Mice bearing subcutaneous EMT-6 mammary carcinomas received a single intravenous injection of 1.9 nm diameter gold particles (up to 2.7 g Au/kg body weight), which elevated concentrations of gold to 7 mg Au/g in tumours. Tumour-to-normal-tissue gold concentration ratios remained approximately 8:1 during several minutes of 250 kVp x-ray therapy. One-year survival was 86% versus 20% with x-rays alone and 0% with gold alone. The increase in tumours safely ablated was dependent on the amount of gold injected. The gold nanoparticles were apparently non-toxic to mice and were largely cleared from the body through the kidneys. This novel use of small gold nanoparticles permitted achievement of the high metal content in tumours necessary for significant high-Z radioenhancement.

There have been few fundamental improvements in clinical X-ray contrast agents in more than 25 years, and the chemical platform of tri-iodobenzene has not changed. Current agents impose serious limitations on medical imaging: short imaging times, the need for catheterization in many cases, occasional renal toxicity, and poor contrast in large patients. This report is the first demonstration that gold nanoparticles may overcome these limitations. Gold has higher absorption than iodine with less bone and tissue interference achieving better contrast with lower X-ray dose. Nanoparticles clear the blood more slowly than iodine agents, permitting longer imaging times. Gold nanoparticles, 1.9 nm in diameter, were injected intravenously into mice and images recorded over time with a standard mammography unit. Gold biodistribution was measured by atomic absorption. Retention in liver and spleen was low with elimination by the kidneys. Organs such as kidneys and tumours were seen with unusual clarity and high spatial resolution. Blood vessels less than 100 microm in diameter were delineated, thus enabling in vivo vascular casting. Regions of increased vascularization and angiogenesis could be distinguished. With 10 mg Au ml(-1) initially in the blood, mouse behaviour was unremarkable and neither blood plasma analytes nor organ histology revealed any evidence of toxicity 11 days and 30 days after injection. Gold nanoparticles can be used as X-ray contrast agents with properties that overcome some significant limitations of iodine-based agents.

Gold is an excellent absorber of X-rays. If tumours could be loaded with gold, this would lead to a higher dose to the cancerous tissue compared with the dose received by normal tissue during a radiotherapy treatment. Calculations indicate that this dose enhancement can be significant, even 200% or greater. In this paper, the physical and biological parameters affecting this enhancement are discussed. Gold nanoparticles have shown therapeutic efficacy in animal trials and these results are reviewed. Some 86% long-term (>1 year) cures of EMT-6 mouse mammary subcutaneous tumours was achieved with an intravenous injection of gold nanoparticles before irradiation with 250-kVp photons, whereas only 20% were cured with radiation alone. The clinical potential of this approach is also discussed.

Adult‐rat‐brain tissues display an unusually high resistance to necrosis when serially irradiated with parallel, thin slices of a microplanar (i.e., microscopically thin and macroscopically broad) beam of synchrotron‐wiggler‐generated, approx. 35–120 keV (median approx. 50 keV) Gd‐filtered X rays at skin‐entrance absorbed doses of 312 to 5000 Gy per slice. Such microplanar beams were used to irradiate young adult rats bearing right frontocerebral 9L gliosarcomas (approx. 4 mm diameter), through a volume of tissue containing the tumor and contiguous brain tissue, either in a single array or in 2 orthogonally crossed arrays of tissue slices. Each array included 101 parallel microplanar slices, 100 μm center‐to‐center distance, each slice being approx. 25 μm wide and 12 mm high, with skin‐entrance absorbed doses of 312.5 Gy or 625 Gy per slice. Compared with unirradiated controls with a median survival time of 20 days after tumor initiation, the median survival time was extended in irradiated rats by 139 days (625 Gy, crossed arrays), 96 days (312.Gy, crossed arrays) or 24 days (625 Gy, single array). The tumors disappeared in 22 of the 36 irradiated rats, 4/ 11 even after unidirectional microbeam irradiation. The extent and severity of radiation damage to the normal brain in rats with or without tumor was graded histopathologically. Correlation of those grades with radiation doses shows that loss of tissue structure was confined to beam‐crossing regions and that only minor damage was done to zones of the brain irradiated unidirectionally. Int. J. Cancer 78:654–660, 1998. © 1998 Wiley‐Liss, Inc.