DEVELOPMENT OF SMART AND MULTIFUNCTIONAL MAGNETIC NANOPARTICLES MNP-TMZ-CRGD FOR COMBINED THERAPY - CHEMOTHERAPY AND THERMOTHERAPY - IN GLIOBLASTOMA TUMORS USING THE MICROFLUIDIC DEVICE PLATFORM

• Grant number: 25/12479-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: August 01, 2025
• End date: July 31, 2029
• Field of knowledge: Biological Sciences - Biophysics - Biophysics of Processes and Systems
• Principal Investigator: Lionel Fernel Gamarra Contreras
• Grantee: Nicole Mastandrea Ennes do Valle
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil
• Associated research grant: 23/10843-7 - Synthesis and characterisation of multi-functional lipid-based nano particles, with potential biomedical application in Cancer and Atherosclerosis: a multidisciplinary approach, AP.TEM

Abstract

Glioblastoma represents one of the greatest challenges in modern oncology, characterized by its aggressiveness, cellular heterogeneity, and resistance to conventional treatments. Given this scenario, the search for innovative and effective therapeutic approaches becomes critically important. In this context, the present project proposes an innovative therapeutic strategy for glioblastoma treatment, focusing on the development of intelligent and multifunctional magnetic nanoparticles, termed MNP-TMZ-cRGD. These nanoparticles combine the targeted delivery of the chemotherapeutic agent-temozolomide (TMZ)-with the ability to induce hyperthermia (thermotherapy) through their magnetic properties. Functionalization with the cRGD peptide enhances the specificity of the nanoparticles toward tumor cells expressing ¿v¿3 integrins, thereby aiming to improve treatment efficacy and reduce side effects. This multifunctional approach seeks not only to maximize the therapeutic impact against glioblastoma tumors through the synergistic combination of chemotherapy and thermotherapy but also to overcome classical challenges in glioblastoma treatment, such as drug resistance and the difficulty of crossing the blood-brain barrier. This promising work paves the way for significant advances in glioblastoma treatment, offering hope for more effective and targeted strategies against this highly aggressive cancer. After the development of MNP-TMZ-cRGD, their efficacy will be tested on microfluidic platforms such as tumor-on-a-chip, as well as in vitro models.The project will be conducted in sequential and integrated stages. Initially, the synthesis and physicochemical characterization of the MNP-TMZ-cRGD will be carried out, including analyses of size, morphology, stability, encapsulation efficiency, and magnetic and thermal properties. In the next stage, the toxicity of the nanoparticles will be evaluated through concentration gradients generated in microfluidic devices (MFDs), using 2D cell cultures and tumor spheroids. The third stage will focus on analyzing the internalization and targeting of the intelligent nanoparticles, also using optimized MFDs. In the fourth stage, a BBB-on-a-chip model will be employed to investigate nanoparticle translocation and TMZ release, with monitoring of transendothelial electrical resistance (TEER) as an indicator of barrier integrity. Finally, the efficacy of the combined therapy will be evaluated in 2D, 3D, and Brain-on-a-chip models, comparing isolated and combined effects. In silico studies using COMSOL Multiphysics software will support planning, concentration gradient modeling, nanoparticle transport, and thermal distribution.