This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z=22, to Bismuth, Z=83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation

Standard clinical X-ray contrast agents are small iodine-containing molecules that are rapidly cleared by the kidneys and provide robust imaging for only a few seconds, thereby limiting more extensive vascular and tissue biodistribution imaging as well as optimal tumor uptake. They are also not generally useful for preclinical microCT imaging where longer scan times are required for high resolution image acquisition. We here describe a new iodine nanoparticle contrast agent that has a unique combination of properties: 20 nm hydrodynamic diameter, covalent PEG coating, 40 hour blood half-life, 50% liver clearance after six months, accumulation in tumors, and well-tolerated to at least 4 g iodine/kg body weight after intravenous administration in mice. These characteristics are unique among the other iodine nanoparticles that have been previously reported and provide extended-time high contrast vascular imaging and tumor loading. As such, it is useful for preclinical MicroCT animal studies. Potential human applications might include X-ray radiation dose enhancement for cancer therapy and vascular imaging for life-threatening situations where high levels of contrast are needed for extended periods of time.

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.

About 30% of breast cancers metastasize to the brain; those widely disseminated are fatal typically in 3–4 months, even with the best available treatments, including surgery, drugs, and radiotherapy. To address this dire situation, we have developed iodine nanoparticles (INPs) that target brain tumors after intravenous (IV) injection. The iodine then absorbs X-rays during radiotherapy (RT), creating free radicals and local tumor damage, effectively boosting the local RT dose at the tumor. Efficacy was tested using the very aggressive human triple negative breast cancer (TNBC, MDA-MB-231 cells) growing in the brains of athymic nude mice. With a well-tolerated non-toxic IV dose of the INPs (7 g iodine/kg body weight), tumors showed a heavily iodinated rim surrounding the tumor having an average uptake of 2.9% iodine by weight, with uptake peaks at 4.5%. This is calculated to provide a dose enhancement factor of approximately 5.5 (peaks at 8.0), the highest ever reported for any radiation-enhancing agents. With RT alone (15 Gy, single dose), all animals died by 72 days; INP pretreatment resulted in longer-term remissions with 40% of mice surviving 150 days and 30% surviving > 280 days.

BackgroundIntravenously (IV)-injected gold nanoparticles (AuNPs) powerfully enhance the efficacy of X-ray therapy of tumors including advanced gliomas. However, pharmacokinetic issues, such as slow tissue clearance and skin discoloration, may impede clinical translation. The direct infusion of AuNPs into the tumor might be an alternative mode of delivery.Materials and methodsUsing the advanced, invasive, and difficult-to-treat F98 rat glioma model, we have studied the biodistribution of the AuNPs in the tumor and surrounding brain after either IV injection or direct intratumoral infusion by convection-enhanced delivery using light microscopy immunofluorescence and direct gold visualization.ResultsIV-injected AuNPs localize more specifically to intracerebral tumor cells, both in the main tumor mass and in the migrated tumor cells as well as the tumor edema, than do the directly infused AuNPs. Although some of the directly infused AuNPs do access the main tumor region, such access is largely restricted.ConclusionThese data suggest that IV-injected AuNPs are likely to have a greater therapeutic benefit when combined with radiation therapy than after the direct infusion of AuNPs.