Formulation and Evaluation of Isradipine Nanosuspension and Exploring its Role as a Potential Anticancer Drug by Computational Approach

Abstract

Background: T-type calcium channels are aberrantly expressed in different human cancers and regulate cell cycle progression, proliferation, migration, and survival. FAK-1 can promote tumor protein degradation (p53) through ubiquitination, leading to cancer cell growth and proliferation. Similar findings are obtained regarding protease inhibitors' effect on cytokine-induced neutrophil activation that suppresses Granulocyte-macrophage colony-stimulating-factor (GM-CSF) TNF-α-induced O2 release and adherence in human neutrophils without affecting phosphorylation of Extracellular signal-regulated kinase (ERK) and p38. Nanosuspensions are carrier-free, submicron colloidal dispersions which consist of pure drugs and stabilizers. Incorporating drug loaded in nanosuspensions possessed great advantages of passive drug targeting with improved solubility, stability, and bioavailability, as well as lower systemic toxicity. Objective: The present investigation objective was to establish a molecular association of Protease and Focal Adhesion Kinase 1 as cancer targets for isradipine a calcium channel blocker (CCB). Furthermore, the study also aimed to formulate its optimized nanosuspension and how the physical, morphological, and dissolution properties of isradipine impact nanosuspension stability. Material and Method: Five different molecular targets, namely Cysteine Proteases (Cathepsin B), Serine Proteases (Matriptase), Aspartate Proteases, Matrix Metalloproteases (MMP), and FAK-1 were obtained from RCSB-PDB, which has some leading associations with the inhibition in cancer pathogenesis. Molecular interactions of these targets with CCB isradipine were identified and established by the molecular simulation docking studies. Isradipine-loaded nanosuspension was prepared by precipitation technique by employing a 23 factorial design. PVP K-30, poloxamer 188, and sodium lauryl sulfate (SLS) were used as polymer, co-polymer, and surfactant. The nanosuspension particles are characterized for particle size, zeta potential, viscosity, polydispersity index (PDI), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), In-vitro drug release kinetics, and short-term stability study. Result: It was found to show considerable interaction with Cysteine, Serine, Aspartate, Threonine, and Matrix metalloproteases with the binding energy of -3.91, -6.7, -3.48, -8.42, respectively. Furthermore, the interaction of isradipine with FAK-1 was compared with 7 native ligands and was found to show significant interaction with a binding energy of -8.62, -7.27, -7.69, -5.67, -5.41, -7.44, -8.21. The optimized nanosuspension was evaluated and exhibited the particle size of 754.9 nm, zeta potential of 32.5 mV, the viscosity of 1.287 cp, and PDI of 1.000. The in-vitro dissolution of the optimized formulation (F8) was higher (96.57%). Conclusion: Isradipine could act as a potential inhibitor of different proteases and FAK-1 associated with tumor growth initiation, progression, and metastasis. Furthermore, isradipine-loaded nanosuspension with optimized release could be utilized to deliver the anticancer drug in a more targeted way as emerging cancer nanotechnology.