Formulation and Evaluation of Isradipine Nanosuspension and Exploring its Role as
a Potential Anticancer Drug by Computational Approach
Authors: Mohapatra Prasanta Kumar , Srivastava Rajnish , Varshney Krishna Kumar , Babu S. Haresh 
Published: August 2021

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-stimulatingfactor
(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 offer a 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 potential associations with inhibition in cancer pathogenesis. Molecular interactions of these targets
with CCB isradipine were identified and established by 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, respectively. The nanosuspension particles
were assessed 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:

Considerable interactions were found with Cysteine, Serine, Aspartate, Threonine, and Matrix metalloproteases
with binding energies 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 binding energies of -
8.62, -7.27, -7.69, -5.67, -5.41, -7.44, -8.21, respectively. The optimized nanosuspension was evaluated and exhibited a
particle size of 754.9 nm, zeta potential of 32.5 mV, viscosity of 1.287 cp, and PDI of 1.000. The In-vitro dissolution
of the optimized formulation (F8) was found to be higher (96.57%) as compared to other formulations

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.