Bi-specific T1 Positive-contrast-enhanced Magnetic Resonance Imaging Molecular Probe for Hepatocellular Carcinoma in an Orthotopic Mouse Model

Overview

Journal World J Gastrointest Oncol

Publisher Baishideng Publishing Group

Date 2022 May 18

PMID 35582105

Authors

Xiao-Hong Ma

Kun Chen

Shuang Wang

Si-Yun Liu

Deng-Feng Li

Yong-Tao Mi

Zhi-Yuan Wu

Chun-Feng Qu

Xin-Ming Zhao

Affiliations

Soon will be listed here.

Abstract

Background: Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. HCC-targeted magnetic resonance imaging (MRI) is an effective noninvasive diagnostic method that involves targeting clinically-related HCC biomarkers, such as alpha-fetoprotein (AFP) or glypican-3 (GPC3), with iron oxide nanoparticles. However, studies of HCC-targeted MRI utilize single-target iron oxide nanoprobes as negative (T2) contrast agents, which might weaken their future clinical applications due to tumor heterogeneity and negative MRI contrast. Ultra-small superparamagnetic iron oxide (USPIO) nanoparticles (approximately 5 nm) are potential optimal positive (T1) contrast agents. We previously verified the efficiency of AFP/GPC3-double-antibody-labeled iron oxide MR molecular probe .

Aim: To validate the effectiveness of a bi-specific probe for enhancing T1-weighted positive contrast to diagnose the early-stage HCC.

Methods: The single- and double-antibody-conjugated 5-nm USPIO probes, including anti-AFP-USPIO (UA), anti-GPC3-USPIO (UG), and anti-AFP-USPIO-anti-GPC3 (UAG), were synthesized. T1- and T2-weighted MRI were performed on day 10 after establishment of the orthotopic HCC mouse model. Following intravenous injection of U, UA, UG, and UAG probes, T1- and T2-weighted images were obtained at 12, 12, and 32 h post-injection. At the end of scanning, mice were euthanized, and a histologic analysis was performed on tumor samples.

Results: T1- and T2-weighted MRI showed that absolute tumor-to-background ratios in UAG-treated HCC mice peaked at 24 h post-injection, with the T1- and T2-weighted signals increasing by 46.7% and decreasing by 11.1%, respectively, relative to pre-injection levels. Additionally, T1-weighted contrast in the UAG-treated group at 24 h post-injection was enhanced 1.52-, 2.64-, and 4.38-fold compared to those observed for single-targeted anti-GPC3-USPIO, anti-AFP-USPIO, and non-targeted USPIO probes, respectively. Comparison of U-, UA-, UG-, and UAG-treated tumor sections revealed that UAG-treated mice exhibited increased stained regions compared to those observed in UG- or UA-treated mice.

Conclusion: The bi-specific T1-positive contrast-enhanced MRI probe (UAG) for HCC demonstrated increased specificity and sensitivity to diagnose early-stage HCC irrespective of tumor size and/or heterogeneity.

References

Veiseh O, Gunn J, Zhang M . Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliv Rev. 2009; 62(3):284-304. PMC: 2827645. DOI: 10.1016/j.addr.2009.11.002. View

Horvat N, Monti S, Oliveira B, Rocha C, Giancipoli R, Mannelli L . State of the art in magnetic resonance imaging of hepatocellular carcinoma. Radiol Oncol. 2018; 52(4):353-364. PMC: 6287184. DOI: 10.2478/raon-2018-0044. View

Zhao M, Liu Z, Dong L, Zhou H, Yang S, Wu W . A GPC3-specific aptamer-mediated magnetic resonance probe for hepatocellular carcinoma. Int J Nanomedicine. 2018; 13:4433-4443. PMC: 6078089. DOI: 10.2147/IJN.S168268. View

Gao Z, Ma T, Zhao E, Docter D, Yang W, Stauber R . Small is Smarter: Nano MRI Contrast Agents - Advantages and Recent Achievements. Small. 2015; 12(5):556-76. DOI: 10.1002/smll.201502309. View

Yang D, She H, Wang X, Yang Z, Wang Z . Diagnostic accuracy of quantitative diffusion parameters in the pathological grading of hepatocellular carcinoma: A meta-analysis. J Magn Reson Imaging. 2019; 51(5):1581-1593. DOI: 10.1002/jmri.26963. View

Cortajarena A, Ortega D, Ocampo S, Gonzalez-Garcia A, Couleaud P, Miranda R . Engineering Iron Oxide Nanoparticles for Clinical Settings. Nanobiomedicine (Rij). 2018; 1:2. PMC: 6029241. DOI: 10.5772/58841. View

Song Y, Kang Y, Jung H, Kim H, Kang S, Cho H . Lumazine Synthase Protein Nanoparticle-Gd(III)-DOTA Conjugate as a T1 contrast agent for high-field MRI. Sci Rep. 2015; 5:15656. PMC: 4616051. DOI: 10.1038/srep15656. View

Choi M, Choi J, Lee Y, Park M, Eun Rha S, Lall C . MRI of Small Hepatocellular Carcinoma: Typical Features Are Less Frequent Below a Size Cutoff of 1.5 cm. AJR Am J Roentgenol. 2016; 208(3):544-551. DOI: 10.2214/AJR.16.16414. View

Kandasamy G, Maity D . Recent advances in superparamagnetic iron oxide nanoparticles (SPIONs) for in vitro and in vivo cancer nanotheranostics. Int J Pharm. 2015; 496(2):191-218. DOI: 10.1016/j.ijpharm.2015.10.058. View

10.

Smolensky E, Park H, Zhou Y, Rolla G, Marjanska M, Botta M . Scaling Laws at the Nano Size: The Effect of Particle Size and Shape on the Magnetism and Relaxivity of Iron Oxide Nanoparticle Contrast Agents. J Mater Chem B. 2013; 1(22):2818-2828. PMC: 3695630. DOI: 10.1039/C3TB00369H. View

11.

Chauhan R, Lahiri N . Tissue- and Serum-Associated Biomarkers of Hepatocellular Carcinoma. Biomark Cancer. 2016; 8(Suppl 1):37-55. PMC: 4933537. DOI: 10.4137/BIC.S34413. View

12.

Vavricka S, Jung D, Fried M, Grutzner U, Meier P, Kullak-Ublick G . The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. J Hepatol. 2004; 40(2):212-8. DOI: 10.1016/j.jhep.2003.10.008. View

13.

Huang K, Chieh J, Horng H, Hong C, Yang H . Characteristics of magnetic labeling on liver tumors with anti-alpha-fetoprotein-mediated Fe3O4 magnetic nanoparticles. Int J Nanomedicine. 2012; 7:2987-96. PMC: 3392145. DOI: 10.2147/IJN.S30061. View

14.

Li W, Xiao X, Li X, Xu Y, Ma L, Guo L . Detecting GPC3-Expressing Hepatocellular Carcinoma with L5 Peptide-Guided Pretargeting Approach: In Vitro and In Vivo MR Imaging Experiments. Contrast Media Mol Imaging. 2018; 2018:9169072. PMC: 6151370. DOI: 10.1155/2018/9169072. View

15.

Zhang C, Liu H, Cui Y, Li X, Zhang Z, Zhang Y . Molecular magnetic resonance imaging of activated hepatic stellate cells with ultrasmall superparamagnetic iron oxide targeting integrin αvβ₃ for staging liver fibrosis in rat model. Int J Nanomedicine. 2016; 11:1097-108. PMC: 4807947. DOI: 10.2147/IJN.S101366. View

16.

Leonhardt M, Keiser M, Oswald S, Kuhn J, Jia J, Grube M . Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos. 2010; 38(7):1024-8. DOI: 10.1124/dmd.110.032862. View

17.

Feng Q, Liu Y, Huang J, Chen K, Huang J, Xiao K . Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings. Sci Rep. 2018; 8(1):2082. PMC: 5794763. DOI: 10.1038/s41598-018-19628-z. View

18.

Zhou Z, Lu Z . Gadolinium-based contrast agents for magnetic resonance cancer imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2012; 5(1):1-18. PMC: 3552562. DOI: 10.1002/wnan.1198. View

19.

Mu K, Zhang S, Ai T, Jiang J, Yao Y, Jiang L . Monoclonal antibody-conjugated superparamagnetic iron oxide nanoparticles for imaging of epidermal growth factor receptor-targeted cells and gliomas. Mol Imaging. 2015; 14. DOI: 10.2310/7290.2015.00002. View

20.

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View