Molecular Targeting Radiotherapy with Cyclo-RGDfK(C) Peptides Conjugated to ¹⁷⁷Lu-Labeled Gold Nanoparticles in Tumor-Bearing Mice

Abstract

Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been designed to antagonize the function of alpha(v)beta(3) integrin, thereby inhibiting angiogenesis. The conjugation of RGD peptides to radiolabeled gold nanoparticles (AuNP) produces biocompatible and stable multimeric systems with target-specific molecular recognition. The aim of this research was to evaluate the therapeutic response of 177Lu-AuNP-RGD in athymic mice bearing alpha(v)beta(3)-integrin-positive C6 gliomas and compare it with that of 177Lu-AuNP or 177Lu-RGD. The radiation absorbed dose, metabolic activity (SUV, [18F]fluor-deoxy-glucose-microPET/CT), histological characteristics and VEGF gene expression (by real-time polymerase chain reaction) in tumor tissues following treatment with 177Lu-AuNP-RGD, 177Lu-AuNP or 177Lu-RGD were assessed. Of the radiopharmaceuticals evaluated, 1177Lu-AuNP-RGD delivered the highest tumor radiation absorbed dose (63.8 +/- 7.9 Gy). These results correlated with the observed therapeutic response, in which 177Lu-AuNP-RGD significantly (p < 0.05) induced less tumor progression, less tumor metabolic activity, fewer intratumoral vessels and less VEGF gene expression than the other radiopharmaceuticals, a consequence of high tumor retention and a combination of molecular targeting therapy (multimeric RGD system) and radiotherapy (177Lu). There was a low uptake in non-target organs and no induction of renal toxicity. 177Lu-labeled gold nanoparticles conjugated to cyclo-RGDfK(C) demonstrate properties suitable for use as an agent for molecular targeting radiotherapy.

RGD-conjugated mesoporous silica-encapsulated gold nanorods enhance the sensitization of triple-negative breast cancer to megavoltage radiation therapy

“…Ultimately, we conjugated RGD peptides to the terminal PEG groups on GNRs@mSiO 2 , and cyclic RGDfC (c(RGDfC)) peptides were chosen based on the rigidity and variety of possible chemical modifications. Recently, studies have been published on the application of RGD-conjugated GNPs (RGD-GNPs) in radiotherapy, 25,26 and our previous studies demonstrated that RGD-modified gold nanorods (RGD-GNRs) markedly enhanced the radiosensitization of melanoma cells by downregulating α v β 3 expression in vitro. 27,28 In this study, we selected the MDA-MB-231 TNBC cell line as the model system and investigated the radiosensitizing effects of RGD-conjugated mesoporous silica-encapsulated gold nanorods (pGNRs@mSiO 2 -RGD) multifunctional nanoprobes in response to megavoltage RT energy both in vitro and in vivo.…”

Efficient Uptake of 177Lu‐Porphyrin‐PEG Nanocomplexes by Tumor Mitochondria for Multimodal‐Imaging‐Guided Combination Therapy

“…[6] As such, 177 Lu promises to benefit nanoparticle-mediated combination therapy.Previous studies explored 177 Lu-labeled gold nanoparticles for preclinical nuclear medicine. [7] However,t he clinical translation of the reported nanosystem was impeded because of high and long-term accumulation in the reticuloendothelial system (RES) and low intratumor uptake.T hus,i tr emains ab ig challenge to integrate nanocarrier tumor-targeted delivery and multi-modal imaging using 177 Lu to obtain an anotheranostic agent with high efficiacy.…”

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

“…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]. …”