Cetuximab-functionalized lipid-based nanocarriers dispersed in hydrogels for nasal administration of temozolamide: pharmacotechnical development and potential application in the treatment of Glioblastoma Multiforme

• Grant number: 23/04571-4
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2023
• End date: November 30, 2025
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Marlus Chorilli
• Grantee: Marlus Chorilli
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated researchers: Cauê Benito Scarim ; Joao Conde

Abstract

Glioblastoma multiforme (GBM) is the most aggressive and prevalent variation of glioma. The first choice treatment is temozolamide (TMZ), an alkylating agent administered orally or intravenously. However, the drug has some limitations, such as the difficulty in crossing the blood-brain barrier (BBB) and the cellular efflux mechanism resistance. As a consequence, the survival rate of patients increases only a few months, without leading to a cure. In addition, higher doses of the drug are required, which in turn accumulate in non-target tissues, resulting in adverse effects. In this context, the search for alternative routes and release systems has been gaining prominence. A promising approach to efficiently overcome the BBB and increase drug availability is to encapsulate TMZ in lipid-based nanocarriers such as nanostructured lipid carriers (CLN), which can be 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 hydrogels for nasal administration. The nasal route is a promising and advantageous option due to its action in the CNS via the olfactory bulb, avoiding first-pass metabolism and BBB passage. Thus, the objective of this project is to evaluate the potential of CLNs functionalized with CTX dispersed in hydrogels for nasal administration of TMZ in the treatment of GBM. CLNs functionalized with CTX containing TMZ (CLN-TMZ-CTX) will be developed and characterized for their morphology, size, polydispersion index, zeta potential and thermal behavior. The TMZ encapsulation efficiency will also be determined, as well as the coupling efficiency of the CTX to the CLN, in addition to verifying its integrity. The obtained systems will be incorporated into hydrogels and analyzed by rheological assays, release, retention, permeation in an ex vivo model and in vitro cytotoxicity studies. The anti-tumor and anti-angiogenic activity of CLN-TMZ-CTX incorporated or not in hydrogels will be determined using in vitro and in vivo models. It is expected to obtain a formulation that favors the local treatment of the disease, selectively delivering the drug to cancer cells, reducing systemic toxicity and increasing treatment effectiveness. (AU)