title: Molecularly targeted gold nanoparticles enhance the radiation response of breast cancer cells and tumor xenografts to X-radiation.
abstract: The purpose of this study was to evaluate the effect of molecularly targeted gold nanoparticles (AuNPs) on tumor radiosensitization both in vitro and in vivo. Human Epidermal Growth Factor Receptor-2 (HER-2)-targeted AuNPs (Au-T) were synthesized by conjugating trastuzumab (Herceptin) to 30 nm AuNPs. In vitro, the cytotoxicity of Au-T or non-targeted AuNPs (Au-P) was assessed by γ-H2AX immunofluorescence microscopy for DNA damage and clonogenic survival assays. In vivo, athymic mice bearing subcutaneous MDA-MB-361 xenografts were treated with a single dose of 11 Gy of 100 kVp X-rays 24 h after intratumoral injection of Au-T (~0.8 mg of Au) or no X-radiation. Normal tissue toxicity was determined by hematology or biochemistry parameters. The combination of Au-P or Au-T with X-ray exposure increased the formation of γ-H2AX foci by 1.7 (P = 0.054) and 3.3 (P = 0.024) fold in comparison to X-radiation alone, respectively. The clonogenic survival of cells exposed to Au-T and X-rays was significantly lower from that of cells exposed to X-radiation alone, which translated to a dose enhancement factor of 1.6. In contrast, survival of cells exposed to Au-P and X-rays versus X-radiation alone were not significantly different. In vivo, the combination of Au-T and X-radiation resulted in regression of MDA-MB-361 tumors by 46 % as compared to treatment with X-radiation (16.0 % increase in tumor volume). No significant normal tissue toxicity was observed. Radiosensitization of breast cancer to X-radiation with AuNPs was successfully achieved with an optimized therapeutic strategy of molecular targeting of HER-2 and intratumoral administration.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Niladri
authors.initials: N
authors.lastname: Chattopadhyay
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Cai
authors.forename: Yongkyu Luke
authors.initials: YL
authors.lastname: Kwon
authors.forename: Eli
authors.initials: E
authors.lastname: Lechtman
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pignol
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D005260:Female; D006046:Gold / Q000737:chemistry*; D006657:Histones / Q000378:metabolism; D006801:Humans; D015552:Injections, Intralesional; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D011879:Radiotherapy Dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D047368:Tumor Burden / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D006046:Gold; D006657:Histones; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C468783:H2AX protein, human; C508053:ERBB2 protein, human