Development of Antifungal and Immunomodulatory Lipid Nanoparticles for Treating Invasive Fungal Rhinosinusitis Caused by Aspergillus fumigatus

• Grant number: 24/10691-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2024
• Status: Discontinued
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Fabiana Cardoso Pereira Valera
• Grantee: Yugo Araújo Martins
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Invasive Fungal Rhinosinusitis (IFRS) is a disease with low prevalence but profound impact due to its high mortality rate, ranging from 30-80% depending on the center and underlying conditions. It primarily affects immunocompromised patients, including those with diabetes, severe neutropenia, such as those in chemotherapy or bone marrow transplant (BMT) recipients. In these conditions, the fungus, typically present in the nasosinusal microbiota, gains the ability to invade the mucosa, leading to necrosis of the nasal sinuses or adjacent structures. Aspergillus sp. is the most common IFRS causative agent in neutropenic patients. Despite the implementation of a specialized protocol in our institution - where every febrile neutropenic patient undergoes nasal endoscopy for early detection of IFRS by an Otorhinolaryngologist - the morbidity and mortality rates of this disease remain significant. Prompt treatment involves surgical debridement of necrotic areas and systemic antifungal therapy. However, treating invasive aspergillosis poses challenges due to the limited bioavailability of antifungal drugs at infection sites, rapid drug metabolism, systemic side effects, and the risk of antimicrobial resistance. Inspired by A. fumigatus' adherence to host sulfated proteoglycans (PS) via electrostatic interactions with host glycosaminoglycans (GAGs), we aim to develop lipid nanoparticles (NPLs) with spherical and elongated morphology, decorated with host PS mimetics (PS-like NPLs). These NPLs are designed to compete with fungal binding and prevent adhesion to respiratory system structures. Additionally, their modified morphology may enhance interaction with pathogens, penetrate biofilms and tissues efficiently, and selectively modulate the immune response to improve host antimicrobial activity. Therefore, our proposal focuses on developing lipid nanoparticles with PS-like surfaces and distinct morphologies, exhibiting both antifungal and immunomodulatory properties for treating A. fumigatus infection. We will prepare and characterize spherical and elongated NPLs, evaluate their interactions with respiratory tract mucins/mucosae, assess cytotoxicity in primary culture of nasal sinus epithelial cells, and investigate their antifungal mechanism of action. Finally, we will assess the efficacy of prophylactic and therapeutic NPL treatment and their potential for immunomodulation in a reconstructed model of the upper airway epithelium culture. If successful, further studies will be conducted in animals and ultimately in humans to develop a nasal topical device for pre-chemotherapy/BMT application, aiming to prevent fungal invasiveness in the nasosinusal mucosa.