Early detection and clear delineation of microscopic lesions during surgery are critical to the prognosis and survival of patients with hepatocellular carcinoma (HCC), a devastating malignancy without effective treatments except for resection. Tools to specifically identify and differentiate micronodules from normal tissue in HCC patients can have a positive impact on survival. Here, we discovered a peptide that preferentially binds to HCC cells through phage display. Significant accumulation of the fluorescence-labeled peptide in tumor from ectopic and orthotopic HCC mice was observed within 2 hours of systemic injection. Contrast between tumor and surrounding liver is up to 6.5-fold, and useful contrast lasts for 30 hours. Micronodules (0.03 cm in diameter) in liver and lung can clearly be distinguished from normal tissue with this fluorescence-labeled peptide in orthotopic HCC mice and HCC patients. Compared to indocyanine green, a Food and Drug Administration–approved imaging contrast agent, an up to 8.7-fold higher differentiation ratio of tumor to fibrosis is achieved with this fluorescence-labeled peptide. Importantly, this peptide enables up to 10-fold differentiation between HCC and peritumoral tissue in human tissues and the complete removal of tumor in HCC mice with surgical navigation. No abnormalities in behavior or activity are observed after systemic treatment, indicating the absence of overt toxicity. The peptide is metabolized with a half-life of approximately 4 hours in serum. Conclusion: Our findings demonstrate that micronodules can be specifically differentiated with high sensitivity from surrounding tissue with this molecule, opening clinical possibilities for early detection and precise surgery of HCC. (Hepatology 2018).
Bibliographical noteFunding Information:
Received October 11, 2017; accepted January 31, 2018. Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/10.1002/hep.29829/suppinfo. Supported by the National Key R&D Program of China (2017YFC1001902), the National Natural Science Foundation of China (81501531, 81672124, 81273420, 81671528, and 81372403), and the Tianjin Municipal 13th Five-Year Plan (Tianjin Medical University Talent Project). VC 2018 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.29829
The authors thank Dr. Yiqi Seow (Biomedical Sciences Institutes, A*STAR, Singapore) for critical review of the manuscript and Drs. Wenting Shang and Tianpei Guan (Institute of Automation, Chinese Academy of Sciences, Beijing, China) for assistance with the surgical navigation.
© 2018 by the American Association for the Study of Liver Diseases.