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

Abstract

Glioblastoma multiforme (GBM) is the most frequent and most aggressive Central Nervous System (CNS) cancer. Temozolomide (TMZ), the first-line drug 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-chemical limitations that hinder its use, such as short biological half-life (~2 hours) and non-selective biodistribution, which promotes adverse effects from systemic toxicity. To overcome these limitations and increase the drug bioavailability, a promising approach is the encapsulation of TMZ in nanostructured lipid carriers (NLC) functionalized with specific ligands of EGFR receptors, such as cetuximab (CTX), which are overexpressed in GBM tumor cells, with subsequent dispersion of the nanoparticles in mucoadhesive thermo-responsive hydrogels (MTRH) for intranasal administration, a pathway that may be advantageous due to the absence of first-pass metabolism, avoiding the passage through BBB and optimizing its action in the CNS via bulb-olfactory transport. Thus, the objective of this work is to evaluate the potential of NLC functionalized with CTX dispersed in MTRH for intranasal administration of TMZ in the treatment of GBM. Functionalized NLCs with CTX containing TMZ (CTX-NLC-TMZ) will be fully characterized regarding their physical-chemical properties and will be incorporated into previously characterized MTRH, which after will be submitted to in vitro models using U251MG and U87MG cells to determine the cytotoxic properties and the cellular uptake of the formulations. The biodistribution and antitumor properties after intranasal administration will be determined using in vivo orthotopic mice model. It is expected to obtain a formulation that favors the local treatment of the disease, selectively delivering the drug to cancer cells, decreasing systemic toxicity, and increasing the effectiveness of treatment. (AU)