Development and preclinical validation of an intranasal delivery platform for combined gene and chemotherapy in high-grade glioma models.

• Grant number: 25/27048-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2026
• End date: July 31, 2029
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Marlus Chorilli
• Grantee: Leonardo Delello Di Filippo
• 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 brain tumor of the central nervous system, characterized by rapid progression, therapeutic resistance, and poor overall survival. Temozolomide (TMZ), the standard chemotherapeutic agent, presents low brain bioavailability and resistance associated with the blood-brain barrier (BBB) and tumor heterogeneity. Restoration of the p53 pathway, frequently inactivated in GBM, represents a promising strategy to sensitize tumors to TMZ. In addition, the overexpression of the CD44 receptor in glioma cells implicated in invasion and resistance, and offers an opportunity for active targeting through hyaluronic acid (HA), its natural ligand. This project proposes the development and preclinical validation of an intranasal delivery platform combining p53 mRNA and TMZ, using lipid nanoparticles (LNPs) functionalized with HA for CD44 targeting and incorporated into an ion-sensitive, mucoadhesive in situ gelling hydrogel to enhance nasal retention and direct nose-to-brain transport. HA will be conjugated to the DSPE-PEG2000-NH¿ lipid via EDC/NHS coupling and confirmed by FTIR and ¹H NMR analyses. HA-LNPs will be produced by the ethanol injection method and characterized for particle size, polydispersity, zeta potential, morphology, encapsulation efficiency, and in vitro release profile. The hydrogel will be evaluated for viscosity, rheological behavior, mucoadhesion, biocompatibility (HET-CAM assay), and ex vivo permeation across porcine nasal mucosa. In vitro and in vivo studies will assess cellular internalization, p53 expression, cytotoxicity, cell death mechanisms, and antitumor efficacy in an orthotopic murine model of GBM. This project aims to develop a non-invasive, selective, and effective system capable of restoring p53 function, enhancing TMZ activity, and improving brain bioavailability, representing an innovative and translational therapeutic strategy for GBM treatment. (AU)