A dual energy CT study on vascular effects of gold nanoparticles in radiation therapy

Gold nanoparticles (AuNPs) are emerging as promising agents for both cancer therapy and CT imaging. AuNPs are delivered to tumors via the enhanced permeability and retention effect and they preferentially accumulate in close proximity to the tumor blood vessels. AuNPs produce low-energy, short-range photoelectrons during external beam radiation therapy (RT), boosting dose. This work is focused on understanding how tumor vascular permeability is influenced by AuNP-augmented radiation therapy (RT), and how this knowledge can potentially improve the delivery of additional nanoparticle-based chemotherapeutics. We use dual energy (DE) CT to detect accumulation of AuNPs and increased vascular permeability to liposomal iodine (i.e. a surrogate for chemotherapeutics with liposome encapsulation) following RT. We used sarcoma tumors generated in LSL-KrasG12D; p53FL/FL conditional mutant mice. A total of n=37 mice were used in this study. The treated mice were injected with 20 mg AuNP (0.1 ml/25 g mouse) 24 hours before delivery of 5 Gy RT (n=5), 10 Gy RT (n=3) or 20 Gy RT (n=6). The control mice received no AuNP injection and either no RT (n=6), 5 Gy RT (n=3), 10 Gy RT (n=3), 20 Gy RT (n=11). Twenty four hours post-RT, the mice were injected with liposomal iodine (0.3 ml/25 mouse) and imaged with DE-CT three days later. The results suggest that independent of any AuNP usage, RT levels of 10 Gy and 20 Gy increase the permeability of tumor vasculature to liposomal iodine and that the increase in permeability is dose-dependent. We found that the effect of RT on vasculature may already be at its maximum response i.e. saturated at 20 Gy, and therefore the addition of AuNPs had almost no added benefit. Similarly, at 5 Gy RT, our data suggests that there was no effect of AuNP augmentation on tumor vascular permeability. However, by using AuNPs with 10 Gy RT, we observed an increase in the vascular permeability, however this is not yet statistically significant due to the small number of mice in these groups. Such an approach can be used together with a liposomal drug delivery system to increase specific tumor delivery of chemotherapeutics. Our method has the potential to significantly improve tumor therapy and reduce the side effects from both RT and chemotherapy.