Development and evaluation of the potential of chitosan nanoparticles modified with hyaluronic acid and functionalized with transferrin for intranasal delivery of temozolomide in the treatment of glioblastoma

• Grant number: 22/14992-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2025
• End date: August 31, 2027
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Marlus Chorilli
• Grantee: Geanne Aparecida de Paula
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive malignant tumor affecting the Central Nervous System (CNS), with high mortality and low survival rates. Temozolomide (TMZ) is the chemotherapy of choice for GBM treatment, an alkylating agent administered orally. However, the drug has limitations such as short plasma half-life, lack of cellular specificity, toxicity to both tumor and healthy cells, and difficulty in overcoming drug efflux cellular mechanisms, which compromise treatment success. Thus, a significant portion of the orally administered dose does not reach the tumor cells and affects healthy tissues, causing side effects. In this context, the search for alternative delivery routes and systems, such as nasal administration of TMZ in nanocarriers, is gaining attention. Nasal administration is a promising option to bypass first-pass effect and systemic distribution, as the drug is administered in the nasal cavity and transported to the brain via the olfactory and trigeminal nerves. The drug can be incorporated into mucoadhesive polymer-based nanoparticles (NPs), such as chitosan and hyaluronic acid, to increase residence time on the nasal mucosa. Furthermore, surface modification of these NPs with targeting ligands enhances selectivity for cancer cells. GBM cells overexpress transferrin (Tf) and CD44 receptors; therefore, functionalizing NPs with molecules that bind to these receptors (Tf and hyaluronic acid, respectively) can help target the drug to its site of action. This study aims to develop and evaluate the potential of chitosan-based nanoparticles modified with hyaluronic acid and functionalized with Tf for intranasal administration of TMZ in GBM treatment. Thus, the goal is to achieve effective targeted therapy that minimizes treatment side effects, contributing to the patient's quality of life.