title: Technetium-99 conjugated with methylene diphosphonate (99Tc-MDP) inhibits experimental choroidal neovascularization in vivo and VEGF-induced cell migration and tube formation in vitro.
abstract: OBJECTIVE
  To investigate the effects of (99)Tc-MDP, a decay product of (99m)Tc-MDP, on the development of choroidal neovascularization (CNV), together with its underlying mechanisms.
  
  
  METHODS
  C57BL/6J mice were used to induce CNV by laser photocoagulation. (99)Tc-MDP at the doses of 0.5 × 10(-1), 1 × 10(-1), and 2 × 10(-1) μg/kg or the same volume of PBS was intraperitoneally injected daily after photocoagulation until the end of the experiment. Seven days after laser injury, mice were perfused with fluorescein-labeled dextran, and areas of CNV were measured. Numbers of infiltrating macrophages, protein levels of VEGF, and inflammation-related molecules including intercellular adhesion molecule (ICAM)-1, tumor necrosis factor (TNF)-α, and matrix metalloproteinases (MMPs) in the RPE-choroid complex were detected 3 days after laser photocoagulation. Effects of (99)Tc-MDP on VEGF-induced endothelial cell migration and tube formation were also studied. Toxicity of (99)Tc-MDP was evaluated in vivo and in vitro.
  
  
  RESULTS
  Areas of CNV were significantly suppressed by (99)Tc-MDP treatment without toxicity to the retina compared with PBS treatment in a dose-dependent manner: (99)Tc-MDP treatment of 0.5 × 10(-1) μg/kg (5698.60 ± 1037.70 μm(2)), 1 × 10(-1) μg/kg (3678.34 ± 1328.18 μm(2)), and 2 × 10(-1) μg/kg (2365.78 ± 923.80 μm(2)) suppressed the development of CNV by 36.12%, 58.76%, and 73.48%, respectively, compared with that in the PBS treatment group (8920.36 ± 1097.29 μm(2); P < 0.001). (99)Tc-MDP treatment led to significant inhibition of macrophages infiltrating to CNV together with downregulated protein expressions of VEGF, ICAM-1, TNF-α, and MMP-2. (99)Tc-MDP also showed an inhibitive effect on cell proliferation and VEGF-induced migration and capillary-like tube formation of endothelial cells.
  
  
  CONCLUSIONS
  Anti-inflammatory treatment with (99)Tc-MDP has therapeutic potential for CNV-related diseases.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Kunbei
authors.initials: K
authors.lastname: Lai
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Chenjin
authors.initials: C
authors.lastname: Jin
authors.forename: Kaili
authors.initials: K
authors.lastname: Wu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tian
authors.forename: Chuangxin
authors.initials: C
authors.lastname: Huang
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhong
authors.forename: Haiyun
authors.initials: H
authors.lastname: Ye
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002829:Choroid / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D020256:Choroidal Neovascularization / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D004596:Electroretinography; D042783:Endothelial Cells / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects; D066298:In Vitro Techniques; D008028:Light Coagulation; D008253:Macaca mulatta; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000494:pharmacology; D012160:Retina / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013669:Technetium Tc 99m Medronate / Q000138:chemical synthesis / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D061965:Matrix Metalloproteinase Inhibitors; D019275:Radiopharmaceuticals; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D013669:Technetium Tc 99m Medronate