Hybrid nanoparticles development for brain delivery of the single chain antibody NUsc1 aiming for Alzheimer's disease treatment

• Grant number: 22/16868-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: June 01, 2023
• End date: March 31, 2026
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Renata Fonseca Vianna Lopez
• Grantee: Mariane Fávero Carraro
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by the accumulation of ²-amyloid peptide aggregates, with soluble oligomers (A²Os) being the main neurotoxic species responsible for the loss of synapses and neuronal death, leading patients to cognitive impairment and dementia. Despite scientific advances in the area, there are still no treatments to cure AD, nor definitive pre-death diagnostic methods. Faced with this lack of efficient therapeutic and diagnostic approaches for AD, an artificial single-chain antibody (scFv), called NUsc1, which recognizes A²Os with high affinity and specificity, was obtained and characterized by collaborators of this project. However, due to the limitations associated with drug delivery to the brain, the protection of the blood-brain barrier (BBB), and the susceptibility of scFv antibodies to degradation, it becomes necessary to develop a delivery system for NUsc1. The delivery system must protect it from enzymatic degradation, provide therapeutic concentrations of the antibody in the central nervous system (CNS) and not be toxic to brain structures. Therefore, the aim is to develop innovative lipid-polymeric hybrid nanoparticles (NLPs) for nasal delivery of NUsc1 in the brain. Nanoparticles formed by a core of hyaluronic acid, a polymer biocompatible with the cerebral extracellular matrix, coated by a lipid shell functionalized with polyarginine peptides, which have intrinsic properties of inhibiting the formation of protein aggregates, will be designed and developed for encapsulation of NUsc1. It is estimated that the negative charges of hyaluronic acid favor the encapsulation of cationic NUsc1 and protect it from enzymatic degradation in the nasal cavity. The nanometer size and mucoadhesive properties should also contribute to the success of nasal administration. In this way, we hope to demonstrate the potential of NUsc1 as a therapeutic and diagnostic tool for AD and the essential role of nanoparticles in the delivery of antibodies to the brain.