title: Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with177Lu.
abstract: To compare the effectiveness of trastuzumab-modified gold nanoparticles (AuNP) labeled with177Lu (trastuzumab-AuNP-177Lu) targeted to HER2 with non-targeted AuNP-177Lu for killing HER2-overexpressing breast cancer (BC) cells in vitro and inhibiting tumor growth in vivo following intratumoral (i.t.) injection.
  
  
  
  AuNP (30 nm) were modified with polyethylene glycol (PEG) polymers linked to trastuzumab or to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators to complex177Lu. The binding and internalization of trastuzumab-AuNP-177Lu in HER2-positive SK-BR-3, BT-474 and MDA-MB-361 human BC cells were studied. Clonogenic survival and DNA double-strand breaks (DSBs) were measured after exposure of SK-BR-3 or MDA-MB-361 cells to trastuzumab-AuNP-177Lu or AuNP-177Lu. NOD/SCID mice with s.c. MDA-MB-361 tumor xenografts were treated by i.t. injection of 3 MBq (0.15 mg) of trastuzumab-AuNP-177Lu, AuNP-177Lu or normal saline. Tumor growth was measured over 16 days and normal tissue toxicity evaluated.
  
  
  
  Trastuzumab-AuNP-177Lu was bound and internalized by HER2 positive BC cells (KD= 7.6 ± 2.0 nM). Trastuzumab-AuNP-177Lu was 42.9 and 2.6-fold more effective than AuNP-177Lu at decreasing the clonogenic survival of SK-BR-3 (1.3 × 106HER2/cell) and MDA-MB-361 (5.1 × 105HER2/cell) cells, respectively, exposed overnight to these agents (1.5 nM; 20 MBq/mg Au). Under the same treatment conditions, 10-fold and 2.8-fold more DNA DSBs were observed in SK-BR-3 and MDA-MB-361 cells, respectively, exposed to trastuzumab-AuNP-177Lu than AuNP-177Lu. Trastuzumab-AuNP-177Lu was 1.8-fold more effective at inhibiting tumor growth than AuNP-177Lu. No or minimal normal tissue toxicity was observed for trastuzumab-AuNP-177Lu or AuNP-177Lu treatments.
  
  
  
  Trastuzumab-AuNP-177Lu enables an efficient local radiation treatment of HER2-positive BC.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 3M2, Canada.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 3M2, Canada.|College of Pharmacy, Keimyung University, Daegu, South Korea.
authors.forename: Simmyung
authors.initials: S
authors.lastname: Yook
authors.affiliation: Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada.
authors.forename: Yijie
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 3M2, Canada.
authors.forename: Dane
authors.initials: D
authors.lastname: Bergstrom
authors.affiliation: Department of Chemistry, University of Toronto, Toronto, Ontario, M5S 3H6, Canada.
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Winnik
authors.affiliation: Department of Radiation Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pignol
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 3M2, Canada. raymond.reilly@utoronto.ca.|Department of Medical Imaging, University of Toronto, Toronto, Ontario, M5T 1W7, Canada. raymond.reilly@utoronto.ca.|Toronto General Research Institute and Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, M5G 1L7, Canada. raymond.reilly@utoronto.ca.|Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St, Toronto, Ontario, M5S 3M2, Canada. raymond.reilly@utoronto.ca.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D056831:Coordination Complexes / Q000737:chemistry; D005260:Female; D006046:Gold / Q000737:chemistry*; D006801:Humans; D007205:Indium Radioisotopes; D008187:Lutetium / Q000737:chemistry*; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D013499:Surface Properties; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000074322:Antineoplastic Agents, Immunological; D056831:Coordination Complexes; D006046:Gold; D007205:Indium Radioisotopes; D008187:Lutetium; D011092:Polyethylene Glycols; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
keywords: HER2; breast cancer; gold nanoparticles; intratumoral injection; lutetium-177