Nanostructured biomimetic systems based on tumor membranes for the treatment of neuroblastoma

• Grant number: 23/04193-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: November 01, 2023
• End date: February 28, 2025
• Field of knowledge: Physical Sciences and Mathematics - Physics - Condensed Matter Physics
• Principal Investigator: Valtencir Zucolotto
• Grantee: Yara Gabriele Botassio
• Host Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil

Abstract

Neuroblastoma (NB) is an extracranial tumor with high incidence in pediatric patients, and its biological complexity results in low survival rates. Despite advances in conventional treatments (surgery, radiotherapy, and chemotherapy), it has been observed that over the last three decades, few successes have been achieved in terms of patient survival rates, which are still considered very low. The scenario underscores the seriousness of the situation and the urgent need to search for new therapeutic alternatives to increase treatment efficacy. In this context, nanotechnology emerges as a promising solution, allowing more targeted approaches to specific tumor targets/receptors, improving pharmacokinetic and pharmacodynamic properties of nanoencapsulated drugs, and reducing toxicity. One of the most recent advancements in nanoengineering is the surface modification of nanoparticles using cell membranes. This bioinspired and biomimetic strategy is capable of promoting targeting through self-recognition and the accumulation of nanostructures in the tumor microenvironment, as well as evading the immune system. This project proposes the development of poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with paclitaxel (PTX), coated with membranes from neuroblastoma tumor cells (SH-SY5Y), as a rational and innovative strategy to enhance NB therapy effectiveness. The choice of PLGA for obtaining nanoparticles is due to its biocompatibility, biodegradability, and non-toxicity. PTX is one of the most commonly used chemotherapeutics for treating various types of cancers, but it has high toxicity, low aqueous solubility, and metabolic instability. Nanoencapsulation of PTX offers an opportunity to improve its physicochemical properties and increase its antitumor efficacy. Thus, the nanoparticles will be synthesized using the nanoprecipitation or double emulsion method and subjected to physicochemical analyses to determine their size and zeta potential. These analyses will be conducted using Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA). The morphology and shape of the nanoparticles will be evaluated using scanning (SEM) or transmission electron microscopy (TEM), and the encapsulation efficiency (EE%) as well as the in vitro release profile will be assessed using a previously developed and validated high-performance liquid chromatography (HPLC) quantification method. SH-SY5Y cells will be cultured and used in the coating of PLGA nanoparticles and in in vitro biological assays. Viability/cytotoxicity and cellular internalization will be evaluated using flow cytometry and/or alternatively confocal microscopy. The results obtained in this project will be unprecedented, and we believe that the developed nanosystems represent an unparalleled therapeutic opportunity for NB treatment, opening new perspectives in the medical field.