Radiogallium Complex-Conjugated Bifunctional Peptides for Detecting Primary Cancer and Bone Metastases Simultaneously

Bioconjug Chem. 2015 Aug 19;26(8):1561-70. doi: 10.1021/acs.bioconjchem.5b00186. Epub 2015 Jul 2.

Abstract

(68)Ga (T(1/2) = 68 min, a generator-produced nuclide) is an interesting radionuclide for clinical positron emission tomography (PET). Recently, it was reported that radiogallium-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated (Asp)n peptide [Ga-DOTA-(Asp)n] has great potential for bone metastases imaging. In the current study, a compound containing an aspartic acid peptide linker (D11) as a carrier to bone metastases, an RGD peptide [c(RGDfK) peptide] as a carrier to the primary cancer, and Ga-DOTA as a stable radiometal complex for imaging in one molecule, Ga-DOTA-D11-c(RGDfK), was designed, prepared, and evaluated to detect both the primary cancer and bone metastases simultaneously using (67)Ga, which is easy to handle. After DOTA-D11-c(RGDfK) was synthesized using Fmoc-based solid-phase methodology, (67)Ga-DOTA-D11-c(RGDfK) was prepared by complexing DOTA-D11-c(RGDfK) with (67)Ga. Hydroxyapatite binding assays, integrin binding assays, biodistribution experiments, and single photon emission tomography (SPECT) imaging using tumor-bearing mice were performed using (67)Ga-DOTA-D11-c(RGDfK). (67)Ga-DOTA-D11-c(RGDfK) was prepared with a radiochemical purity of >97%. In vitro, (67)Ga-DOTA-D11-c(RGDfK) had a high affinity for hydroxyapatite and αvβ3 integrin. In vivo, (67)Ga-DOTA-D11-c(RGDfK) exhibited high uptake in bone and tumor. The accumulation of (67)Ga-DOTA-D11-c(RGDfK) in tumor decreased when it was co-injected with c(RGDfK) peptide. (68)Ga-DOTA-D11-c(RGDfK) has great potential as a PET tracer for the diagnosis of both the primary cancer and bone metastases simultaneously.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / secondary*
  • Female
  • Gallium Radioisotopes / pharmacokinetics*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Integrin alphaVbeta3 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Peptide Fragments / metabolism*
  • Positron-Emission Tomography / methods*
  • Radiochemistry
  • Radiopharmaceuticals / pharmacokinetics*
  • Tissue Distribution
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Gallium Radioisotopes
  • Integrin alphaVbeta3
  • Peptide Fragments
  • Radiopharmaceuticals