Theranostic nanoparticles enhance the response of glioblastomas to radiation

Abstract

Despite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. Methods: NSG mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre-and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG mice underwent survival analyses with Kaplan-Meier curves and a log rank (Mantel-Cox) test. Results: At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Conclusion: Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs.

Colchicine Alkaloids and Synthetic Analogues: Current Progress and Perspectives

“…A treatment approach for glioblastoma multiforme with theranostic nanoparticles (TNPs) in mouse models developed and validated in 2010 by Gill and coauthors now evolved to a new strategy of combining TNPs with radiotherapy . TNPs are composed of FDA-approved cross-linked iron oxide nanoparticles and the highly effective vascular disrupting agent azademethylcolchicine (ICT2552).…”

Noninvasive Imaging of Cancer Immunotherapy

“…Of note, and in line with the advancement of noninvasive imaging approaches, significant advances are being made in the realm of multifunctional “nanotheranostics” to develop new imaging and therapeutic approaches. Recent nanotheranostic therapeutic advancements include the development of a new liquid brachytherapy approach via novel cationic micelle and liposome formulations 175 , and the use of cross-linked iron oxide nanoparticles conjugated to azademethylcolchicine (CLIOT-ICT) as a method to eradicate a subpopulation of quiescent glioblastoma initiating cells 176 . Another recent theranostic advancement is the analysis of cancer cells by ultrasensitive dark-field imaging using gold nanoparticle bouquets 177 .…”

Iron Oxide Nanoparticles as Theranostic Agents in Cancer Immunotherapy

“…A cross-linked iron oxide NP (CLIO) conjugated with a highly effective vascular disrupting agent, azademethylcolchicine (ICT2552), has been recently developed to target and eradicate the subpopulation of GIC cells, which could be a reason for radioresistance and relapse in glioblastoma patients [ 35 ]. Glioblastoma (GBM) is the most common and the most aggressive primary brain tumor.…”

“…MRI can monitor the intratumoral inflammation that is produced during oncolytic virotherapy. By using 19F MRI [ 34 ] and iron oxide NPs [ 35 ], it is possible to indirectly detect and quantify virus localization, monitor the therapeutic outcome of oncolytic virotherapy and optimize new therapeutic virus strains.…”