pH-responsive Nanosystems for Targeted Drug Delivery to Glioblastoma Multiforme and MRI-facilitated Monitoring of Content Release

Abstract

Abstract Despite the current state-of-the-art glioblastoma treatment options, a clear indication of therapeutic delivery and efficacy is still missing, especially in early therapy. Substantial advancements, particularly in the areas of image-guided and targeted therapy of the most aggressive type of brain cancer-Glioblastoma multiforme (GBM), are needed to improve the quality of life and survival rates of patients. Herein we describe a proof of principle study toward developing a novel methodology for non-invasive monitoring of the release of cargo molecules from theranostic nanoparticles. This is achieved by quantifying changes in longitudinal relaxation time (T1) before and after the pH-responsive release of contrast agents for magnetic resonance imaging (MRI), from the pores of GBM-targeted mesoporous silica nanoparticles (MSNs). The pores of MSNs were loaded either with the anticancer drug paclitaxel (PTX) or FDA-approved contrast agent Gadobutrol, and their retention inside the pores was ensured by covalent attachment of β-cyclodextrin monoaldehyde to hydrazine-functionalized MSN, through acidification-cleavable hydrazone linkage. In vitro studies using a GBM cell line revealed that the developed nanoparticles effectively delivered their therapeutic cargo, leading to cell death, which was further enhanced with additional functionalization of MSNs with glioma-homing oligopeptide chlorotoxin (CHX). Furthermore, the changes in T1, occurring in response to the release of GdB from the pores of MSNs were successfully demonstrated by MRI measurements. These results are promising for the development of MRI-based methodology for monitoring and tracking the release of therapeutic content in tumor tissues. It is envisioned that this approach using contrast agent-loaded nanoparticles, before the treatment with the drug-filled analogues, could be applied in the future to provide increasingly personalized clinical management of cancer patients.