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.

Effective and durable treatment of glioblastoma is an urgent unmet medical need. In this article, we summarize a novel approach of a physical method that enhances the effectiveness of radiotherapy. High atomic number nanoparticles that target brain tumors are intravenously administered. Upon irradiation, the nanoparticles absorb X-rays creating free radicals, increasing the tumor dose several fold. Radiotherapy of mice with orthotopic human gliomas and human triple negative breast cancers growing in the brain showed significant life extensions when the nanoparticles were included. An extensive study of the properties of the iodine-containing nanoparticle (Niodx) by the Nanotechnology Characterization Laboratory, including sterility, physicochemical characterization, in vitro cytotoxicity, in vivo immunological characterization, and in vivo toxicology, is presented. In summary, the iodine nanoparticle Niodx appears safe and effective for translational studies toward human use.

Triple negative breast cancer (TNBC), ~ 10–20% of diagnosed breast cancers, metastasizes to brain, lungs, liver. Iodine nanoparticle (INP) radioenhancers specifically localize to human TNBC MDA-MB-231 tumors growing in mouse brains after iv injection, significantly extending survival of mice after radiation therapy (RT). A prominent rim of INP contrast (MicroCT) previously seen in subcutaneous tumors but not intracerebral gliomas, provide calculated X-ray dose-enhancements up to > eightfold. Here, MDA-MB-231-cells, INPs, CD31 were examined by fluorescence confocal microscopy. Most INP staining co-localized with CD31 in the tumor center and periphery. Greatest INP/CD31 staining was in the tumor periphery, the region of increased MicroCT contrast. Tumor cells are seen to line irregularly-shaped spaces (ISS) with INP, CD31 staining very close to or on the tumor cell surface and PAS stain on their boundary and may represent a unique form of CD31-expressing vascular mimicry in intracerebral 231-tumors. INP/CD31 co-staining is also seen around ISS formed around tumor cells migrating on CD31+ blood-vessels. The significant radiation dose enhancement to the prolific collagen I containing, INP-binding ISS found throughout the tumor but concentrated in the tumor rim, may contribute significantly to the life extensions observed after INP-RT; VM could represent a new drug/NP, particularly INP, tumor-homing target.