Synthesis and biological evaluation of 2.4 nm thiolate-protected gold nanoparticles conjugated to Cetuximab for targeting glioblastoma cancer cells via the EGFR.

Published on May 3, 2019in Nanotechnology3.551
· DOI :10.1088/1361-6528/AAFF0A
Nadja Groysbeck2
Estimated H-index: 2
(UDS: University of Strasbourg),
Audrey Stoessel5
Estimated H-index: 5
(UDS: University of Strasbourg)
+ 6 AuthorsGuy Zuber26
Estimated H-index: 26
(UDS: University of Strasbourg)
: Therapeutic monoclonal antibodies benefit to patients and the conjugation to gold nanoparticles (AuNPs) might bring additional activities to these macromolecules. However, the behavior of the conjugate will largely depend on the bulkiness of the AuNP and small sizes are moreover preferable for diffusion. Water-soluble thiolate-protected AuNPs having diameters of 2-3 nm can be synthesized with narrow polydispersity and can selectively react with incoming organic thiols via a SN2-like mechanism. We therefore synthesized a mixed thionitrobenzoic acid- , thioaminobenzoic acid-monolayered AuNP of 2.4 nm in diameter and developed a site-selective conjugation strategy to link the AuNP to Cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody used in clinic. The water-soluble 80 kDa AuNP was fully characterized and then reacted to the hinge area of Cetuximab, which was selectively reduced using mild concentration of TCEP. The conjugation proceeded smoothly and could be analyzed by polyacrylamide gel electrophoresis, indicating the formation of a 1:1 AuNP-IgG conjugate as the main product. When added to EGFR expressing glioblastoma cells, the AuNP-Cetuximab conjugate selectively bound to the cell surface receptor, inhibited EGFR autophosphorylation and entered into endosomes like Cetuximab. Altogether, we describe a simple and robust protocol for a site-directed conjugation of a thiolate-protected AuNP to Cetuximab, which could be easily monitored, thereby allowing to assess the quality of the product formation. The conjugated 2.4 nm AuNP did not majorly affect the biological behavior of Cetuximab, but provided it with the electronic properties of the AuNP. This offers the ability to detect the tagged antibody and opens application for targeted cancer radiotherapy.
Figures & Tables
📖 Papers frequently viewed together
64 Citations
201414.59ACS Nano
4 Authors (Ung Yeol Lee, ..., Eun Seong Lee)
37 Citations
21 Citations
#1Alexander Yu. Polyakov (MSU: Moscow State University)H-Index: 7
#1Alexander Yu. Polyakov (MSU: Moscow State University)H-Index: 7
Last. Eugene A. Goodilin (MSU: Moscow State University)H-Index: 25
view all 8 authors...
: Composites of WS2 nanotubes (NT-WS2 ) and gold nanoparticles (AuNPs) were prepared using aqueous HAuCl4 solutions and subjected to surface analysis. The obtained materials were jointly characterized by X-ray photoelectron (XPS), Raman scattering (RSS), and ultraviolet photoelectron (UPS) spectroscopies. Optical extinction spectroscopy and electron energy loss spectroscopy in the scanning transmission electron microscopy regime (STEM-EELS) were also employed to study plasmon features of the nan...
16 CitationsSource
#2Mojtaba Abbasian (PNU: Payame Noor University)H-Index: 18
Last. Elnaz Bagherzadeh-Khajehmarjan (University of Tabriz)H-Index: 2
view all 5 authors...
Abstract The chemo-photothermal therapy performance of a novel theranostic nanoparticles that fabricated through the conjugation of HS–poly(e-caprolactone)-block-poly(N-isopropylacrylamide)-block-poly(acrylic acid) (HS-PCL-b-PNIPAAm-b-PAA) and gold nanoparticles (GNPs) was extensively investigated. The GNPs@polymer conjugate theranostic NPs was loaded with doxorubicin hydrochloride (DOX) as an anticancer drug through electrostatic interactions to afford GNPs@polymer-DOX theranostic nanomedicine....
18 CitationsSource
Abstract In this study, internalization of positively charged chitosan-coated nanoparticles (198AuNPs@chitosan) on MCF-7 cells was investigated by γ-ray spectroscopy and then statistically compared to that of 198Au and negatively charged citrate-stabilized nanoparticles (198AuNPs). Sub-50 nm 198AuNPs@chitosan had a higher internalization compared to 198Au and 198AuNPs (p
6 CitationsSource
#1Lisa E. Cole (ND: University of Notre Dame)H-Index: 8
#2Tracie L. McGinnity (ND: University of Notre Dame)H-Index: 4
Last. Ryan K. Roeder (ND: University of Notre Dame)H-Index: 30
view all 5 authors...
Abstract A preclinical murine model of hydroxyapatite (HA) breast microcalcifications (µcals), which are an important clinical biomarker for breast cancer detection, was used to investigate the independent effects of high affinity bisphosphonate (BP) ligands and a polyethylene glycol (PEG) spacer on targeted delivery of gold nanoparticles (Au NPs) for contrast-enhanced radiographic detection. The addition of BP ligands to PEGylated Au NPs (BP-PEG-Au NPs) resulted in five-fold greater binding aff...
11 CitationsSource
#1Jihye Choi (Stanford University)H-Index: 20
#2Kyung Oh Jung (Stanford University)H-Index: 7
Last. Guillem Pratx (Stanford University)H-Index: 29
view all 4 authors...
Gold nanoparticles (AuNPs) are known to sensitize cancer cells to radiation therapy (RT) by increasing the deposition of ionizing energy in their immediate vicinity. However, this process of dose enhancement is challenging to monitor because it is heterogeneous at the sub-cellular scale. Furthermore, radiation damage is primarily mediated by reactive oxygen species (ROS) that are produced following water radiolysis. Here, radiation-responsive PEGylated gold nanoparticles (RPAuNPs) were synthesiz...
13 CitationsSource
#1Dominique Desplancq (UDS: University of Strasbourg)H-Index: 12
#2Nadja GroysbeckH-Index: 2
Last. Guy Zuber (UDS: University of Strasbourg)H-Index: 26
view all 15 authors...
For biological and medical applications, a definable nanomaterial and knowledge on its fate after administration are highly recommended if not mandatory. Here, we synthesized a water-soluble gold nanocluster by sodium borohydride reduction of chloroauric acid in the presence of 5,5′-dithio-bis(2-nitrobenzoic acid). The resulting gold nanocluster displayed the physical characteristics of a cluster containing an inner core of about 100 gold atoms that was surrounded by an organic monolayer made of...
4 CitationsSource
#1Xin Ma (UM: University of Macau)H-Index: 2
#2Yunfang Xiong (UM: University of Macau)H-Index: 1
Last. Leo T. O. Lee (UM: University of Macau)H-Index: 18
view all 3 authors...
Nanoparticles (NPs) have attracted unequivocal attention in recent years due to their potential applications in therapeutics, bio-imaging and material sciences. For drug delivery, NP-based carrier systems offer several advantages over conventional methods. When conjugated with ligands and drugs (or other therapeutic molecules), administrated NPs are able to deliver cargo to targeted sites through ligand-receptor recognition. Such targeted delivery is especially important in cancer therapy. Throu...
20 CitationsSource
#1Nadda Muhamad (Hodges University)H-Index: 1
#2Tullayakorn Plengsuriyakarn (Hodges University)H-Index: 8
Last. Kesara Na-Bangchang (Hodges University)H-Index: 1
view all 3 authors...
Patients treated with conventional cancer chemotherapy suffer from side effects of the drugs due to non-selective action of chemotherapeutic drugs to normal cells. Active targeting nanoparticles that are conjugated to targeting ligands on the surface of nanoparticles play an important role in improving drug selectivity to the cancer cell. Several chemotherapeutic drugs and traditional/herbal medicines reported for anticancer activities have been investigated for their selective delivery to cance...
129 CitationsSource
#1Selma M. H. Al-Jawad (University of Technology, Iraq)H-Index: 10
#2Ali A. Taha (University of Technology, Iraq)H-Index: 9
Last. Lamyaa F. A. AL-BarramH-Index: 2
view all 4 authors...
: In the present study, small gold nanoparticles <5 nm coated with natural protein Bovine Serum Albumin (BSA) was synthesized and characterized using UV-vis spectrophotometer, Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), zeta potential and scanning electron microscopy (SEM). Three types of cancer cell lines; Rhabdomyosarcoma (RD), Murine fibroblast (L20B) and RAW 264.7 monocyte-macrophage (MQ) were tested and treated by photothermal strategy, in vitro, by conjugating B...
26 CitationsSource
#1Manuela Chiper (UDS: University of Strasbourg)H-Index: 14
#2Karen Niederreither (UDS: University of Strasbourg)H-Index: 5
Last. Guy Zuber (UDS: University of Strasbourg)H-Index: 26
view all 3 authors...
: The human organism and its constituting cells rely on interplay between multiple proteins exerting specific functions. Progress in molecular biotechnologies has facilitated the production of recombinant proteins. When administrated to patients, recombinant proteins can provide important healthcare benefits. To date, most therapeutic proteins must act from the extracellular environment, with their targets being secreted modulators or extracellular receptors. This is because proteins cannot pass...
12 CitationsSource
Cited By10
#1Guillaume F. Combes (University of Split)
#2Ana-Marija Vučković (University of Split)
Last. Katarina Trajković (University of Split)H-Index: 1
view all 0 authors...
Cancer is one of the leading causes of premature death, and, as such, it can be prevented by developing strategies for early and accurate diagnosis. Cancer diagnostics has evolved from the macroscopic detection of malignant tissues to the fine analysis of tumor biomarkers using personalized medicine approaches. Recently, various nanomaterials have been introduced into the molecular diagnostics of cancer. This has resulted in a number of tumor biomarkers that have been detected in vitro and in vi...
#2Ting WangH-Index: 2
Last. Wenliang LiH-Index: 21
view all 7 authors...
#1Ralph El Hallal (Macquarie University)
#2Nana Lyu (Macquarie University)
Last. Yuling Wang (Macquarie University)
view all 3 authors...
Epidermal growth factor receptor (EGFR) is estimated to be overexpressed in 60~80% of colorectal cancer (CRC), which is associated with a poor prognosis. Anti-EGFR targeted monoclonal antibodies (cetuximab and panitumumab) have played an important role in the treatment of metastatic CRC. However, the therapeutic response of anti-EGFR monoclonal antibodies is limited due to multiple resistance mechanisms. With the discovery of new functions for gold nanoparticles (AuNPs), we hypothesize that cetu...
Last. Devegowda Vishakante Gowda (Jagadguru Sri Shivarathreeswara University)H-Index: 8
view all 8 authors...
A paradigm shift in treating the most aggressive and malignant form of glioma is continuously evolving; however, these strategies do not provide a better life and survival index. Currently, neurosurgical debulking, radiotherapy, and chemotherapy are the treatment options available for glioma, but these are non-specific in action. Patients invariably develop resistance to these therapies, leading to recurrence and death. Receptor Tyrosine Kinases (RTKs) are among the most common cell surface prot...
2 CitationsSource
#1Zhiguang Wang (Xi'an Jiaotong University)H-Index: 1
#2Jianyu Dong (Southern Medical University)H-Index: 1
Last. Shanshan JiangH-Index: 6
view all 10 authors...
Paclitaxel is a potent antineoplastic agent, but poor solubility and resistance have limited its use. Gold nanoparticles (AuNPs) are widely studied as drug carriers because they can be engineered to prevent drug insolubility, carry nucleic acid payloads for gene therapy, target specific tumor cell lines, modulate drug release and amplify photothermal therapy. Consequently, the conjugation of paclitaxel with AuNPs to improve antiproliferative and pro‑apoptotic potency may enable improved clinical...
4 CitationsSource
#1Danièle SpehnerH-Index: 35
#2Anna M. Steyer (MPG: Max Planck Society)H-Index: 9
Last. Patrick SchultzH-Index: 48
view all 8 authors...
Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM) is an invaluable tool to visualize the 3D architecture of cell constituents and map cell networks. Recently, amorphous ice embedding techniques have been associated with FIB-SEM to ensure that the biological material remains as close as possible to its native state. Here we have vitrified human HeLa cells and directly imaged them by cryo-FIB-SEM with the secondary electron InLens detector at cryogenic temperature and without any staining. I...
9 CitationsSource
#1Mohammad Norouzi (UdeM: Université de Montréal)H-Index: 2
#1Mohammad Norouzi (UdeM: Université de Montréal)H-Index: 16
Abstract Despite many endeavors to treat malignant gliomas in the last decades, the median survival of patients has not significantly improved. The infiltrative nature of high-grade gliomas and the impermeability of the blood-brain barrier to the most therapeutic agents remain major hurdles, impeding an efficacious treatment. Theranostic platforms bridging diagnosis and therapeutic modalities aim to surmount the current limitations in diagnosis and therapy of glioma. Gold nanoparticles (AuNPs) d...
13 CitationsSource
#1Lídia M. Andrade (UFMG: Universidade Federal de Minas Gerais)H-Index: 10
#2Estefânia Mara do Nascimento Martins (UFMG: Universidade Federal de Minas Gerais)H-Index: 8
Last. Luiz O. Ladeira (UFMG: Universidade Federal de Minas Gerais)H-Index: 3
view all 9 authors...
Abstract Nanotechnology is one of the most promising tools for future diagnosis and therapy. Thus, we have produced gold nanoparticles coated with cetuximab at a dose-range from 5 μg up to 200 μg, and prolonged stable nanocomplexes were obtained. The nanocomplexes were characterized by UV-Vis, zeta potential, TEM, fluorometry, infrared regions, XPS and atomic absorption spectrometry. For biological characterization the A431 cell line was used. Cellular uptake, target affinity and cell death were...
5 CitationsSource
#1Steven Zanganeh (Kettering University)H-Index: 3
#2Petrina Georgala (Kettering University)H-Index: 1
Last. Morteza Mahmoudi (MSU: Michigan State University)H-Index: 85
view all 16 authors...
: Patients diagnosed with glioblastoma have poor prognosis. Conventional treatment strategies such as surgery, chemotherapy, and radiation therapy demonstrated limited clinical success and have considerable side effects on healthy tissues. A central challenge in treating brain tumors is the poor permeability of the blood-brain barrier (BBB) to therapeutics. Recently, various methods based on immunotherapy and nanotechnology have demonstrated potential in addressing these obstacles by enabling pr...
8 CitationsSource
#1Siyu Guan (Anhui Medical University)H-Index: 3
#2Qianqian Zhang (Anhui Medical University)H-Index: 3
Last. Jihui Tang (Anhui Medical University)H-Index: 4
view all 6 authors...
BACKGROUND: Target-homing drug delivery systems are now gaining significant traction for use as novel therapeutic approaches in antitumor targeting for cancer therapy. Numerous targeted drug delivery systems have been designed to improve the targeting effects because these systems can display a range of favorable properties. Thus, providing suitable characteristics for clinical applicability of anticancer drugs, such as increasing the solubility, and improving the drug distribution at target sit...
4 CitationsSource