¹⁷⁷Lu‐labeled monomeric, dimeric and multimeric RGD peptides for the therapy of tumors expressing α(ν)β(3) integrins

Abstract

The conjugation of peptides to gold nanoparticles (AuNPs) produces biocompatible and stable multimeric systems with target-specific molecular recognition. Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been reported as high-affinity agents for the a(n)b(3) integrin. The aim of this research was to prepare a multimeric system of 177 Lu-labeled gold nanoparticles conjugated to c(RGDfK)C (cyclo(Arg-Gly-Asp-Phe-Lys)Cys) and to compare the radiation-absorbed dose with that of 177 Lu-labeled monomeric and dimeric RGD peptides to a(n)b(3) integrin-positive U87MG tumors in mice. DOTA-GGC (1,4,7,10-tetraazacyclododecane-N-N′,N 00 ,N 000 -tetraacetic acid-Gly-Gly-Cys) and c(RGDfK)C peptides were synthesized and conjugated to AuNPs by a spontaneous reaction of the thiol groups. Transmission electron microscopy, ultraviolet-visible, X-ray photoelectron spectroscopy, Raman and far-infrared spectroscopy techniques demonstrated that AuNPs were functionalized with the peptides. For the 177 Lu-AuNP-c(RGDfK)C to be obtained, the 177 Lu-DOTA-GGC radiopeptide was first prepared and added to a solution of AuNPs followed by c(RGDfK)C (25 ml, 5 mM) at 18 C for 15 min. 177 Lu-DOTA-GGC, 177 Lu-DOTA-cRGDfK and 177 Lu-DOTA-E-c(RGDfK) 2 were prepared by adding 177 LuCl 3 (370 MBq) to 5 ml (1 mg/ml) of the DOTA derivative diluted with 50 ml of 1 M acetate buffer pH 5. The mixture was incubated at 90 C in a block heater for 30 min. Radiochemical purity was determined by ultrafiltration and HPLC analyses. Biokinetic studies were accomplished in athymic mice with U87MG-induced tumors. The radiochemical purity for all 177 Lu-RGD derivatives was 96 AE 2%. 177 Lu-absorbed doses per injected activity delivered to U87MG tumors were 0.357 AE 0.052 Gy/MBq (multimer), 0.252 AE 0.027 Gy/MBq (dimer) and 0.102 AE 0.018 Gy/MBq (monomer). 177 Lu-labeled dimeric and multimeric RGD peptides demonstrated properties suitable for targeted radionuclide therapy of tumors expressing a(n)b(3) integrins.

177Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

“…Considering that one Becquerel (Bq) of Lu-177 produces 841558 disintegrations until total decay (total disintegrations = ∫ 0 ( ) ) with a maximum − -particle energy of 0.498 MeV, it is expected that, with the high 177 Lu-DenAuNPfolate-bombesin retention observed in tumors, the total radiation absorbed dose to the malignant tissue could easily reach 2 Gy per MBq [33]. However, further preclinical studies must 10 Journal of Nanomaterials be carried out in order to evaluate the toxicity, biokinetics, and dosimetry of this radiopharmaceutical.…”

Study of the Optical Properties of Functionalized Gold Nanoparticles in Different Tissues and Their Correlation with the Temperature Increase

“…Before laser irradiation, the chemical conjugation was confirmed by UV-Vis, medium-and far-IR, Raman spectroscopy, and Transmission Electron Microscopy (TEM), as previously reported [16,19].…”

“…This shifting is attributed to the changes in the refraction index as a consequence of the interaction between the peptide and the AuNP surface [16].…”

“…Raman spectroscopy and medium-and far-infrared showed several well-defined bands characteristics of the AuNP-c[RGDfK(C)] conjugate [16]. The Far-IR spectrum of the AuNP-c[RGDfK(C)] showed a characteristic band at 279±1 cm −1 , which is representative of the Au-S bond [18,19].…”

Development of computational small animal models and their applications in preclinical imaging and therapy research

“…11,15,17,18,21,24,27,33,39,45,46,49,53,[78][79][80][81][82] These were largely adopted for calculation of organ absorbed dose and dosimetry of radionuclide-labeled compounds in preclinical experiments. [83][84][85][86][87][88][89][90][91][92][93][94][95] These computational models were also integrated in comparative Monte Carlo-based simulations studies investigating patterns of uptake and biodistribution data of radiopharmaceuticals for the purpose of dose estimation in molecular radiotherapy and diagnostic nuclear medical imaging procedures. [96][97][98][99][100][101][102][103][104][105][106][107] For external exposure to ionizing radiation, few studies reported on the calculation of organ dose conversion coefficients for small animals under ideal irradiation conditions (left lateral, right lateral, dorsal-ventral, ventral-dorsal, and isotropic irradiation directions), …”