Ibrutinib Loaded Nanostructured Lipid Carriers for the Management of Chronic Lymphocytic Leukemia: Synchronizing In Silico, In Vitro, and In Vivo Studies.

Introduction: Ibrutinib is a selective tyrosine kinase inhibitor used to treat chronic lymphocytic leukemia (CLL). However, it has low oral bioavailability (2.9%), which is attributed to low solubility (0.002 mg/mL) and a first-pass effect. Ibrutinib-loaded nanostructured lipid carriers (IBR-NLCs) were prepared and investigated in this study to overcome the solubility and presystemic metabolism issues. The goal of the current study was to formulate IBR-NLCs for enhanced bioavailability. IBR-NLCs were optimized using a 32 factorial design and evaluated using various in vitro and in vivo parameters.

Methods: IBR interaction with solid lipid (Glyceryl monostearate) and liquid lipid (oleic acid) was studied using molecular docking. The hot-melt ultrasonication method was used to formulate IBR-NLCs, and a 32 factorial design was used for optimization. Particle size, PDI, zeta potential, entrapment efficiency, DSC, XRD, FTIR, SEM, and in vitro study were used to evaluate the NLCs. HepG2 cell lines were used to study the in vitro cytotoxicity of IBR-NLCs and IBR suspension. IBR-NLCs were administered to male Wistar rats in the presence and absence of cycloheximide (CXI) to compare pharmacokinetic parameters.

Results: Molecular docking confirmed good interaction between IBR-GMS and IBR-oleic acid. The optimized IBR-NLCs showed particle size, PDI, zeta potential, and %EE of 154.5 ± 0.7 nm, 0.2 ± 0.0, -25.8 ± 1.1 mV, and 84.0 ± 1.2%, respectively. The IC50 values of IBR suspension and IBR-NLCs were 3.03 and 4.155 μg/mL. The AUC0-24 of IBR-NLCs administered in the absence of CXI was 1.60 times higher than the AUC0-24 values in the presence of CXI, indicating lymphatic transport.

Conclusion: IBR-NLCs appear to be promising as a novel innovative nanocarrier for the management of CLL.