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

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          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.

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          The use of gold nanoparticles to enhance radiotherapy in mice.

          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.
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            Radiotherapy enhancement with gold nanoparticles.

            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.
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              Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials.

              To determine aggregate outcomes and prognostic covariates in patients with recurrent glioma enrolled onto phase II chemotherapy trials. Patients from eight consecutive phase II trials included 225 with recurrent glioblastoma multiforme (GBM) and 150 with recurrent anaplastic astrocytoma (AA). Their median age was 45 years (range, 15 to 82 years) and their median Karnofsky performance score was 80 (range, 60 to 100). Prognostic covariates were analyzed with respect to tumor response, progression-free survival (PFS), and overall survival (OS) by multivariate logistic and Cox proportional hazards regression analyses. Overall, 34 (9%) had complete or partial response, whereas 80 (21%) were alive and progression-free at 6 months (APF6). The median PFS was 10 weeks and median OS was 30 weeks. Histology was a robust prognostic factor across all outcomes. GBM patients had significantly poorer outcomes than AA patients. The APF6 proportion was 15% for GBM and 31% for AA, whereas the median PFS was 9 weeks for GBM and 13 weeks for AA. Results were also significantly poorer for patients with more than two prior surgeries or chemotherapy regimens. Histology is a dominant factor in determining outcome in patients with recurrent glioma enrolled onto phase II trials. Future trials should be designed with separate histology strata.
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                Author and article information

                Contributors
                hainfeld@nanoprobes.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                24 September 2020
                24 September 2020
                2020
                : 10
                : 15627
                Affiliations
                [1 ]GRID grid.281323.9, ISNI 0000 0004 0548 0605, Nanoprobes, Inc., ; 95 Horseblock Rd., Unit 1, Yaphank, NY 11980 USA
                [2 ]GRID grid.208078.5, ISNI 0000000419370394, Department of Cell Biology, , University of Connecticut Health Center, ; 263 Farmington Ave., Farmington, CT 06030 USA
                Article
                72268
                10.1038/s41598-020-72268-0
                7515899
                32973267
                503ebef4-1bb8-4bed-bea5-f64e2276a432
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 27 April 2020
                : 18 August 2020
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                © The Author(s) 2020

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                nanomedicine,nanoparticles,breast cancer,cancer imaging,cancer therapy,metastasis,cancer,cns cancer,nanobiotechnology,biotechnology,oncology,nanoscience and technology

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