pharmaceutics Article Improving the Antitumor Activity and Bioavailability of Sonidegib for the Treatment of Skin Cancer Amr Gamal 1 , Haitham Saeed 2 , Fatma I. Abo El-Ela 3 and Heba F. Salem 1, *   Citation: Gamal, A.; Saeed, H.; El-Ela, F.I.A.; Salem, H.F. Improving the Antitumor Activity and Bioavailability of Sonidegib for the Treatment of Skin Cancer. Pharmaceutics 2021, 13, 1560. https:// doi.org/10.3390/pharmaceutics13101560 Academic Editor: Hassan Bousbaa Received: 24 August 2021 Accepted: 16 September 2021 Published: 26 September 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 625617, Egypt; Amr_g@pharm.bsu.edu.eg 2 Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 625617, Egypt; Haitham.sedawy@pharm.bsu.edu.eg 3 Department of Pharmacology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 625617, Egypt; Fatma.aboel3la@vet.bsu.edu * Correspondence: heba_salem111@yahoo.com or heba_salem2004@yahoo.co.uk; Tel.: +20-1001-944-381 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 bioavail- ability, 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/cm 2 /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. Keywords: skin cancer; Sonidegib; ethosomes; targeting; bioavailability 1. Introduction Skin cancer is a malignant epidermal tumor, characterized by the uncontrolled growth of skin cells [1,2]. In the world, the most common kind of cancer is skin cancer, which accounts for at least 40% of all cancer cases [3,4]. Sonidegib (SNG) is a hedgehog inhibitor that has been used for skin cancer treatment [5]. SNG inhibits Smoothened (SMO), which plays a critical role in stem cell maintenance and tissue repair [5]. Despite the fact that SNG has been shown to be effective in the treatment of skin cancer, it has low bioavailability and is associated with adverse effects and resistance [6,7]. The use of nanoparticles holds great promise, both clinically and in pharmaceutical research. Nanoparticles are drug delivery systems which deliver therapeutic agents in a targeted and controlled manner [8,9]. Drug-loaded nanoparticles improve bioavailability, efficacy and selectivity in targeting neoplastic cells [8,9]. Liposomes are the most widely used nanoparticles to treat skin cancer. Liposomes are phospholipid vesicles with an interior aqueous phase [8]. Liposomes are ideal carriers for drug delivery because they have excellent diffusion properties and they can deliver therapeutic agents in a targeted and controlled manner. However, liposomes can provide a sustained and activated release of their payload, but they undergo leakage of encap- sulated drug, low stability and low dermal penetration properties [10,11]. To improve the vesicular properties and skin permeability of liposomes, ethosomes vesicles have Pharmaceutics 2021, 13, 1560. https://doi.org/10.3390/pharmaceutics13101560 https://www.mdpi.com/journal/pharmaceutics