Chitosan-coated nanoemulsion for intranasal administration increases temozolomide mucosal permeation, cellular uptake, and In vitro cytotoxicity in glioblastoma multiforme cells

Author(s)

Duarte, Jonatas Lobato ; Di Filippo, Leonardo Delello ; Vilella, Kelle Jarcy Azevedo ; Dutra, Jessyca Aparecida Paes ; Ribeiro, Diego Messalle ; da Silva, Monica Freitas ; de Medeiros, Alexandra Ivo ; Chorilli, Marlus

• Document type: Journal article
• Source: JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY; v. 102, p. 10-pg., 2024-12-01.

Abstract

Glioblastoma multiforme (GBM) is the most prevalent and aggressive type of brain cancer in adults. Temozolomide (TMZ) is the chemotherapeutic agent used to treat primary central nervous system tumors. However, TMZ's clinical effectiveness faces several challenges due to its physical-chemical properties and biological features of GBM, such as the blood-brain barrier (BBB). Mucoadhesive nanosystems such as those coated with chitosan represent a promising alternative for optimizing the delivery of therapeutic agents to the central nervous system, as they possess ideal characteristics that enhance their interaction with the intranasal mucosa. We aimed to develop a chitosan-coated nanoemulsion containing temozolomide (CS-NE-TMZ) for nose-to-brain delivery and characterize its physical-chemical and in vitro biological properties. CS-NE-TMZ were obtained by emulsification followed by sonication. The optimized CS-NE-TMZ presented droplet size of 123,4 + 2,3 nm, polydispersity index of 0.273 + 0.028, zeta potential of +21,5 + 0,81 mV, entrapment efficiency of 100 + 1,91 % and drug loading of 2 + 0,007 %. An in vitro release study of CS-NE-TMZ showed sustained release for up to 24 h following the Korsmeyer-Peppas model with Fickian diffusion. CS-NE-TMZ demonstrated significantly enhanced ex vivo mucosal permeation, compared to free TMZ, and showed enhanced in vitro cellular uptake, selectively increasing cytotoxicity in U-87MG glioma cells but not in healthy L929 fibroblasts, reinforcing the potential of mucoadhesive nanoemulsions as effective intranasal drug delivery systems for future brain cancer therapies. (AU)

• FAPESP's process: 14/50928-2 - INCT 2014: Pharmaceutical Nanotechnology: a transdisciplinary approach
• Grantee: Maria Vitória Lopes Badra Bentley
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 20/12622-0 - Evaluation of the biological potential of nanostructured lipid carriers functionalized with cetuximab dispersed in mucoadhesive thermo-responsive hydrogels for intranasal administration of temozolomide in the treatment of Glioblastoma Multiforme
• Grantee: Leonardo Delello Di Filippo
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 22/11101-1 - Exploring the potential of functionalized nanostructured lipid carriers loaded with cetuximab dispersed in thermo-responsive mucoadhesive hydrogels for the intranasal administration of temozolomide and ellagic acid in the treatment of GBM
• Grantee: Jonatas Lobato Duarte
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/02609-9 - Evaluation of the potential of transferrin functionalized liposomes dispersed in mucoadhesive hydrogels for nasal delivery of temozolomide in the treatment of glioblastoma multiform.
• Grantee: Jessyca Aparecida Paes Dutra
• Support Opportunities: Scholarships in Brazil - Doctorate