The Topical Nanodelivery of Vismodegib Enhances Its Skin Penetration and Performance In Vitro While Reducing Its Toxicity In Vivo.

Maria Natalia Calienni,Silvia Del Valle Alonso,María Cecilia Izquierdo,Ezequiel Bernabeu,C Facundo Temprana,Daniela Maza Vega,María Jimena Prieto,Jorge Montanari,Marcela Moretton,Diego Chiappetta,David E Ybarra,Fernando C Alvira

doi:10.3390/pharmaceutics13020186

Abstract

Vismodegib is a first-in-class inhibitor for advanced basal cell carcinoma treatment. Its daily oral doses present a high distribution volume and several side effects. We evaluated its skin penetration loaded in diverse nanosystems as potential strategies to reduce side effects and drug quantities. Ultradeformable liposomes, ethosomes, colloidal liquid crystals, and dendrimers were able to transport Vismodegib to deep skin layers, while polymeric micelles failed at this. As lipidic systems were the most effective, we assessed the in vitro and in vivo toxicity of Vismodegib-loaded ultradeformable liposomes, apoptosis, and cellular uptake. Vismodegib emerges as a versatile drug that can be loaded in several delivery systems for topical application. These findings may be also useful for the consideration of topical delivery of other drugs with a low water solubility.

Highlights

Basal cell carcinoma (BCC) is the most common type of skin cancer, representing 80%of all cases [1]
The incorporation of Vismodegib in drug-delivery nanosystems suitable for the topical administration route could reduce the side effects reported after oral administration by sitespecific delivery
Even though we have not studied if the drug can reach systemic distribution after topical administration, due to the amounts needed to be applied to the skin being significantly lower than those for the oral route, it would be expected not to see side effects or to see side effects drastically reduced

Summary

Introduction

Basal cell carcinoma (BCC) is the most common type of skin cancer, representing 80%of all cases [1]. Genetic alterations leading to the aberrant constitutive activation of the Hedgehog (Hh) signaling pathway, such as mutations which inactivate patched-1 tumor suppressor gene (PTCH1) or, less frequently, gain-of-function mutations in smoothened transmembrane protein (SMO), are associated with the development of most BCCs [2,3]. Vismodegib (Erivedge® , Genentech) is a first-in-class selective inhibitor for the SMO that acts on the Hh signaling pathway. Vismodegib was approved by the US Food and Drug. Administration in 2012 for the treatment of locally advanced and metastatic BCC [4]. The treatment with Vismodegib consists of the daily oral administration of Erivedge®. There are several side effects associated with the systemic administration of this active principle that frequently cause patients to discontinue treatment [3]

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