Intranasal administration of temozolomide conjugated nanoparticles with transcranial magnetic stimulation improves the survival in glioblastoma xenograft models

Abstract

Glioblastoma Multiforme (GBM) is the most common primary malignancy of the central nervous system with an average survival time of 15 months following standard therapy. Furthermore, since its clinical introduction in 1999, temozolomide (TMZ) remains the chief therapeutic agent for GBM to date. However, because TMZ is administered orally, the blood-brain barrier (BBB) poses a significant challenge in GBM treatment, with efforts to overcome it complicated by unsustainable immunosuppression side effects. In this clinical context, there is a pressing need to develop more effective methods of delivering TMZ to GBM. We used temozolomide attached to superparamagnetic iron oxide nanoparticles (TMZ-SPION). First, its efficacy was compared to unconjugated temozolomide in vitro against U87 and U373 glioblastoma cell lines. Second, it was administered intranasally to U87 xenograft mice models and then guided to the brain parenchyma using transcranial magnetic stimulation (TMS), bypassing BBB. The efficacy was evaluated through a survival experiment. We found that TMZ-SPION was as effective as TMZ against glioblastoma cell lines. In the survival experiment, we found that TMZ-SPION + TMS treated mice survived twice longer than the untreated control group while requiring less than one-tenth of the conventional dose. TMZ-SPION guided by a magnetic field is a promising candidate for precise drug delivery to CNS tumor sites. Additionally, the intranasal route has been demonstrated as a reliable method for bypassing the BBB.

Keywords: Glioblastoma multiforme; Nanoparticle; Temozolomide; Transcranial magnetic stimulation.