Abstract
Thymoquinone (TQ) is the main active ingredient of Nigella sativa essential oil, with remarkable anti-neoplastic activities with anti-invasive and anti-migratory abilities on a variety of cancer cell lines. However, its poor water solubility, high instability in aqueous solution and pharmacokinetic drawbacks limits its use in therapy. Soluplus® and Solutol® HS15 were employed as amphiphilic polymers for developing polymeric micelles (SSM). Chemical and physical characterization studies of micelles are reported, in terms of size, homogeneity, zeta potential, critical micelle concentration (CMC), cloud point, encapsulation efficiency (EE%), load capacity (DL), in vitro release, and stability. This study reports for the first time the anti-migratory activity of TQ and TQ loaded in SSM (TQ-SSM) in the SH-SY5Y human neuroblastoma cell line. The inhibitory effect was assessed by the wound-healing assay and compared with that of the unformulated TQ. The optimal TQ-SSM were provided with small size (56.71 ± 1.41 nm) and spherical shape at ratio of 1:4 (Soluplus:Solutol HS15), thus increasing the solubility of about 10-fold in water. The entrapment efficiency and drug loading were 92.4 ± 1.6% and 4.68 ± 0.12, respectively, and the colloidal dispersion are stable during storage for a period of 40 days. The TQ-SSM were also lyophilized to obtain a more workable product and with increased stability. In vitro release study indicated a prolonged release of TQ. In conclusion, the formulation of TQ into SSM allows a bio-enhancement of TQ anti-migration activity, suggesting that TQ-SSM is a better candidate than unformulated TQ to inhibit human SH-SY5Y neuroblastoma cell migration.
Highlights
Neuroblastoma (NB) is by far the most common extracranial solid tumor diagnosed in infancy, with an average age of 1–2 years at the diagnosis
Polymeric micelles were developed to improve the aqueous solubility of TQ and to test the influence of the carrier on the inhibitory potential on cancer cell migration, providing a sustained and prolonged release
The optimized formulation consisted of Soluplus:Solutol 1:4 gravimetric ratio (SSM) and it is able to load 5 mg/mL of TQ, with an EE% of 92.4 ± 1.6% and DL% of 4.68 ± 0.12
Summary
Neuroblastoma (NB) is by far the most common extracranial solid tumor diagnosed in infancy, with an average age of 1–2 years at the diagnosis. It is a neuroendocrine tumor that originates from the developing sympathetic nervous system and with a highly variable clinical picture, depending on the stage and location of the tumor. It accounts for 7% of all childhood cancers with nearly 500 new cases each year and 15% of all cancer deaths in the pediatric population [1]. As a matter of fact, more than half of children with high-risk aggressive NB are still suffering from refractory or relapsing diseases developing widespread metastasis, especially in liver, non-contiguous lymph nodes, bone marrow, and other organs [4]. Among various therapeutic options, targeting tumor cell invasion and migration is a possible strategy against tumor progression [6]
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