title: Significant Radiation Enhancement Effects by Gold Nanoparticles in Combination with Cisplatin in Triple Negative Breast Cancer Cells and Tumor Xenografts.
abstract: Gold nanoparticles (AuNPs) and cisplatin have been explored in concomitant chemoradiotherapy, wherein they elicit their effects by distinct and overlapping mechanisms. Cisplatin is one of the most frequently utilized radiosensitizers in the clinical setting; however, the therapeutic window of cisplatin-aided chemoradiotherapy is limited by its toxicity. The goal of this study was to determine whether AuNPs contribute to improving the treatment response when combined with fractionated cisplatin-based chemoradiation in both in vitro and in vivo models of triple-negative breast cancer (MDA-MB-231Luc+). Cellular-targeting AuNPs with receptor-mediated endocytosis (AuNP-RME) in vitro at a noncytotoxic concentration (0.5 mg/ml) or cisplatin at IC25(12 μM) demonstrated dose enhancement factors (DEFs) of 1.25 and 1.14, respectively; the combination of AuNP-RME and cisplatin resulted in a significant DEF of 1.39 in vitro. Transmission electron microscopy (TEM) images showed effective cellular uptake of AuNPs at tumor sites 24 h after intratumoral infusion. Computed tomography (CT) images demonstrated that the intratumoral levels of gold remained stable up to 120 h after infusion. AuNPs (0.5 mg gold per tumor) demonstrated a radiation enhancement effect that was equivalent to three doses of cisplatin at IC25(4 mg/kg), but did not induce intrinsic toxicity or increased radiotoxicity. Results from this study suggest that AuNPs are the true radiosensitizer in these settings. Importantly, AuNPs enhance the treatment response when combined with cisplatin-based fractionated chemoradiation. This combination of AuNPs and cisplatin provides a promising approach to improving the therapeutic ratio of fractionated radiotherapy.
authors.affiliation: Departments of a   Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy.
authors.forename: Lei
authors.initials: L
authors.lastname: Cui
authors.affiliation: Departments of a   Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy.
authors.forename: Sohyoung
authors.initials: S
authors.lastname: Her
authors.affiliation: Departments of a   Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy.
authors.forename: Michael
authors.initials: M
authors.lastname: Dunne
authors.affiliation: d   Department of Radiation Oncology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; and.
authors.forename: Gerben R
authors.initials: GR
authors.lastname: Borst
authors.affiliation: Departments of a   Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy.
authors.forename: Raquel
authors.initials: R
authors.lastname: De Souza
authors.affiliation: b   Radiation Oncology and Medical Biophysics and.|e   Ontario Cancer Institute.|f   STTARR Innovation Centre, Radiation Medicine Program.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.affiliation: b   Radiation Oncology and Medical Biophysics and.|c   Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.|f   STTARR Innovation Centre, Radiation Medicine Program.|g   TECHNA Institute and.|h   Department of Radiation Physics, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Jaffray
authors.affiliation: Departments of a   Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy.|c   Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada.|f   STTARR Innovation Centre, Radiation Medicine Program.
authors.forename: Christine
authors.initials: C
authors.lastname: Allen
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000528:radiation effects; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006046:Gold / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D053768:Metal Nanoparticles; D051379:Mice; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000473:pathology* / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D011838:Radiation-Sensitizing Agents; D006046:Gold; D002945:Cisplatin