Liver cancer is globally the most common, highly lethal liver malignancies. My liver cancer incidence in the world, and the 5-year overall survival rate of only 14. 1% of the combat situation is very grim.Liver cancer early diagnosis is to enhance their survival rate and improve the prognosis of the key.With his cancer is different, liver cancer is only through the image for the clinical diagnosis of malignant tumors, and magnetic resonance hepatobiliary imaging is considered to be the most sensitive liver cancer diagnostic imaging means, wherein the hepatocyte-specific contrast agent sensitivity and specificity of the decision-enhanced magnetic resonance imaging for early cancer diagnosis. The current clinical application of hepatocyte-specific contrast agent, mainly for gadolinium plug acid disodium, Gd-EOB-DTPA signal enhancement is low, the specificity and Affinity is insufficient, which leads to less than 1cm of early liver cancer small lesions are difficult to qualitative detection of 1-2cm lesion detection rate of only 47% and at this time of liver cancer often has happened to liver metastasis, and it is difficult to meet early liver cancer accurate diagnosis of needs.

A recent study found that the size of less than 5nm ultra-small ferrite due to its significantly smaller size of the effect can be demonstrated with conventional superparamagnetic iron oxide nanoparticles distinct T1 relaxation enhancement and high T1/T2 ratio and other characteristics, is expected to build a high-performance hepatocyte-specific Nano-contrast agent. However, it has been reported that the ultra-small iron oxide contrast agent in the T1 relaxation rate of only 4. 6mM^-1s^-1With the clinical gadolinium-based contrast agent compared to the signal enhancement and no advantage; and by the small size of the controllable preparation difficult, and nano-contrast agent relaxation enhances the theoretical development of the hysteresis of the limit, it is difficult to optimize their performanceMaterials Today Advances, 2020; The Progress in Biomedical Engineering 2022it.

In response to these challenges, fan Hamming research group through the system in-depth study, first proposedDynamic synchronous thermal decomposition methodTo achieve a high monodisperse, size-controllable ultra-small ferrite nanomaterials macro amount of preparation, and in order to build aUltra-small manganese ferrite T1 Nano-contrast agentsACS Nano, 2017）The contrast agent by coupling a targeting peptide, the realization of the living mouse breast cancer systemic metastases of high-resolution magnetic resonance imaging, the effective detection of sub-millimeter tumor lesions（0.4 mm）（Advanced Materials, 2019 in. The research group further revealed ultra-small ferrite nanoparticles core/shell-type quasi-paramagnetic new structure, sets out the structure of the lead inside and outside the ball T1 relaxation synergistic enhancement mechanism, improve the ultra-small nano-contrast agent relaxation enhancement theory(Nano Letters, 2021; and a pharmaceutically acceptable progress, 2021)。 In particular foundUltra-small manganese ferrite nanoparticles contrast agent to the surface of the manganese ions and the liver cell surface SLC39A14 protein that specifically binds to achieve liver-enhanced imaging(Theranostics, 2019)For its build high-performance hepatocyte-specific contrast agent has laid an important Foundation.

In the early series of studies on the basis ofThe research group studies peopleMember of the design of new, dualThe target point of the liver cell-specific quasi-superparamagnetic small manganese ferrite Nano-contrast agent（MnFe₂O₄-EOB-PEG）（Nat. Biomed. Eng. 2022 airport. The contrast agent by the liver cells of SLC39A14 and OATP1 two receptors for efficient binding, specifically targeting the liver cells, and the use of the two receptors in normal liver cells with high expression of tumor cells with low expression of the characteristics to achieve early cancer of the liver tiny lesions accurate image detection.

Liver cell-specificMnFe₂O₄-EOB-PEGNano-contrast agent design

Research results show that the MnFe₂O₄纳米颗粒表面的Mn离子和其表面修饰的乙氧苯（EOB）配体可实现对肝细胞SLC39A14和OATP1的双靶点协同靶向作用，显著提升了特异性和亲和力，活体（猪）实验显示其肝细胞特异性分布可高达70.59%。猴、猪等大动物实验肝胆成像结果显示，与临床Gd-EOB-DTPA相比，可使肝对比度增强5.8倍，并可高清晰分辨0.5毫米的肝管。同时肝实质和胆管显像速度也提升了2倍以上，显著减少患者检测时间，提高了检查效率。活体肝癌成像结果显示，该对比剂可将微小肝癌病灶（<0.5厘米）的检出率从48%提高至92%，并可清晰判断胆梗阻位置与梗阻程度，有望用于无创胆管成像。初步非临床GLP评价和大动物安全性评价结果均显示出良好的安全性，可通过肝、肾快速清除，7天残留率小于1%，具有极好的临床转化潜力。The study of dual-target design of new liver cell-specific quasi-paramagnetic Nano-contrast agent for liver cancer early detection provide new diagnostic imaging tools.MnFe₂O₄-EOB-PEG has registered trademark“玵 significant legislation”, is currently in XI'an ultra-magnetic technology for Clinical Translational Research.

MnFe₂O₄-EOB-PEGNano-contrast agent for magnetic resonance hepatobiliary imaging