title: Radionuclide therapy using ¹³¹I-labeled anti-epidermal growth factor receptor-targeted nanoparticles suppresses cancer cell growth caused by EGFR overexpression.
abstract: BACKGROUND
  Anti-epidermal growth factor receptor (EGFR)-targeted nanoparticles can be used to deliver a therapeutic and imaging agent to EGFR-overexpressing tumor cells. (131)I-labeled anti-EGFR nanoparticles derived from cetuximab were used as a tumor-targeting vehicle in radionuclide therapy.
  
  
  METHODS
  This paper describes the construction of the anti-EGFR nanoparticle EGFR-BSA-PCL. This nanoparticle was characterized for EGFR-targeted binding and cellular uptake in EGFR-overexpressing cancer cells by using flow cytometry and confocal microscopy. Anti-EGFR and non-targeted nanoparticles were labeled with (131)I using the chloramine-T method. Analyses of cytotoxicity and targeted cell killing with (131)I were performed using the MTT assay. The time-dependent cellular uptake of (131)I-labeled anti-EGFR nanoparticles proved the slow-release effects of nanoparticles. A radioiodine therapy study was also performed in mice.
  
  
  RESULTS
  The EGFR-targeted nanoparticle EGFR-BSA-PCL and the non-targeted nanoparticle BSA-PCL were constructed; the effective diameters were approximately 100 nm. The results from flow cytometry and confocal microscopy revealed significant uptake of EGFR-BSA-PCL in EGFR-overexpressing tumor cells. Compared with EGFR-BSA-PCL, BSA-PCL could also bind to cells, but tumor cell retention was minimal and weak. In MTT assays, the EGFR-targeted radioactive nanoparticle (131)I-EGFR-BSA-PCL showed greater cytotoxicity and targeted cell killing than the non-targeted nanoparticle (131)I-BSA-PCL. The radioiodine uptake of both (131)I-labeled nanoparticles, (131)I-EGFR-BSA-PCL and (131)I-BSA-PCL, was rapid and reached maximal levels 4 h after incubation, but the (131)I uptake of (131)I-EGFR-BSA-PCL was higher than that of (131)I-BSA-PCL. On day 15, the average tumor volumes of the (131)I-EGFR-BSA-PCL and (131)I-BSA-PCL groups showed a slow growth relationship compared with that of the control group.
  
  
  CONCLUSIONS
  The EGFR-targeted nanoparticle EGFR-BSA-PCL demonstrated superior cellular binding and uptake compared with those of the control BSA-PCL. The EGFR-targeted radioactive nanoparticle (131)I-EGFR-BSA-PCL exhibited favorable intracellular retention of (131)I. Radionuclide therapy using (131)I-EGFR-BSA-PCL, which showed excellent targeted cell killing, suppressed cancer cell growth caused by EGFR overexpression.
authors.affiliation: Department of Nuclear Medicine, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, People's Republic of China.
authors.forename: Wei
authors.identifier: http://orcid.org/0000-0002-2035-0134
authors.initials: W
authors.lastname: Li
authors.affiliation: Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, 264003, Shandong, People's Republic of China.
authors.forename: Zhongyun
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, People's Republic of China.
authors.forename: Chengxia
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Nuclear Medicine, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Institute of Nanobiotechnology, School of Materials Science and Engineering, Tianjin Key Laboratory of Composites and Functional Materials, Tianjin University, Tianjin, 300072, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: Institute of Nanobiotechnology, School of Materials Science and Engineering, Tianjin Key Laboratory of Composites and Functional Materials, Tianjin University, Tianjin, 300072, People's Republic of China.
authors.forename: Jin
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Nuclear Medicine, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin, 300052, People's Republic of China. tanpost@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Tan
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage / Q000494:pharmacology; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D053758:Nanoparticles / Q000008:administration & dosage; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007457:Iodine Radioisotopes; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: 131I; Epidermal growth factor receptor; Nanoparticles; Radioiodine therapy; Tumor-targeting