Iodine nanoparticles enhance radiotherapy of intracerebral human glioma in mice and increase efficacy of chemotherapy

Abstract

Gliomas and other brain tumors have evaded durable therapies, ultimately causing about 20% of all cancer deaths. Tumors are widespread in the brain at time of diagnosis, limiting surgery and radiotherapy effectiveness. Drugs are also poorly effective. Radiotherapy (RT) is limited by dose to normal tissue. However, high-atomic-number elements absorb X-rays and deposit the absorbed dose locally, even doubling (or more) the local dose. Previously we showed that gold nanoparticles (AuNPs) with RT could eradicate some brain tumors in mice and many other preclinical studies confirmed AuNPs as outstanding radioenhancers. However, impediments to clinical translation of AuNPs have been poor clearance, skin discoloration, and cost. We therefore developed iodine nanoparticles (INPs) that are almost colorless, non-toxic, lower cost, and have reasonable clearance, thus overcoming major drawbacks of AuNPs. Here we report the use of iodine nanoparticle radiotherapy (INRT) in treating advanced human gliomas (U87) grown orthotopically in nude mice resulting in a more than a doubling of median life extension compared to RT alone. Significantly, INRT also enhanced the efficacy of chemotherapy when it was combined with the chemotherapeutic agent Doxil, resulting in some longer-term survivors. While ongoing optimization studies should further improve INRT, clinical translation appears promising.

Convergence of the Study on Monochromatic X-rays and the Research on Nanoparticles Opens Up a Possibility to Develop a New Type of Radiation Therapy

“…It has been reported that high Z elements such as gadolinium can absorb energy from conventional X-ray and this results in the enhancement of radiation therapy [38]. Similar studies have used iodine nanoparticles [39]. These studies emphasize the importance of high Z elements on enhancing conventional X-ray therapy.…”

Dose Enhancement for the Flattening-Filter-Free and Flattening-Filter Photon Beams in Nanoparticle-Enhanced Radiotherapy: A Monte Carlo Phantom Study

“…In this study, nanoparticle materials, which have proven experimental evidence and high potential to be applicable in radiotherapy were selected and investigated. These materials included gold [25], platinum [26], iodine [27], silver [28], and iron oxide (Fe 2 O 3 ) [29]. The nanoparticle materials added to the soft tissue (water) were created with concentrations equal to 3, 7, 18, 30, and 40 mg/ml.…”

Nano-Therapies for Glioblastoma Treatment

“…Together with surgery and chemotherapy, radiotherapy is the third leg of GBM treatments. It has been shown that anti-GBM nano-formulations could enhance the effect of radiotherapy by: (i) increasing the downregulation of PD-L1 and EGFR using solid/lipid nanoparticles, resulting in a decrease of glioblastoma growth and prolonged mouse survival [41], (ii) enhancing the EPR effect, leading to better diffusion of nanoparticles to GBM tumors [90], (iii) sensitizing GBM cells to radiation by making GBM stem cells enter the radiation sensitive G2/M phase using the Sonic hedgehog ligand [91], by increasing DNA double-strand breaks using BSA-Au nanoparticles [92], or by exposing iodine nanoparticles to radiations [93], and (iv) enhancing the expression of the targets of CTX (i.e., MMP-2 and ClC-3), as well as BBB permeability and cellular internalization, leading to GBM tumor growth inhibition in vivo, using PLGA nanoparticles conjugated to chlorotoxin (CTX) [94]. The radio-sensitizing effect, which is often sought for when exposing nanoparticles to X-rays, is usually described as being optimal for nanoparticles of high atomic number Z, due to certain physical effects such as photoelectric ones, which are enhanced at high Z values.…”