title: Monitoring tumor response to linifanib therapy with SPECT/CT using the integrin αvβ3-targeted radiotracer 99mTc-3P-RGD2.
abstract: The objective of this study was to determine the utility of (99m)Tc-3P-Arg-Gly-Asp (RGD2) single photon emission computed tomography (SPECT)/computed tomography (CT) for noninvasive monitoring of integrin αvβ3-expression response to antiangiogenic treatment with linifanib. Linifanib or vehicle therapy was carried out in female athymic nu/nu mice bearing U87MG glioma (high αvβ3 expression) or PC-3 prostate (low αvβ3 expression) tumors at 12.5 mg/kg twice daily. The average tumor volume was 180 ± 90 mm(3) the day prior to baseline SPECT/CT. Longitudinal (99m)Tc-3P-RGD2 SPECT/CT imaging was performed at baseline (-1 day) and days 1, 4, 11, and 18. Tumors were harvested at all imaging time points for histopathological analysis with H&E and immunohistochemistry. A significant difference in tumor volumes between vehicle- and linifanib-treated groups was observed after 4 days of linifanib therapy in the U87MG model. The percent injected dose (%ID) tumor uptake of (99m)Tc-3P-RGD2 peaked in the vehicle-treated group at day 11, while the %ID/cm(3) tumor uptake decreased slowly over the whole study period. During the first 2 days of linifanib treatment, a rapid decrease in both %ID/cm(3) tumor uptake and tumor/muscle ratios of (99m)Tc-3P-RGD2 was observed, followed by a slow decrease until day 18. No decrease in tumor uptake of (99m)Tc-3P-RGD2 or tumor volume was observed for either treatment group in the PC-3 model. Changes in tumor vasculature were confirmed by histopathological H&E analysis and immunohistochemistry. Longitudinal imaging using (99m)Tc-3P-RGD2 SPECT/CT may be a useful tool for monitoring the downstream biologic effects of linifanib therapy.
authors.affiliation: School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Shundong
authors.initials: S
authors.lastname: Ji
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Voorbach
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Shao
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Fox
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.forename: Yanping
authors.initials: Y
authors.lastname: Luo
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Mudd
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D019281:Dimerization; D005260:Female; D005910:Glioma; D006801:Humans; D007191:Indazoles / Q000627:therapeutic use*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D064847:Multimodal Imaging; D009842:Oligopeptides; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019275:Radiopharmaceuticals; D013667:Technetium; D014057:Tomography, X-Ray Computed; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007191:Indazoles; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D010671:Phenylurea Compounds; D019275:Radiopharmaceuticals; C561921:technetium 99m (HYNIC-3PRGD(2))(tricine)(TPPTS); D013667:Technetium; C047981:arginyl-glycyl-aspartic acid; C513486:linifanib; D011505:Protein-Tyrosine Kinases