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

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)