Improving the Antitumor Activity and Bioavailability of Sonidegib for the Treatment of Skin Cancer

Abstract

Throughout the United States and the world, skin cancer is the most frequent form of cancer. Sonidegib (SNG) is a hedgehog inhibitor that has been used for skin cancer treatment. However, SNG has low bioavailability and is associated with resistance. The focus of this work is to enhance bioavailability, anti-tumor efficacy and targeting of SNG via developing ethosome gel as a potential treatment for skin cancer. SNG-loaded ethosomes formulation was prepared and characterized in vitro by %entrapment efficiency (%EE), vesicle size, morphology, %release and steady-state flux. The results showed that the prepared formulation was spherical nanovesicles with a %EE of 85.4 ± 0.57%, a particle size of 199.53 ± 4.51 nm and a steady-state flux of 5.58 ± 0.08 µg/cm2/h. In addition, SNG-loaded ethosomes formulation was incorporated into carbopol gel to study the anti-tumor efficacy, localization and bioavailability in vivo. Compared with oral SNG, the formulation showed 3.18 times higher relative bioavailability and consequently significant anti-tumor activity. In addition, this formulation showed a higher rate of SNG penetration in the skin’s deep layers and passive targeting in tumor cells. Briefly, SNG-loaded ethosome gel can produce desirable therapeutic benefits for treatment of skin cancer.

Enhancing the Bioavailability and Efficacy of Vismodegib for the Control of Skin Cancer: In Vitro and In Vivo Studies

“…The particle size of the VLI formulation was significantly (p < 0.05) lower than that of the VLL formulation due to the steric repulsion among terpene molecules [25]. Additionally, ethanol reduces vesicle aggregation by increasing the negative charges of vesicles and electrostatic repulsion [1,11]. The polydispersity index analysis of the prepared formulations revealed a low polydispersity index, which supported the presence of homogeneity and a narrow distribution of particle size.…”

“…The prepared formulations possessed a negative surface charge, indicating good physical and chemical stability, enough for electrostatic stabilization [20]. The DSC analysis was performed to determine the melting point, compatibility of vesicles' components, and how much a material's enthalpy had changed over time as a result of changes in its physical and chemical properties [11,26]. The crystallinity of cholesterol and phospholipon 90 G was diminished upon mixing together due to the lipid bilayer formation.…”

“…Nanoparticle-based drug delivery systems improve bioavailability, target action on specific sites, and sustained drug release [9,10]. They can enhance the pharmacokinetics, selectivity, and efficacy of drugs while lowering their toxicity [4,11,12]. Liposomes were first described as nanoparticles Pharmaceuticals 2022, 15, 126 2 of 14 for transdermal use [11,13].…”

“…They can enhance the pharmacokinetics, selectivity, and efficacy of drugs while lowering their toxicity [4,11,12]. Liposomes were first described as nanoparticles Pharmaceuticals 2022, 15, 126 2 of 14 for transdermal use [11,13]. Phospholipids and cholesterol are the main components of liposomes.…”

“…Phospholipids and cholesterol are the main components of liposomes. Liposomes can enhance the pharmacokinetics and the efficacy of drugs, but they lack the ability to effectively penetrate the skin [11,13]. A new generation of liposomes was designed to enhance the liposome's physic-chemical properties.…”