Fluorescent peptide highlights micronodules in murine hepatocellular carcinoma models and humans in vitro

Jing, Renwei; Zhou, Xiaoli; Zhao, Junfeng; Wei, Yushuang; Zuo, Bingfeng; You, A-Bin; Rao, Quan; Gao, Xianjun; Yang, Rong; Chen, Lu; Lu, Zhen; Zhou, Qibing; Zhang, Ning; Yin, Hai Fang

doi:10.1002/hep.29829

Cited by 13 publications

(18 citation statements)

References 30 publications

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“…In the future, this methodology will benefit by expanding our single α v β 3 fluorescent probe into a family of contrast agents specific for different targets such as epithelial cell adhesion molecule (EpCAM) and glypican-3 (GPC3), which are overexpressed in HCC and liver metastatic carcinoma. − We anticipate that the expanded library may provide the capacity to intraoperatively delineate tumor boundaries and guide tumor resection during photoacoustic imaging-guided irregular hepatectomy in clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Contrast-Enhanced Multispectral Photoacoustic Imaging for Irregular Hepatectomy Navigation: A Pilot Study

Zhang

Liu

et al. 2020

ACS Biomater. Sci. Eng.

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Irregular hepatectomy plays a prominent role in the treatment of small hepatocellular carcinoma (HCC) patients with severe cirrhosis and localized liver metastasis. In clinical practices, intraoperative tumor boundaries delineation facilitates to accomplish tumor resection with negative margin, remarkably decreasing the recurrence rates. Currently, ultrasound (US) and ICG fluorescence-guided surgery has been used for intraoperative navigation in irregular hepatectomy, but insufficient specificity results in a limited prevalence. Inspired by the high resolution of photoacoustic (PA) imaging and established clinical efficacy of 18F-Alfatide that is specific for integrin αvβ3-overexpressed tumors, we herein developed a fluorescent analogue IR820-E[c(RGDfK)]2, and a proof-of-concept intraoperative multispectral PA imaging navigation for precise irregular hepatectomy using hand-held PA/US imaging system. An integrin αvβ3-targeted fluorescent contrast agent IR820-E[c(RGDfK)]2 was designed, synthesized, and characterized. In vitro studies were performed to determine optical and PA properties, affinity and specificity and biocompatibility. Multispectral PA imaging, the optimal imaging time point and contrast, multispectral PA imaging-guided irregular hepatectomy, pharmacokinetics, and safety profile were evaluated in subcutaneous and orthotopic HCC tumor models. Ex vivo macroscopic three-dimensions (3D) PA imaging with IR820-E[c(RGDfK)]2 staining was also performed in surgical biospecimens from patients with HCC. IR820-E[c(RGDfK)]2 has a simple synthetic method at gram scale, high affinity, and specificity for integrin αvβ3, excellent pharmacokinetic and safety profile can effectively differentiate tumor from normal liver tissues in animal models and surgical biospecimens from HCC patients. Preoperative tumor localization, intraoperative tumor boundaries delineation, and tumor excision, and postoperative negative margin assessment were successfully achieved during irregular hepatectomy. This initial attempt allows one to preoperatively detect tumor lesions, intraoperatively delineate tumor boundaries and guide tumor resection, and postoperatively evaluate tumor margin status during irregular hepatectomy. IR820-E[c(RGDfK)]2 has the potential to be an investigational new drug for clinical use in multispectral photoacoustic imaging-guided irregular hepatectomy.

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Section: Discussionmentioning

confidence: 99%

Contrast-Enhanced Multispectral Photoacoustic Imaging for Irregular Hepatectomy Navigation: A Pilot Study

Zhang

Liu

et al. 2020

ACS Biomater. Sci. Eng.

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“…We standardized the quantitative detection of huAlu in resected tumours and surrounding margin tissues according to previously published methods. 32,33 Human tumour cells in the five groups (ICG-p28, ICG alone, ICG-AA3H, ICG-RI p28, and PBS; 8 mice in each group) were identified based on the quantitative detection of huAlu present in the mice. Genomic DNA was extracted from harvested tissues using the DNeasy Blood & Tissue Kit (Qiagen).…”

Section: Detection Of Residual Cancer Cells In the Tumour Margin By Alu Sequencingmentioning

confidence: 99%

Image-guided surgery with a new tumour-targeting probe improves the identification of positive margins

et al. 2022

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Background Given the lack of visual discrepancy between malignant and surrounding normal tissue, current breast conserving surgery (BCS) is associated with a high re-excision rate. Due to the increasing cases of BCS, a novel method of complete tumour removal at the initial surgical resection is critically needed in the operating room to help optimize the surgical procedure and to confirm tumour-free edges.Methods We developed a unique near-infrared (NIR) fluorescence imaging probe, ICG-p28, composed of the clinically nontoxic tumour-targeting peptide p28 and the FDA-approved NIR dye indocyanine green (ICG). ICG-p28 was characterized in vitro and evaluated in multiple breast cancer animal models with appropriate control probes. Our experimental approach with multiple-validations and -blinded procedures was designed to determine whether ICG-p28 can accurately identify tumour margins in mimicked intraoperative settings.Findings The in vivo kinetics were analysed to optimize settings for potential clinical use. Xenograft tumours stably expressing iRFP as a tumour marker showed significant colocalization with ICG-p28, but not ICG alone. Imageguided surgery with ICG-p28 showed an over 6.6 £ 10 3 -fold reduction in residual normalized tumour DNA at the margin site relative to control approaches (i.e., surgery with ICG or palpation/visible inspection alone), resulting in an improved tumour recurrence rate (92% specificity) in multiple breast cancer animal models independent of the receptor expression status. ICG-p28 allowed accurate identification of tumour cells in the margin to increase the complete resection rate.Interpretation Our simple and cost-effective approach has translational potential and offers a new surgical procedure that enables surgeons to intraoperatively identify tumour margins in a real-time, 3D fashion and that notably improves overall outcomes by reducing re-excision rates.

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“…A Cy5.5-labeled 12mer peptide, SRRPASFRTARE specifically binding to Barrett’s esophagus was selected, characterized, and reported as a candidate to be developed as a probe for the detection of early esophagus cancer and pre-malignant mucosa (Zhou et al 2017 ). By now, fluorescent labeled peptide probes have been successfully used in imaging diagnosis of multiple tumors (Haque et al 2019 ; Hou et al 2018 ; Jing et al 2018 ; Lee et al 2016 ; Li et al 2017 ; Scodeller et al 2017 ; Xing et al 2018 ; Zhang et al 2015 ).…”

Section: Potential Applications Of Targeting Peptidesmentioning

confidence: 99%

Application of Phage-Displayed Peptides in Tumor Imaging Diagnosis and Targeting Therapy

Xü

et al. 2020

Int J Pept Res Ther

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Phage display is an effective and powerful technique that provides a route to discovery unique peptides targeting to tumor cells. Specifically binding peptides are considered as the valuable target directing molecule fragments with potential efficiency to improve the current tumor clinic, and offer new approaches for tumor prevention, diagnosis and treatment. We focus on the recent advances in the isolation of tumor-targeting peptides by biopanning methods, with particular emphasis on molecular imaging, and pharmaceutical targeting therapy.

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Fluorescent peptide highlights micronodules in murine hepatocellular carcinoma models and humans in vitro

Abstract: 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).

Cited by 13 publications

References 30 publications

Contrast-Enhanced Multispectral Photoacoustic Imaging for Irregular Hepatectomy Navigation: A Pilot Study

Contrast-Enhanced Multispectral Photoacoustic Imaging for Irregular Hepatectomy Navigation: A Pilot Study

Image-guided surgery with a new tumour-targeting probe improves the identification of positive margins

Application of Phage-Displayed Peptides in Tumor Imaging Diagnosis and Targeting Therapy

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