c-Met-Targeting 19F MRI Nanoparticles with Ultralong Tumor Retention for Precisely Detecting Small or Ill-Defined Colorectal Liver Metastases

Daoshuang Li,1,2,* Jie Yang,1,2,* Zuoyu Xu,1,2 Yingbo Li,1,2 Yige Sun,1,2 Yuchen Wang,1,2 Hongyan Zou,1,2 Kai Wang,1,2 Lili Yang,1,2 Lina Wu,1,2 Xilin Sun1,2 1Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China; 2NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and Therapy, Molecular Imaging Research Center (MIRC) of Harbin Medical University, Harbin, Heilongjiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xilin Sun; Lina Wu, Department of Nuclear Medicine, the Fourth Hospital of Harbin Medical University, 766 Xiangan N Street, Songbei District, Harbin, Heilongjiang, 150028, People’s Republic of China, Tel +86-451-88118600, Fax +86-451-82576509, Email sunxl@ems.hrbmu.edu.cn; LinaWu@hrbmu.edu.cnPurpose: Precisely detecting colorectal liver metastases (CLMs), the leading cause of colorectal cancer-associated mortality, is extremely important. 1H MRI with high soft tissue resolution plays a key role in the diagnosing liver lesions; however, precise detecting CLMs by 1H MRI is a great challenge due to the limited sensitivity. Even though contrast agents may improve the sensitivity, due to their short half-life, repeated injections are required to monitor the changes of CLMs. Herein, we synthesized c-Met-targeting peptide-functionalized perfluoro-15-crown-5-ether nanoparticles (AH111972-PFCE NPs), for highly sensitive and early diagnosis of small CLMs.Methods: The size, morphology and optimal properties of the AH111972-PFCE NPs were characterized. c-Met specificity of the AH111972-PFCE NPs was validated by in vitro experiment and in vivo 19F MRI study in the subcutaneous tumor murine model. The molecular imaging practicability and long tumor retention of the AH111972-PFCE NPs were evaluated in the liver metastases mouse model. The biocompatibility of the AH111972-PFCE NPs was assessed by toxicity study.Results: AH111972-PFCE NPs with regular shape have particle size of 89.3 ± 17.8 nm. The AH111972-PFCE NPs exhibit high specificity, strong c-Met-targeting ability, and precise detection capability of CLMs, especially small or ill-defined fused metastases in 1H MRI. Moreover, AH111972-PFCE NPs could be ultralong retained in metastatic liver tumors for at least 7 days, which is conductive to the implementation of continuous therapeutic efficacy monitoring. The NPs with minimal side effects and good biocompatibility are cleared mainly via the spleen and liver.Conclusion: The c-Met targeting and ultralong tumor retention of AH111972-PFCE NPs will contribute to increasing therapeutic agent accumulation in metastatic sites, laying a foundation for CLMs diagnosis and further c-Met targeted treatment integration. This work provides a promising nanoplatform for the future clinical application to patients with CLMs.Keywords: c-Met-targeted, perfluorocarbon, 19F MRI, colorectal liver metastases, precise detection