Evaluation of the potential of transferrin functionalized liposomes dispersed in mucoadhesive hydrogels for nasal delivery of temozolomide in the treatment of glioblastoma multiform.

• Grant number: 21/02609-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): June 01, 2023
• Effective date (End): May 31, 2025
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Marlus Chorilli
• Grantee: Jessyca Aparecida Paes Dutra
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and prevalent variant of glioma. Temozolomide (TMZ), the treatment of first choice, is a prodrug that undergoes hydrolysis at physiological pH to form the methyldiazonic cation responsible for DNA alkylation. TMZ is the only drug available for the treatment of GBM, however, the low half-life of the drug associated with its biopharmaceutical characteristics at blood pH (7.4) and the presence of the blood-brain barrier (BHE) limit its delivery to the tumor, contributing to the inefficiency of treatment and the appearance of side effects. For these reasons, its clinical use only increases the survival rate of patients by a few months, not leading to a cure. In this context, a set of strategies can help in the search for new therapeutic alternatives to improve the treatment of GBM. One set of promising approaches is the targeted delivery of TMZ to tumor tissue by encapsulation in transferrin-functionalized liposomes for nasal administration. The conveyance of TMZ in liposomes increases the permeation of the drug through the BHE due to the nanometric and lipophilicity characteristics of liposomes. Furthermore, the nasal route represents a non-invasive and direct way of access to the brain via the olfactory nerves. The use of mucoadhesive hydrogels as a carrier matrix for liposomes allows a longer contact time of the formulation with the nasal mucosa and therefore favors its permeation to the brain region, in addition to avoiding nasal pH variations and ciliary clearance. The increase in brain availability does not guarantee the targeting of liposomes to tumor cells. Based on this, the functionalization with transferrin, a receptor protein overexpressed in GBM cells, allows the liposomes to be directed to tumor cells, increasing the efficacy of the drug and reducing adverse effects. In this context, the work aims to develop, characterize and evaluate the potential transferrin functionalized liposomes dispersed in mucoadhesive hydrogels for nasal administration of temozolomide in the treatment of glioblastoma multiforme.