Every year more than 22,000 people in the U.S. are diagnosed with primary brain tumors, with 13,000 deaths. The five-year survival rate is 24%. Primary brain tumors also account for 20% of the cancers in children. More effective treatments of malignant brain tumors are desperately needed. We have pioneered the use of gold nanoparticles (AuNPs) to enhance radiotherapy. In previous work we showed that Nanogold-enhanced radiosurgery of a very aggressive orthotopic glioma in mice resulted in 50% long term survival (>200 days) compared to 0% with radiosurgery alone. The AuNPs were IV administered. Concerns about translation to humans of this very promising result include: a) the high cost of gold (actually less than many antibody therapies), b) slow body clearance, and c) effectiveness of the Enhanced Permeability & Retention (EPR) effect for delivery in humans. Upon further analysis, we now propose a novel procedure to overcome not just these objections, but the true barriers to effective glioma therapy. After urgent surgery to remove the primary brain tumor and relieve dangerous intracranial pressure, recurrence invariably develops. Surgery typically does not remove the entire tumor, especially difficult since tumor cells migrate even up to 4 cm. A number of studies have shown escaping tumor cells migrate in the peritumor edema, often along white matter tracts. Our hypothesis is that AuNPs can be designed to also move and distribute in this peritumor edema. When infused in the primary tumor site, they will, because of their smaller size, catch up to and engulf migrating tumor cells. A gold concentration will be administered that will lead to enhancing radiotherapy by a factor of ~4 (boosting 25Gy to 100Gy). Normal brain would be spared since the X-ray generated electrons from the gold only travel several microns, thus tightly confining the boosted radiation dose. To test this, F98 tumor cells will be transduced with red fluorescent protein and luciferase, and tumors orthotopically grown in rats. The small AuNPs will be visualized with silver enhancement and the coincidence of AuNPs and tumor cells will be studied histologically. Edema will be stained with anti-albumin-FITC. Acceptable toxicity will be sought. Radiotherapy will test efficacy. Another advantage of this approach is that radiation-resistant cancer stem cell as well as dormant and drug resistant tumor cells will be killed since the target of the increased radiation is the tumor cells' DNA itself rather than any particular metabolic pathway. This approach overcomes concerns of cost of an IV injection of gold (a much smaller amount needed locally). Loading other organs and whole body retention will be minimal, and the gold no longer has to pass through a leaky endothelium - it is administered directly to the edema in which the tumor cells reside. Importantly, it addresses the main reason why all current GBM therapies fail- ineffective treatment of residual and migrant cells. This approach represents a major paradigm shift for radiotherapy since a larger brain volume to cover the escaped cells will be irradiated, a procedure now forbidden due to whole brain radiation constraints, but now made possible via the very specific gold boost.
A new method is proposed using gold nanoparticles to kill brain tumor cells that currently evade surgery, radiotherapy, and chemotherapy. This could significantly improve outcomes from one of the most dangerous and difficult to treat cancers.
| Smilowitz, Henry M; Meyers, Alexandria; Rahman, Khalil et al. (2018) Intravenously-injected gold nanoparticles (AuNPs) access intracerebral F98 rat gliomas better than AuNPs infused directly into the tumor site by convection enhanced delivery. Int J Nanomedicine 13:3937-3948 |
| Sung, Wonmo; Schuemann, Jan (2018) Energy optimization in gold nanoparticle enhanced radiation therapy. Phys Med Biol 63:135001 |
| Sung, Wonmo; Ye, Sung-Joon; McNamara, Aimee L et al. (2017) Dependence of gold nanoparticle radiosensitization on cell geometry. Nanoscale 9:5843-5853 |
