EDB-FN targeted probes for the surgical navigation, radionuclide imaging, and therapy of thyroid cancer

Abstract

Extradomain B of bronectin (EDB-FN) is a promising diagnostic and therapeutic biomarker for thyroid cancer (TC). Here, we identi ed a high-a nity EDB-FN targeted peptide named EDBp, and developed three EDBp-based probes, Cy5-EDBp, [ 18 F]-EDBp and [ 177 Lu]-EDBp the surgical navigation, radionuclide imaging and therapy of TC. MethodsBased on the previously identi ed EDB-FN targeted peptide ZD2, the optimized EDB-FN targeted peptide EDBp was identi ed by using the alanine scan strategy. Three EDBp-based probes, Cy5-EDBp, [ 18 F]-EDBp and [ 177 Lu]-EDBp, were developed for uorescence imaging, positron emission tomography (PET) imaging and radiotherapy in TC tumor-bearing mice, respectively. Additionally, [ 18 F]-EDBp was evaluated in two TC patients. ResultsThe binding a nity of EDBp to the EDB fragment protein (Kd = 14.4 ± 1.4 nM, n = 3) was approximately 336-fold greater than that of the ZD2 (Kd = 4839.7 ± 361.7 nM, n = 3). Fluorescence imaging with Cy5-EDBp facilitated the complete removal of TC tumors. [ 18 F]-EDBp PET imaging clearly delineated TC tumors, with high tumor uptake (16.43 ± 1.008%ID/g, n = 6, at 1 h postinjection). Radiotherapy with [ 177 Lu]-EDBp inhibited tumor growth and prolonged survival in TC tumor-bearing mice (survival time of different treatment groups: Saline vs. EDBp vs. ABRAXANE vs. [ 177 Lu]-EDBp = 8 d vs. 8 d vs. 11.67 d vs. 22.33 d, ***p < 0.001). Importantly, the rst-in-human evaluation of [ 18 F]-EDBp demonstrated that it had speci c targeting properties (SUVmax value of 3.6) and safety. Conclusion Cy5-EDBp, [ 18 F]-EDBp and [ 177 Lu]-EDBp are promising candidates for the surgical navigation, radionuclide imaging and radionuclide therapy of TC, respectively.

EDB-FN-Targeted Positron Emission Tomography Imaging of Breast Cancer in Mice

“…EDBp was optimized from the classical EDB-FN-targeting peptide ZD2 by alanine scanning, and its a nity with EDB-FN substantially increased from 4.8 µM to 14 nM [21]. PET/CT imaging showed that the radiotracer [ 18 F]-EDBp had high accumulation in bilateral primary thyroid lesions and bone metastases in two patients with thyroid cancer [21].…”

“…Synthesis of the Peptides. The red uorescence peptide EDBp-Cy5 (chemical structure: AVRTSAD-PEG 4 -K-Cy5) and CG7C-Cy5 (chemical structure: CGGGGGGGC-Cy5) and the PET precursor peptide EDBp-NOTA (chemical structure: AVRTSAD-PEG 4 -K-NOTA) were designed by Feng et al [21]. (Fig.…”

“…One of the sections was used for IHC with an anti-EDB-FN monoclonal antibody (1:1000, Abcam, #ab268021). IHC was performed following the conventional procedure as previously reported [21]. Finally, images were visualized and captured by a confocal microscopy confocal scanning system (Olympus FV1000, Japan).…”

“…Recently, Feng et al optimized ZD2 using alanine scanning technology to increase its binding a nity to EDB-FN from 4.8 µM to 14 nM. The optimized peptide was named EDBp, and its NIRF and PET molecular probes were applied to the molecular imaging of thyroid cancer [21]. In this study, we rst examined the expression levels of EDB-FN in several types of breast cancer cells and their binding to EDBp.…”

Radiolabeled multi-layered coated gold nanoparticles as potential biocompatible PET/SPECT tracers

“…[32][33][34] Typically, DOTA/ NOTA chelators have been commonly utilized for the purpose of radionuclide complexation. 35 These chelators are characterized by their polydentate macrocyclic structures, which enable them to effectively accommodate di-and tri-valent metal ions through coordinative binding. Conjugation of macrocyclic structures capable of radionuclide chelation with the polymeric shell of nanoparticles would result in complex structures that require supplementary synthesis and purification procedures, thereby causing a significant increase in the production costs of a radiopharmaceutical compound.…”