title: Anti-tumor effect of integrin targeted (177)Lu-3PRGD2 and combined therapy with Endostar.
abstract: OBJECTIVE
  Targeted radiotherapy (TRT) is an emerging approach for tumor treatment. Previously, 3PRGD2 (a dimeric RGD peptide with 3 PEG4 linkers) has been demonstrated to be of advantage for integrin αvβ3 targeting. Given the promising results of (99m)Tc-3PRGD2 for lung cancer detection in human beings, we are encouraged to investigate the radiotherapeutic efficacy of radiolabeled 3PRGD2. The goal of this study was to investigate and optimize the integrin αvβ3 mediated therapeutic effect of (177)Lu-3PRGD2 in the animal model.
  
  
  METHODS
  Biodistribution, gamma imaging and maximum tolerated dose (MTD) studies of (177)Lu-3PRGD2 were performed. The targeted radiotherapy (TRT) with single dose and repeated doses as well as the combined therapy of TRT and the anti-angiogenic therapy (AAT) with Endostar were conducted in U87MG tumor model. The hematoxylin and eosin (H&E) staining and immunochemistry (IHC) were performed post-treatment to evaluate the therapeutic effect.
  
  
  RESULTS
  The U87MG tumor uptake of (177)Lu-3PRGD2 was relatively high (6.03 ± 0.65 %ID/g, 4.62 ± 1.44 %ID/g, 3.55 ± 1.08 %ID/g, and 1.22 ± 0.18 %ID/g at 1 h, 4 h, 24 h, and 72 h postinjection, respectively), and the gamma imaging could visualize the tumors clearly. The MTD of (177)Lu-3PRGD2 in nude mice (>111 MBq) was twice to that of (90)Y-3PRGD2 (55.5 MBq). U87MG tumor growth was significantly delayed by (177)Lu-3PRGD2 TRT. Significantly increased anti-tumor effects were observed in the two doses or combined treatment groups.
  
  
  CONCLUSIONS
  The two-dose TRT and combined therapy with Endostar potently enhanced the tumor growth inhibition, but the former does not need to inject daily for weeks, avoiding a lot of unnecessary inconvenience and suffering for patients, which could potentially be rapidly translated into clinical practice in the future.
authors: 1. Medical Isotopes Research Center, Peking University, Beijing 100191, China; ; 2. Medical and Healthy Analytical Center, Peking University, Beijing 100191, China;
authors: Jiyun
authors: J
authors: Shi
authors: 1. Medical Isotopes Research Center, Peking University, Beijing 100191, China; ; 3. Department of Radiation Medicine, Basic Medical Sciences, Peking University, Beijing 100191, China;
authors: Di
authors: D
authors: Fan
authors: 1. Medical Isotopes Research Center, Peking University, Beijing 100191, China; ; 3. Department of Radiation Medicine, Basic Medical Sciences, Peking University, Beijing 100191, China;
authors: Chengyan
authors: C
authors: Dong
authors: 1. Medical Isotopes Research Center, Peking University, Beijing 100191, China; ; 3. Department of Radiation Medicine, Basic Medical Sciences, Peking University, Beijing 100191, China;
authors: Hao
authors: H
authors: Liu
authors: 1. Medical Isotopes Research Center, Peking University, Beijing 100191, China; ; 3. Department of Radiation Medicine, Basic Medical Sciences, Peking University, Beijing 100191, China;
authors: Bing
authors: B
authors: Jia
authors: 1. Medical Isotopes Research Center, Peking University, Beijing 100191, China; ; 2. Medical and Healthy Analytical Center, Peking University, Beijing 100191, China;
authors: Huiyun
authors: H
authors: Zhao
authors: 4. Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing 100857, China.
authors: Xiaona
authors: X
authors: Jin
authors: 1. Medical Isotopes Research Center, Peking University, Beijing 100191, China; ; 3. Department of Radiation Medicine, Basic Medical Sciences, Peking University, Beijing 100191, China;
authors: Zhaofei
authors: Z
authors: Liu
authors: 4. Department of Nuclear Medicine, Peking Union Medical College Hospital, Beijing 100857, China.
authors: Fang
authors: F
authors: Li
authors: 1. Medical Isotopes Research Center, Peking University, Beijing 100191, China; ; 3. Department of Radiation Medicine, Basic Medical Sciences, Peking University, Beijing 100191, China;
authors: Fan
authors: F
authors: Wang
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D056831:Coordination Complexes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043169:Endostatins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010456:Peptides, Cyclic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins; D000090324:Tumor Protein, Translationally-Controlled 1; D023041:Xenograft Model Antitumor Assays
chemical_list: C000592471:177Lu-3PRGD2; D020533:Angiogenesis Inhibitors; D056831:Coordination Complexes; D043169:Endostatins; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1; C522911:endostar protein
keywords: 177Lu; Arg-Gly-Asp (RGD); Integrin αvβ3; combination therapy.; radionuclide therapy