Targeting the αvβ3 integrin for small-animal PET/CT of osteolytic bone metastases

Thaddeus J. Wadas, Hongju Deng, Jennifer E. Sprague, Alexander Zheleznyak, Katherine N. Weilbaecher, Carolyn J. Anderson

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

This article describes the evaluation of the radiopharmaceutical 64Cu-CB-TE2A-c(RGDyK) (64Cu-RGD) as an imaging agent for osteolytic bone metastases and their associated inflammation by targeting of the αvβ3 integrin on osteoclasts and the proinflammatory cells involved at the bone metastatic site. Methods: The 64Cu-RGD radiotracer was evaluated in the transgenic mouse expressing Tax (Tax+), which spontaneously develops osteolytic tumors throughout the vertebrae and hind limbs, using biodistribution studies and small-animal PET/CT. Histologic analysis was also performed on Tax+ mouse tails, using hematoxylin and eosin and tartrate-resistant acid phosphatase to confirm the presence of osteolytic bone lesions and the presence of osteoclasts, respectively. Additionally, a proof-of-principle study was conducted with a small group of Tax+ animals presenting with osteolytic lesions. These animals were treated with the bisphosphonate zoledronic acid and imaged with 64Cu-RGD to determine whether this radiopharmaceutical was sensitive enough to detect a response to the bisphosphonate therapy. Results: Biodistribution studies using 64Cu-RGD demonstrated that Tax+ mice between the ages of 6 and 12 mo had a greater accumulation of activity in their tail vertebrae than did the wild-type (WT) cohort (P = 0.013). Additionally, Tax+ mice between the ages of 6 and 12 mo had significantly more tracer activity associated with their tail vertebrae than did Tax+ mice older than 12 mo (P = 0.003), suggesting that earlier bone metastases cause an increased recruitment of αvβ3-expressing cells. Small-animal PET/CT with 64Cu-RGD was conducted on Tax+ and WT mice. On the basis of standardized uptake value analysis, Tax+ mice had approximately 2-fold more tail-associated activity than did WT animals (P = 0.0157). Additionally, decreases in uptake were observed in the tails of Tax+ mice after treatment with the osteoclast inhibitor zoledronic acid, and histologic analysis of Tax+ mouse-tail vertebrae revealed the presence of Tax+ tumor cells, osteoclasts, and proinflammatory cells within the bone microenvironment. Conclusion: Together, these data suggest that 64Cu-RGD has the potential to effectively image osteolytic bone metastases and monitor the physiologic changes in the bone metastatic microenvironment after osteoclast-inhibiting bisphosphonate therapy.

Original languageEnglish
Pages (from-to)1873-1880
Number of pages8
JournalJournal of Nuclear Medicine
Volume50
Issue number11
DOIs
StatePublished - Nov 1 2009

Keywords

  • Bisphosphonate
  • Bone
  • Integrin
  • Metastasis
  • PET

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