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Development And In Vitro Study Of A Bi-specific Magnetic Resonance Imaging Molecular Probe For Hepatocellular Carcinoma

X. Ma, S. Wang, Si-Yun Liu, K. Chen, Z. Wu, Dengfeng Li, Yongtao Mi, Long-Bin Hu, Z. Chen, X. Zhao
Published 2019 · Chemistry, Medicine

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BACKGROUND Hepatocellular carcinoma (HCC) ranks second in terms of cancer mortality worldwide. Molecular magnetic resonance imaging (MRI) targeting HCC biomarkers such as alpha-fetoprotein (AFP) or glypican-3 (GPC3) offers new strategies to enhance specificity and help early diagnosis of HCC. However, the existing iron oxide nanoparticle-based MR molecular probes singly target AFP or GPC3, which may hinder their efficiency to detect heterogeneous micro malignant HCC tumors < 1 cm (MHCC). We hypothesized that the strategy of double antibody-conjugated iron oxide nanoparticles which simultaneously target AFP and GPC3 antigens may potentially be used to overcome the tumor heterogeneity and enhance the detection rate for MRI-based MHCC diagnosis. AIM To synthesize an AFP/GPC3 double antibody-labeled iron oxide MRI molecular probe and to assess its impact on MRI specificity and sensitivity at the cellular level. METHODS A double antigen-targeted MRI probe for MHCC anti-AFP–USPIO–anti-GPC3 (UAG) was developed by simultaneously conjugating AFP andGPC3 antibodies to a 5 nm ultra-small superparamagnetic iron oxide nanoparticle (USPIO). At the same time, the singly labeled probes of anti-AFP–USPIO (UA) and anti-GPC3–USPIO (UG) and non-targeted USPIO (U) were also prepared for comparison. The physical characterization including morphology (transmission electron microscopy), hydrodynamic size, and zeta potential (dynamic light scattering) was conducted for each of the probes. The antigen targeting and MRI ability for these four kinds of USPIO probes were studied in the GPC3-expressing murine hepatoma cell line Hepa1-6/GPC3. First, AFP and GPC3 antigen expression in Hepa1-6/GPC3 cells was confirmed by flow cytometry and immunocytochemistry. Then, the cellular uptake of USPIO probes was investigated by Prussian blue staining assay and in vitro MRI (T2-weighted and T2-map) with a 3.0 Tesla clinical MR scanner. RESULTS Our data showed that the double antibody-conjugated probe UAG had the best specificity in targeting Hepa1-6/GPC3 cells expressing AFP and GPC3 antigens compared with single antibody-conjugated and unconjugated USPIO probes. The iron Prussian blue staining and quantitative T2-map MRI analysis showed that, compared with UA, UG, and U, the uptake of double antigen-targeted UAG probe demonstrated a 23.3% (vs UA), 15.4% (vs UG), and 57.3% (vs U) increased Prussian stained cell percentage and a 14.93% (vs UA), 9.38% (vs UG), and 15.3% (vs U) reduction of T2 relaxation time, respectively. Such bi-specific probe might have the potential to overcome tumor heterogeneity. Meanwhile, the coupling of two antibodies did not influence the magnetic performance of USPIO, and the relatively small hydrodynamic size (59.60 ± 1.87 nm) of double antibody-conjugated USPIO probe makes it a viable candidate for use in MHCC MRI in vivo, as they are slowly phagocytosed by macrophages. CONCLUSION The bi-specific probe presents enhanced targeting efficiency and MRI sensitivity to HCC cells than singly- or non-targeted USPIO, paving the way for in vivo translation to further evaluate its clinical potential.
This paper references
10.5152/dir.2014.13370
MRI of hepatocellular carcinoma: an update of current practices.
Hina Arif-Tiwari (2014)
Version of LI-RADS for CT and MR
RK Do (2017)
10.2147/IJN.S55118
Superparamagnetic iron oxide nanoparticles conjugated with epidermal growth factor (SPION–EGF) for targeting brain tumors
M. Shevtsov (2014)
10.18632/oncotarget.15642
Theranostic imaging of liver cancer using targeted optical/MRI dual-modal probes
Q. Chen (2017)
Cancer statistics in China
W Chen (2015)
10.5772/58841
Engineering Iron Oxide Nanoparticles for Clinical Settings
Aitziber L. Cortajarena (2014)
10.2217/17435889.3.5.703
Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats.
M. Longmire (2008)
10.1038/s41598-018-19628-z
Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings
Qiyi Feng (2018)
10.2147/IJN.S30061
Characteristics of magnetic labeling on liver tumors with anti-alpha-fetoprotein-mediated Fe3O4 magnetic nanoparticles
K. Huang (2012)
10.3748/WJG.V16.I4.418
Present and future possibilities for early diagnosis of hepatocellular carcinoma.
P. Stefaniuk (2010)
10.3748/wjg.v21.i14.4275
Preparation of magnetic resonance probes using one-pot method for detection of hepatocellular carcinoma.
You-wei Li (2015)
10.3390/ijms19010205
Biodistribution and Clearance of Stable Superparamagnetic Maghemite Iron Oxide Nanoparticles in Mice Following Intraperitoneal Administration
B. Pham (2018)
10.4137/BIC.S34413
Tissue- and Serum-Associated Biomarkers of Hepatocellular Carcinoma
R. Chauhan (2016)
10.2310/7290.2015.00002
Monoclonal Antibody–Conjugated Superparamagnetic Iron Oxide Nanoparticles for Imaging of Epidermal Growth Factor Receptor–Targeted Cells and Gliomas
Ketao Mu (2015)
10.2147/IJN.S139011
Double-receptor-targeting multifunctional iron oxide nanoparticles drug delivery system for the treatment and imaging of prostate cancer
Md Shakir Uddin Ahmed (2017)
10.1148/radiol.2017162759
Ten Things You Might Not Know about Iron Oxide Nanoparticles
H. Daldrup-Link (2017)
10.1016/j.addr.2009.11.002
Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging.
O. Veiseh (2010)
10.3748/wjg.v21.i37.10573
Biomarkers for the early diagnosis of hepatocellular carcinoma.
Nobuhiro Tsuchiya (2015)
10.3892/ijmm.2016.2744
MRI contrast agents: Classification and application (Review).
Yu-dong Xiao (2016)
10.1111/febs.12126
Glypican‐3: a marker and a therapeutic target in hepatocellular carcinoma
J. Filmus (2013)
Hepatocellular carcinoma : the potential for an effective genetic screening test
T Richards
10.1002/ijc.29210
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012
J. Ferlay (2015)
10.3892/ol.2017.7313
Study on the diagnosis of small hepatocellular carcinoma caused by hepatitis B cirrhosis via multi-slice spiral CT and MRI.
M. Wang (2018)
10.2147/IJN.S101366
Molecular magnetic resonance imaging of activated hepatic stellate cells with ultrasmall superparamagnetic iron oxide targeting integrin αvβ3 for staging liver fibrosis in rat model
Caiyuan Zhang (2016)
Specific detection of CD 133-positive tumor cells with iron oxide nanoparticles labeling using noninvasive molecular magnetic resonance imaging
Y. Chen (2015)
Immunization with glypican-3 nanovaccine containing TLR7 agonist prevents the development of carcinogen-induced precancerous hepatic lesions to cancer in a murine model.
K. Chen (2018)
10.2147/IJN.S168268
A GPC3-specific aptamer-mediated magnetic resonance probe for hepatocellular carcinoma
Menglong Zhao (2018)
10.1016/j.tiv.2018.09.018
Differential effect of polyvinylpyrrolidone-coated superparamagnetic iron oxide nanoparticles on BT-474 human breast cancer cell viability.
M. Aliakbari (2019)
10.2147/IJN.S86592
Specific detection of CD133-positive tumor cells with iron oxide nanoparticles labeling using noninvasive molecular magnetic resonance imaging
Y. Chen (2015)
10.3322/caac.21338
Cancer statistics in China, 2015
W. Chen (2016)
10.1089/biores.2016.0020
Prospective Preliminary In Vitro Investigation of a Magnetic Iron Oxide Nanoparticle Conjugated with Ligand CD80 and VEGF Antibody As a Targeted Drug Delivery System for the Induction of Cell Death in Rodent Osteosarcoma Cells
AnneMarie Kay Kovach (2016)
10.2147/JHC.S116513
GPC-3 in hepatocellular carcinoma: current perspectives
Y. Wu (2016)
10.1016/j.biomaterials.2016.10.011
MRI/optical dual-modality imaging of vulnerable atherosclerotic plaque with an osteopontin-targeted probe based on Fe3O4 nanoparticles.
Hongyu Qiao (2017)
10.2147/IJN.S32196
Preparation and in vitro studies of MRI-specific superparamagnetic iron oxide antiGPC3 probe for hepatocellular carcinoma
Youwei Li (2012)
10.1517/17425247.2014.924501
Superparamagnetic iron oxide nanoparticles for delivery of therapeutic agents: opportunities and challenges
S. Laurent (2014)
10.1148/rg.2017170098
2017 Version of LI-RADS for CT and MR Imaging: An Update.
K. Elsayes (2017)



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