177Lu-labeled cyclic RGD peptide as an imaging and targeted radionuclide therapeutic agent in non-small cell lung cancer: Biological evaluation and preclinical study

Bioorg Chem. 2020 Sep:102:104100. doi: 10.1016/j.bioorg.2020.104100. Epub 2020 Jul 15.

Abstract

Non-small cell lung carcinoma (NSCLC) is among the most lethal lung cancers responsible for 80-85% of death. αvβ3 integrin receptor subtype has been identified as a lung cancer biomarker since its expression correlates with tumor progression and metastasis. The extracellular domain of the receptor forms a binding site for RGD-based sequences. Therefore, specific targeting of αvβ3 integrin receptors by these short peptides can be an excellent candidate for cancer imaging and therapy. In this research, the radiolabeling of DOTA-E(cRGDfK)2 with 177Lu was efficiently implemented. The Log P value, in vivo, in vitro, metabolic stability, cellular uptake and specific binding of the radiopeptide was determined. The tumor targeting capacity and the therapeutic potential of the radiotracer was studied in A549 tumor-bearing mice. Imaging studies at different time intervals were performed by SPECT/CT. Radiochemical purity of more than 99% and Log P of -3.878 was obtained for 177Lu-labelled peptide. Radiotracer showed favorable in vivo, in vitro and metabolic stability. The radiopeptide dissociation constant (Kd) was 15.07 nM. Radiopeptide specific binding was more than 95%. Biodistribution studies showed high accumulation of the radiopeptide in tumor and rapid excretion by urinary route. Maximum tumor uptake was at 4 h post-injection. Following administration of this radiopeptide to mice, not only tumor growth was suppressed, but significant tumor shrinkage was also observed. In conclusion, this radiopeptide can be employed for staging, follow-up imaging and as peptide receptor radionuclide therapeutic agent allowing efficient therapy for NSCLC and other cancers overexpressing αvβ3 integrin receptors.

Keywords: (177)Lu; E(cRGDfK)(2); Non-small cell lung cancer; Peptide receptor radionuclide therapy; Radiopeptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / diagnostic imaging
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Cells, Cultured
  • Coordination Complexes / chemistry
  • Coordination Complexes / therapeutic use*
  • Dose-Response Relationship, Drug
  • Female
  • Lung Neoplasms / diagnostic imaging
  • Lung Neoplasms / drug therapy*
  • Lutetium
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • NIH 3T3 Cells
  • Neoplasms, Experimental / diagnostic imaging
  • Neoplasms, Experimental / drug therapy
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / therapeutic use*
  • Radioisotopes / chemistry
  • Radioisotopes / therapeutic use*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / therapeutic use*
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • Coordination Complexes
  • Peptides, Cyclic
  • Radioisotopes
  • Radiopharmaceuticals
  • cyclic arginine-glycine-aspartic acid peptide
  • Lutetium
  • Lutetium-177