Design and development of hepatocyte-specific MnFe2O4-EOB-PEG nanocontrast agent and magnetic resonance hepatobiliary imaging. (Photo courtesy of Fan Haiming’s research group)
Recently, Professor Haiming Fan’s research group from the School of Chemistry and Materials Science of Northwest University has made important progress in the research of liver-specific nanocontrast agents and magnetic resonance hepatobiliary imaging, and the relevant results are titled “A Hepatocyte-targeting Nanoparticle for Enhanced Hepatobiliary Magnetic Resonance Imaging”. Published online on December 19, 2022 in the journal Nature Biomedical Engineering, this is Northwestern’s first paper in the journal. This work not only provides a new strategy for the design of nanocontrast agents with high affinity and high specificity, but also provides new imaging diagnostic tools for the early detection of liver cancer.
Liver cancer, including primary hepatocellular carcinoma and cholangiocarcinoma, is the most common and highly fatal liver malignancy in the world. According to the latest statistics, the number of cases of liver cancer in China ranks first in the world, and the overall survival rate of 5 years is only 14.1%, and the prevention and treatment situation is still very grim. Early diagnosis of liver cancer is the key to improving its survival rate and prognosis. Different from other cancers, liver cancer is the only malignant tumor that can be clinically diagnosed by imaging, and magnetic resonance hepatobiliary imaging is considered to be the most sensitive imaging diagnostic method for liver cancer, among which the sensitivity and specificity of hepatocyte-specific contrast agents determine the effect of enhanced magnetic resonance imaging on the diagnosis of early liver cancer. However, the currently clinically applied hepatocyte-specific contrast agents (mainly disodium gadolinated setecate, Gd-EOB-DTPA) have low signal enhancement, insufficient specificity and affinity, resulting in the inability to qualitatively detect small lesions of early liver cancer less than 1cm, which is difficult to meet the needs of accurate diagnosis of early liver cancer.
Recent studies have found that ultra-small ferrites with a size of less than 5 nm can exhibit T1 relaxation enhancement and high T1/T2 ratio that are completely different from traditional ultraparamagnetic iron oxide nanoparticles due to their significant small size effects, and are expected to construct high-performance hepatocyte-specific nanocontrast agents. However, the reported T1 relaxation rate of ultra-small iron oxide contrast medium is only 4.6 mM-1s-1, which has no advantage over clinical gadolinium-based contrast media. It is difficult to optimize its performance due to the limitations of small size controllable preparation and the lag in the development of nanocontrast agent relaxation enhancement theory (Materials Today Advances, 2020; Progress in Biomedical Engineering 2022).
In view of the above problems, Fan Haiming’s research group proposed a dynamic synchronous thermal decomposition method for the first time through systematic in-depth research, realized the macro preparation of ultra-small ferrite nanomaterials with high monodisperse and controllable size, and constructed an ultra-small manganese ferrite T1 nanocontrast agent (ACS Nano, 2017), which achieved high-resolution magnetic resonance imaging of systemic metastases of breast cancer in living mice by coupling targeted peptides, and effectively detected submillimeter-level tumor lesions (0.4 mm) (Advanced). Materials, 2019) 。 The research group further revealed the quasiparamagnetic new structure of ultra-small ferrite nanoparticles in the core/shell type, elucidated the synergistic enhancement mechanism of T1 relaxation of inner and outer spheres caused by this structure, and improved the relaxation enhancement theory of ultra-small nano-contrast agents (Nano Letters, 2021; Progress in Pharmacy, 2021). In particular, it was discovered that manganese ions on the surface of ultra-small manganese ferrite nanocontrast agents can mediate liver-specific imaging (Theranostics, 2019), which laid an important foundation for the construction of high-performance hepatocyte-specific contrast agents.
On the basis of the previous series of studies, the researchers in our group designed a new, dual-target hepatocyte-specific quasiparamagnetic ultra-small manganese ferrite nanocontrast agent (MnFe2O4-EOB-PEG) (Nat. Biomed. Eng. 2022）。 The contrast agent can be efficiently bound to the two receptors SLC39A14 and OATP1 of hepatocytes, specifically target hepatocytes, and use the characteristics of high expression of both receptors in normal hepatocytes and low expression of tumor cells to achieve accurate imaging detection of small lesions of early liver cancer (Figure). The results showed that the Mn ions on the surface of MnFe2O4 nanoparticles and the ethoxybenzene (EOB) ligand modified on their surface could achieve the dual target synergistic targeting effect on hepatocytes SLC39A14 and OATP1, significantly improving the specificity and affinity, and the specific distribution of hepatocytes could be as high as 70.59% in vivo (pig) experiments. Compared with clinical Gd-EOB-DTPA, MnFe2O4-EOB-PEG enhanced liver contrast by 5.8 times and could resolve 0.5 mm liver ducts with high definition. At the same time, the imaging speed of liver parenchyma and bile ducts has also increased by more than 2 times, which significantly reduces the detection time of patients and improves the examination efficiency. In vivo liver cancer imaging results showed that MnFe2O4-EOB-PEG increased the detection rate of microcarcinoma lesions (< 0.5 cm) from 48% (Gd-EOB-DTPA) to 92%. In addition, the contrast agent can clearly determine the location and degree of biliary obstruction, which is expected to be used for noninvasive bile duct imaging. The preliminary non-clinical GLP evaluation and the safety evaluation results of large animals showed that MnFe2O4-EOB-PEG had good safety, could be quickly cleared by liver and kidney, and the 7-day residual rate was less than 1%, which had excellent clinical transformation potential. In summary, the new hepatocyte-specific quasi-magnetic nanocontrast agent designed with dual targets provides a new imaging diagnostic tool for the early detection of liver cancer.
Professor Fan Haiming’s research group (http://www.fanlab.cn/) has long focused on the research of medical magnetic nanomaterials and their diagnosis and treatment applications, and is committed to designing efficient and safe new medical nanomagnetic materials, developing matching magnetic diagnosis and treatment equipment, and creating new technologies and methods for precision magnetic diagnosis and treatment. Dr. Huan Zhang of Northwest University, Professor Yingkun Guo of West China Second Hospital of Sichuan University and Associate Professor Jiao Ju of the Third Affiliated Hospital of Sun Yat-sen University are co-first authors of the research paper, Professor Haiming Fan is the corresponding author, and Professor Boon-Huat Bay of the Yeung Loo Lin School of Medicine, National University of Singapore as a collaborator gave guidance and assistance in tumor molecular biology, and the research was supported by the National Natural Science Foundation of China and the China Postdoctoral Science Foundation. (Source: Yan Tao, China Science News)
Related paper information:https://doi.org/10.1038/s41551-022-00975-2