Intranasal Delivery of Ivermectin Nanosystems as an Antitumor Agent: Focusing on Glioma Suppression.

Abstract

Glioblastoma presents significant challenges in neuro-oncology due to its aggressive nature, drug resistance, and restrictions imposed by the blood-brain barrier. Ivermectin (IVM), known for its antiparasitic properties, has been highlighted as a promising treatment for tumors and an alternative therapy for glioma, although it exhibits low oral bioavailability. Therefore, we investigated the in vivo effect of IVM encapsulation in organic and inorganic nanosystems, first screened in vitro against different tumor cells and subsequently evaluated in vitro and in vivo glioma models. We produced IVM-loaded poly(ε-caprolactone) nanocapsules (IVM-NC) using the interfacial deposition method, and IVM-loaded nanostructured silica particles (IVM-MCM) by loading IVM into commercial MCM-41 silica using the incipient wetness method. IVM-NC had a nanometric size (190 nm), a unimodal size distribution (span <2), and a high encapsulation efficiency (100% at 1 mg/mL). IVM-MCM exhibited a well-organized hexagonal mesoporous structure and high drug loading (0.12 mg/mg). Nanoencapsulated IVM significantly reduced the viability of various cancer cell lines, particularly glioma cell lines, which led us to evaluate them in a preclinical glioma model. We implanted adult male Wistar rats with C6 cells. Intranasal delivery of IVM-NC (60 μg/rat/day for 10 days) resulted in a larger decrease in tumor size compared with the group treated with free IVM, along with histopathological improvements. Treatment with IVM-MCM did not decrease the tumor size. However, both treatments were well-tolerated, with no adverse effects on weight, biochemical, or hematological parameters, or lung histology. Furthermore, the effective equivalent dose of IVM (26 μg/kg) in the rat glioma model was lower than the approved human dose for parasitic infections. This study marks the first exploration of IVM delivery to the brain. In summary, nasal administration of nanoencapsulated IVM via nanocapsules presents a promising avenue for targeted therapy against glioblastoma, with potential implications for clinical translation.