Enhancing solubility and stability of sorafenib through cyclodextrin-based inclusion complexation: in silico and in vitro studies

Abstract

Sorafenib (SOR) is an oral multikinase inhibitor that effectively hampers the growth and spread of cancer cells by targeting angiogenesis and proliferation. However, SOR tablets (Nexavar) have limited oral bioavailability, ranging from 38% to 49%, due to their low water solubility. To address this issue, cyclodextrins (CDs), widely used to enhance the solubility and stability of lipophilic drugs by encapsulating them within their molecular structure, were considered in this study. We focused on β-cyclodextrin (βCD) and its derivatives, including hydroxypropyl-β-cyclodextrin (HPβCD), dimethyl-β-cyclodextrin (DMβCD), sulfobutylether-β-cyclodextrin (SBEβCD), and compared them with γ-cyclodextrin (γCD) for generating inclusion complexes with SOR. The 200 ns molecular dynamics simulations revealed that SOR could form inclusion complexes with all CDs in two possible orientations: pyridine group insertion (P-form) and chlorobenzotrifluoride group insertion (C-form), primarily driven by van der Waals interactions. Among the four βCD derivatives studied, SOR exhibited the highest number of atom contacts with SBEβCD and demonstrated the lowest solvent accessibility within the hydrophobic cavity of SBEβCD. These findings correlated with the highest binding affinity of SOR/SBEβCD complex determined by SIE, MM/GBSA, and MM/PBSA methods. Experimental results further supported our computational predictions, in which SBEβCD exhibited a stability constant of 940 M^-1 at 25 °C, surpassing βCD's stability constant of 210 M^-1. Taken together, our results suggest that the modified CDs, particularly SBEβCD, hold promising potential as an efficient molecular encapsulating agent for SOR, offering improved solubility and stability for this lipophilic drug.

Fig. 1. (A) Chemical structure of SOR containing pyridine group and chlorobenzotrifluoride group. (B) 3D structure of all studied CDs. (C) The possible orientations of SOR in complex with CDs: pyridine group insertion (P-form) and chlorobenzotrifluoride group insertion (C-form).

Fig. 2. %Docked conformations (%DCs) and CDOCKER interaction energy (ΔE) of all docked complexes.

Fig. 3. All-atom RMSD profiles of all complexes in both P-form and C-form, plotted over 200 ns in three replicates (MD1-3).

Fig. 4. Distance analysis of all inclusion complexes plotted over 200 ns, where d[C_m (primary rim) − C_m(P)] (d₁) and d[C_m (primary rim) − C_m(C)] (d₂) are represented in black and red, respectively.

Fig. 5. Representative structures of host–guest inclusion of each RMSD cluster for both P-form and C-form of SOR/CDs inclusion complexes. Clusters population was labelled in a percentage.

Fig. 6. The number of atomic interactions and SASA calculated over last 100 ns for all inclusion complexes. Green and cyan boxes cover the area between the 25th and 75th percentiles. Mean values are represented by a cross, while whiskers determine the standard deviation.

Fig. 7. PES plots generated for all studied CDs in complex with SOR, calculated over last 100 ns.

Fig. 8. Probability of the radius of gyration of all inclusion complexes both in P-form and C-form.

Fig. 9. Binding free energy calculation based on the MM/GBSA and MM/PBSA methods and their energy contribution of SOR in complex with CDs, calculated over last 100 ns simulation, n = 3.

Fig. 10. The 2D and 3D guest–host interactions of βCDs in both orientations (P-form and C-form). Glc, Me, HP and SBE represent glucopyranose unit, methyl, hydroxypropyl, and sulfobutylether substitutions, respectively.

Fig. 11. The solubility behavior of the complex formed between SOR and βCDs at 25 °C as shown in the phase solubility plot.