Iodine nanoparticle radiotherapy of human breast cancer growing in the brains of athymic mice

Abstract

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.

Novel Iodine nanoparticles target vascular mimicry in intracerebral triple negative human MDA-MB-231 breast tumors

“…The efficacy of RT (15 Gy RT at the Stony Brook RT100 facility, given as a single radio-surgical dose) was also greatly enhanced by the presence of the INPs; median survival was increased by ~ 2.6-fold; remarkably, four out of 10 mice experienced ≥ fivefold life extensions with 3 of the mice (30%) experiencing > tenfold life extensions. Single dose 15 Gy irradiations lead to tumor shrinkage in these mice 9 unlike that which has been observed with advanced U87 gliomas 8 .…”

“…Collagen I (Col I) co-localizes with the INPs on the ISS/VM boundary; since INPs interact with Col I directly, Col I is likely to be one of the sites on the ISS/VM to which the INPs bind. We hypothesize that it is the very high dose of radiation to these structures and adjacent radiation sensitive targets that is responsible for the extraordinary tumor control we observe 9 . We believe we are the first to identify NP targeting to ISS/VM structures.…”

“…Consistent with this finding was the observation that INP-enhanced RT (INP-RT) synergized with DOXIL chemotherapy greatly increasing the efficacy of chemotherapy to treat an advanced glioma in mice 8 . In a recent study using microCT we showed that the INPs also localize to advanced human triple negative breast cancers growing in the brains of mice where they concentrate to very high levels in a ~ 100-micron rim of the tumor 9 . The efficacy of RT (15 Gy RT at the Stony Brook RT100 facility, given as a single radio-surgical dose) was also greatly enhanced by the presence of the INPs; median survival was increased by ~ 2.6-fold; remarkably, four out of 10 mice experienced ≥ fivefold life extensions with 3 of the mice (30%) experiencing > tenfold life extensions.…”

“…Largely due to the photoelectric effect, electrons are ejected from the K and L shells after X-ray capture; these electrons travel a relatively short distance and deposit their energy locally in the tumor 4 . Previous studies using advanced experimental gliomas in mice showed that both AuNPs and INPs localize to the tumor region after intravenous injection 6 , 8 , 9 , 17 and significantly extended median survival of mice with advanced orthotopic gliomas by more than twofold 6 , 8 . Microlocalization studies performed on mouse brains bearing advanced human U87 gliomas showed the INPs to be largely localized to the tumor endothelium 8 suggesting that the resulting increased radiation dose may cause greater damage to the tumor endothelium 18 .…”

“…One such new approach that we pioneered is high atomic number (Z) nanoparticle enhanced radiation therapy pioneered by Nanoprobes, Inc. and the Smilowitz lab, first published in 2004 3 . Gold Nanoparticles (AuNPs) and more recently Iodine Nanoparticles (INPs) have been shown to increase the specificity and dose of radiotherapy by enhancing the local dose in tumor regions 3 – 9 . Other high-Z nanoparticles have also been studied, including those of gadolinium 10 , hafnium 11 , holmium 12 , bismuth 13 , platinum 14 , iron 15 , 16 .…”