Development of silica-encapsulated silver nanoparticles as contrast agents intended for dual-energy mammography

Abstract

Objective: Dual-energy (DE) mammography has recently entered the clinic. Previous theoretical and phantom studies demonstrated that silver provides greater contrast than iodine for this technique. Our objective was to characterize and evaluate in vivo a prototype silver contrast agent ultimately intended for DE mammography.

Methods: The prototype silver contrast agent was synthesized using a three-step process: synthesis of a silver core, silica encapsulation and PEG coating. The nanoparticles were then injected into mice to determine their accumulation in various organs, blood half-life and dual-energy contrast. All animal procedures were approved by the institutional animal care and use committee.

Results: The final diameter of the nanoparticles was measured to be 102 (±9) nm. The particles were removed from the vascular circulation with a half-life of 15 min, and accumulated in macrophage-rich organs such as the liver, spleen and lymph nodes. Dual-energy subtraction techniques increased the signal difference-to-noise ratio of the particles by as much as a factor of 15.2 compared to the single-energy images. These nanoparticles produced no adverse effects in mice.

Conclusion: Silver nanoparticles are an effective contrast agent for dual-energy x-ray imaging. With further design improvements, silver nanoparticles may prove valuable in breast cancer screening and diagnosis.

Key points: • Silver has potential as a contrast agent for DE mammography. • Silica-coated silver nanoparticles are biocompatible and suited for in vivo use. • Silver nanoparticles produce strong contrast in vivo using DE mammography imaging systems.

Keywords: Breast cancer; Dual-energy; Gold; Mammography; Nanoparticles; Silver.

Figure 1

(a) Design of prototype silver nanoparticle imaging agent. TEM micrographs of (b) polyvinylpyrrolidone-coated silver cores, (c) silica-encapsulated silver cores, and (d) polyethylene glycol-silica-silver nanoparticles (PEG-SiO₂Ag).

Figure 2

(a) Blood clearance of PEG-SiO₂Ag nanoparticles after intravenous injection into three female mice. The plasma half-life of the nanoparticles was calculated to be 15 minutes. Error bars represent standard deviations. (b) Biodistribution of PEG-SiO₂Ag nanoparticles, 24 hours after intravenous injection into female mice. The majority of the particles are located in the liver and spleen, in addition to accumulation in the lymph nodes, large bowel, and muscle. The remaining organs showed very little uptake of the silver particles. Error bars represent standard deviation.

Figure 3

LE, HE, and DE images of mice immediately after administration via subcutaneous injection of the silver contrast agent (a–c,), saline (d–f) and gold nanoparticles (g–i). DE subtraction emphasizes the signal of the silver contrast agent.

Figure 4

LE, HE, and DE images of a mouse immediately after administration of the silver contrast agent via intraperitoneal injection. The contrast from the silver (arrows) in the DE image highlight various organs. Concentration of the contrast agent in certain locations is seen over time.

Figure 5

LE, HE, and DE images of a mouse after administration of silver nanoparticles via intravenous injection. The DE image successfully suppresses bone, soft tissue and air signals, while maintaining the vascular contrast. The heart (long arrow) and the abdominal aorta (short arrow) are clearly visualized, together with other smaller blood vessels in the abdomen and elsewhere.