phase. Moreover, C1 and C2 decreased tubulin concentrations by approximately 2-folds and 6-folds, respectively. Meanwhile, the conducted molecular docking studies ensure the eligible binding affinities of the assessed compounds. Besides, MD simulations were performed for 1000 ns to confirm the docking results and study the exact behavior of the target candidates (C1 and C2) toward the CBS.

Materials

Span 60 was purchased from Sigma–Aldrich Chemical Co. (St. Louis, Missouri, USA). Sodium taurocholate (STC) was obtained from BASF Co. (Florham Park, New Jersey, USA). Cholesterol was obtained from ITX Biomedicals (Santa Ana California, USA). D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) was attained from Xi’an Healthful Biotechnology Co., (Ankang, Shaanxi, China). Sodium hydroxide, potassium dihydrogen orthophosphate, chloroform.

Ayman Abo Elmaaty, Ahmed A. Al-Karmalawy, Mohamed S. Nafie, Marium M. Shamaa, Islam Zaki, Radwan Alnajjar, Mohamed Y. Zakaria, Experimental Design of D-α-tocopherol polyethylene glycol 1000 succinate Stabilized Bile Salt Based Nano-vesicles for Improved Cytotoxicity and Bioavailability of Colchicine Binding Site Inhibitor Candidates: In Vitro, In silico, and Pharmacokinetic Studies, International Journal of Pharmaceutics, 2023, 122980, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2023.122980.

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