Development, characterization and antitumor evaluation of lactoferrin-functionalized lipid nanoparticles for glioblastoma: Integration of natural products and antitumor agents

• Grant number: 24/22809-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: May 01, 2025
• End date: September 30, 2027
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Priscyla Daniely Marcato Gaspari
• Grantee: Franciely Rufino de Almeida Lima
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Glioblastoma affects approximately 3.21 individuals per 100,000, with a median survival of 12 months and a 5-year relative survival rate of less than 5%. Available therapies show limited efficacy due to high recurrence (~40%) and adverse effects, highlighting the need for more effective strategies with fewer side effects. Cabazitaxel (CBZ), a next-generation taxane with low affinity for P-glycoprotein, exhibits higher activity, but its use is associated with side effects. The co-encapsulation of chemotherapeutics and natural products, such as curcumin (CUR), in lipid nanoparticles emerges as a promising approach, allowing for synergistic and/or additive action, sustained release, and greater compound stability. Curcumin, with antitumor, anti-inflammatory, and chemosensitizing properties, can enhance the effects of CBZ, increasing its efficacy.In this context, the initial stages of this project, conducted during the student's Master's program, focused on the development of a nanoformulation of lipid nanoparticles containing CBZ and CUR. This formulation demonstrated high potential in a 2D in vitro model using U87MG glioblastoma cells, significantly reducing the IC50 of CBZ compared to the free drug. By the end of April, with the student's transition to the Direct Doctorate program, the project scope was expanded, and international partnerships were established, including a letter of acceptance for dual supervision with the University of Groningen. A scientific article regarding the results obtained thus far was also submitted.Thus, the goal of the project is to prepare and characterize lactoferrin-functionalized lipid nanoparticles for the co-encapsulation of CBZ and CUR for glioblastoma treatment. The project will use microfluidics for scaling up and assess the in vitro and in vivo biological effects and toxicity, aiming to develop a formulation with greater efficacy and fewer side effects. The nanoparticles will be prepared using emulsification and sonication methods and characterized using various physicochemical techniques such as DLS, cryo-TEM, AFM, and SAXS to deepen the understanding of their structure. Furthermore, the biological effect of the nanoparticles will be evaluated in a 3D glioblastoma model, better mimicking the tumor microenvironment, assessing permeation across the blood-brain barrier in an in vitro model, and cell death mechanisms by flow cytometry. Hemocompatibility and complement system activation will be evaluated to ensure the safety of nanoparticle use in intravenous applications, minimize immune activation to increase the system's half-life, and reduce potential adverse immune reactions. Finally, efficacy and toxicity will be investigated in an orthotopic in vivo glioblastoma model, contributing to the development of a novel and more effective therapeutic approach for treating this highly aggressive disease.