Evaluation of the biological potential of nanostructured lipid carriers functionalized with cetuximab dispersed in mucoadhesive thermo-responsive hydrogels for intranasal administration of temozolomide in the treatment of Glioblastoma Multiforme

• Grant number: 20/12622-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): June 01, 2021
• Effective date (End): January 25, 2026
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Marlus Chorilli
• Grantee: Leonardo Delello Di Filippo
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated scholarship(s): 22/06224-7 - In vitro and in vivo antitumor evaluation of mucoadhesive thermo-responsive hydrogels based on cetuximab-modified nanostructured lipid carriers containing temozolomide in glioblastoma multiforme models, BE.EP.DR

Abstract

Glioblastoma Multiforme (GBM) is the most incident and most aggressive neoplasm of the Central Nervous System (CNS). Temozolamide (TMZ), the drug of choice for the treatment of GBM, has clinical efficacy, but treatment with this drug is associated with the development of resistance in more advanced stages of the disease, in addition to the fact that TMZ has physical and chemical limitations that make it difficult to use, such as difficulty in crossing the Blood-Brain Barrier (BBB) and non-selective biodistribution, which promotes adverse effects resulting from systemic toxicity. In order to beat BHE and make the drug available more efficiently, a promising approach is the encapsulation of TMZ in nanostructured lipid carriers (CLN) functionalized with specific ligands of EGFR receptors, such as Cetuximab (CTX), which are overexpressed in GBM tumor cells, with subsequent dispersion of the system in mucoadhesive thermo-responsive hydrogels (HTRM) for intranasal administration, a route that can be advantageous due to the absence of first-pass metabolism, avoiding passage through the BBB and optimizing its action in the CNS via bulb-olfactory. Thus, the objective of this work is to evaluate the potential of CTN functionalized CLNs dispersed in HTRM for intranasal administration of TMZ in the treatment of GBM. CLNs functionalized with CTX containing TMZ (CLN-TMZ-CTX) will be developed by the fusion-emulsification technique followed by sonication and characterized as to their morphology, size, polydispersity index, zeta potential and thermal behavior. The encapsulation efficiency of TMZ will also be determined, as well as the coupling efficiency of CTX to CLN, in addition to its integrity. The systems obtained will be incorporated into HTRM and rheological tests, release, retention, permeation studies in ex vivo and in vitro biocompatibility will be performed. The biological potential, anti-tumor and anti-angiogenic activity of CLN-TMZ-CTX incorporated or not in HTRM will be determined using in vitro and in vivo models. It is hoped to obtain a formulation that favors the local treatment of the disease, delivering the drug selectively to cancer cells, decreasing systemic toxicity and increasing the effectiveness of the treatment. (AU)

Publicações científicas

(7)

(Referências obtidas automaticamente do Web of Science e do SciELO, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores)

DI FILIPPO, LEONARDO DELELLO; DE CARVALHO, SUZANA GONCALVES; DUARTE, JONATAS LOBATO; LUIZ, MARCELA TAVARES; PAES DUTRA, JESSYCA APARECIDA; DE PAULA, GEANNE APARECIDA; CHORILLI, MARLUS; CONDE, JOAO. A receptor-mediated landscape of druggable and targeted nanomaterials for gliomas. MATERIALS TODAY BIO, v. 20, p. 23-pg., 2023-06-01. (22/06224-7, 20/12622-0)

DI FILIPPO, LEONARDO DELELLO; DE PAULA, MARIANA CARLOMAGNO; DUARTE, JONATAS LOBATO; DE PAULA, GEANNE APARECIDA; FRIGIERI, ISADORA; CHORILLI, MARLUS. Nanocarrier functionalization strategies for targeted drug delivery in skin cancer therapy: current progress and upcoming challenges. Expert Opinion on Drug Delivery, v. 20, n. 6, p. 19-pg., 2023-06-14. (19/25125-7, 19/17913-5, 20/12622-0)

NICOLETI, LUISA RIBEIRO; DI FILIPPO, LEONARDO DELELLO; DUARTE, JONATAS LOBATO; LUIZ, MARCELA TAVARES; SABIO, RAFAEL MIGUEL; CHORILLI, MARLUS. Development, characterization and in vitro cytotoxicity of kaempferol-loaded nanostructured lipid carriers in glioblastoma multiforme cells. COLLOIDS AND SURFACES B-BIOINTERFACES, v. 226, p. 7-pg., 2023-04-11. (19/25125-7, 19/17913-5, 20/12622-0)

PAES DUTRA, JESSYCA APARECIDA; LUIZ, MARCELA TAVARES; TAVARES JUNIOR, ALBERTO GOMES; DELELLO DI FILIPPO, LEONARDO; CARVALHO, SUZANA GONCALVES; CHORILLI, MARLUS. Temozolomide: An Overview of Biological Properties, Drug Delivery Nanosystems, and Analytical Methods. CURRENT PHARMACEUTICAL DESIGN, v. 28, n. 25, p. 16-pg., 2022-01-01. (20/12622-0)

DI FILIPPO, LEONARDO DELELLO; AZAMBUJA, JULIANA HOFSTATTER; PAES DUTRA, JESSYCA APARECIDA; LUIZ, MARCELA TAVARES; DUARTE, JONATAS LOBATO; NICOLETI, LUIZA RIBEIRO; OLALLA SAAD, SARA TERESINHA; CHORILLI, MARLUS. Improving temozolomide biopharmaceutical properties in glioblastoma multiforme (GBM) treatment using GBM-targeting nanocarriers. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, v. 168, p. 76-89, NOV 2021. (20/12622-0, 20/04133-9, 19/25125-7)

LUIZ, MARCELA TAVARES; DUTRA, JESSYCA APARECIDA PAES; TOFANI, LARISSA BUENO; DE ARAUJO, JENNIFER THAYANNE CAVALCANTE; DI FILIPPO, LEONARDO DELELLO; MARCHETTI, JULIANA MALDONADO; CHORILLI, MARLUS. Targeted Liposomes: A Nonviral Gene Delivery System for Cancer Therapy. PHARMACEUTICS, v. 14, n. 4, p. 31-pg., 2022-04-01. (20/12622-0)

DI FILIPPO, LEONARDO DELELLO; DUARTE, JONATAS; FONSECA-SANTOS, BRUNO; TAVARES JUNIOR, ALBERTO GOMES; ARAUJO, VICTOR; ROQUE BORDA, CESAR AUGUSTO; VICENTE, EDUARDO FESTOZO; CHORILLI, MARLUS. Mucoadhesive Nanosystems for Nose-to-Brain Drug Delivery in the Treatment of Central Nervous System Diseases. Current Medicinal Chemistry, v. 29, n. 17, p. 32-pg., 2022-01-01. (20/12622-0, 19/25125-7, 20/16573-3, 18/23416-1)