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Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer

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机构： [1]Department of Medical Imaging, The Third Affiliated Hospital, Southern Medical University (Academyof Orthopedics Guangdong Province), Guangzhou 510515, P. R. China. [2]Shenzhen Clinical ResearchCentre for Geriatrics and Department of Geriatrics, Shenzhen People’s Hospital/ First Affiliated Hospitalof Southern University of Science and Technology, Second Clinical Medical College of Jinan University,Shenzhen 518020, Guangdong, P. R. China. [3]NMPA Key Laboratory for Research and Evaluation of DrugMetabolism and Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern MedicalUniversity, Guangzhou 510515, P. R. China. [4]Department of Pharmacy, Nanfang Hospital, SouthernMedical University, Guangzhou 510515, P. R. China. [5]Department of Neurosurgery and Medical ResearchCenter, Shunde Hospital, Southern Medical University (The First People’s Hospital of Shunde Foshan),Guangzhou 510515, P. R. China. [6]School of Chemistry and Chemical Engineering, Shanxi DatongUniversity, Pingcheng District, Datong, Shanxi Province 037009, P. R. China. [7]State Key Laboratory forQuality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Instituteof Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, P. R. China. [8]State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng 475004, Henan,P. R. China. [9]Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou646000, Sichuan, P. R. China

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摘要：

Surgery and targeted therapy are of equal importance for colorectal cancer (CRC) treatment. However, complete CRC tumor resection remains challenging, and new targeted agents are also needed for efficient CRC treatment. Cadherin 17 (CDH17) is a membrane protein that is highly expressed in CRC and, therefore, is an ideal target for imaging-guided surgery and therapeutics. This study utilizes CDH17 nanobody (E8-Nb) with the near-infrared (NIR) fluorescent dye IRDye800CW to construct a NIR-II fluorescent probe, E8-Nb-IR800CW, and a Pseudomonas exotoxin (PE)-based immunotoxin, E8-Nb-PE38, to evaluate their performance for CRC imaging, imaging-guided precise tumor excision, and antitumor effects. Our results show that E8-Nb-IR800CW efficiently recognizes CDH17 in CRC cells and tumor tissues, produces high-quality NIR-II images for CRC tumors, and enables precise tumor removal guided by NIR-II imaging. Additionally, fluorescent imaging confirms the targeting ability and specificity of the immunotoxin toward CDH17-positive tumors, providing the direct visible evidence for immunotoxin therapy. E8-Nb-PE38 immunotoxin markedly delays the growth of CRC through the induction of apoptosis and immunogenic cell death (ICD) in multiple CRC tumor models. Furthermore, E8-Nb-PE38 combined with 5-FU exerts synergistically antitumor effects and extends survival. This study highlights CDH17 as a promising target for CRC imaging, imaging-guided surgery, and drug delivery. Nanobodies targeting CDH17 hold great potential to construct NIR-II fluorescent probes for surgery navigation, and PE-based toxins fused with CDH17 nanobodies represent a novel therapeutic strategy for CRC treatment. Further investigation is warranted to validate these findings for potential clinical translation.Copyright © 2024 Youbin Ding et al.

基金：

this work was supported by the Guang Dong Basicand Applied Basic Research Foundation (2024A1515010352,2022A1515110745, and 2021A1515012164), the President Foun-dation of the Third Affiliated Hospital of Southern MedicalUniversity (YM2021012), the National Key Research Program ofChina (2020YFA0908000 and 2022YFC2303600), the HUILANPublic Welfare, the National Natural Science Foundation ofChina (82373775 and 32200540), the International Science andTechnology Cooperation for Shenzhen Technology InnovationPlan (GJHZ20200731095411034), the Innovation Team andTalents Cultivation Program of the National Administration ofTraditional Chinese Medicine (ZYYCXTD-C-202002), the Scienceand Technology Foundation of Shenzhen (Shenzhen ClinicalMedical Research Center for Geriatric Diseases), the ShenzhenMedical Research Fund of Shenzhen Medical Academy of Researchand Translation (B2302051), the Shenzhen Science and TechnologyInnovation Committee (SZSTI) (RCYX20221008092950121),the CACMS Innovation Fund (CI2023E002, CI2021A05101,and CI2021A05104), the Scientific and Technological InnovationProject of China Academy of Chinese Medical Sciences(CI2023D003, CI2023D008, and CI2021B014), the Key SpecialProject of “Strategic Science and Technology InnovationCooperation” from National Key R&D Program of China(2023YFE0204500), the Fundamental Research Funds for theCentral public welfare research institutes (ZZ16-ND-10-23,ZZ15-ND-10, ZZ14-ND-010, ZZ14-FL-002, ZZ14-YQ-050, andZZ14-YQ-051), the Shenzhen Fund for Guangdong ProvincialHigh-level Clinical Key Specialties (SZGSP001), the ShenzhenGovernmental Sustainable Development Fund (KCXFZ-20201221173612034), the Shenzhen key Laboratory of KidneyDiseases (ZDSYS201504301616234), and the Natural Science Foun-dation of Shenzhen City, China (KCXFZ20201221173600001).Author contributions: Y.D. and R.Z.: conceptualization,data curation, and writing. G.S. and Zhifen Li: methodologyand writing. X.X. and J.M.: visualization. J.H., C.F., and H.Z.:validation. Y.J. and H.W.: conceptualization. J.L. and Z.D.:project administration. Q.Y. and K.J.: supervision. Y.A. andL.Y.: data curation and visualization. L.Y., Y.L., and Zhijie Li:language, conceptualization, resources, and review and edit-ing. X.Z. and J.W.: supervision, review and editing, and fund-ing acquisition. All the authors read and approved the finalmanuscript.Competing interests: The authors declare that they have nocompeting interests

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大类 | 1 区医学

小类 | 2 区工程：生物医学 2 区材料科学：生物材料

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Q1 ENGINEERING, BIOMEDICAL Q1 MATERIALS SCIENCE, BIOMATERIALS

影响因子： 8.1 最新[2023版] 0 最新五年平均 8.1 出版当年[2023版] 0 出版当年五年平均 8.1 出版前一年[2023版]

第一作者：

第一作者机构： [1]Department of Medical Imaging, The Third Affiliated Hospital, Southern Medical University (Academyof Orthopedics Guangdong Province), Guangzhou 510515, P. R. China. [2]Shenzhen Clinical ResearchCentre for Geriatrics and Department of Geriatrics, Shenzhen People’s Hospital/ First Affiliated Hospitalof Southern University of Science and Technology, Second Clinical Medical College of Jinan University,Shenzhen 518020, Guangdong, P. R. China.

共同第一作者：

通讯作者：

通讯机构： [1]Department of Medical Imaging, The Third Affiliated Hospital, Southern Medical University (Academyof Orthopedics Guangdong Province), Guangzhou 510515, P. R. China. [2]Shenzhen Clinical ResearchCentre for Geriatrics and Department of Geriatrics, Shenzhen People’s Hospital/ First Affiliated Hospitalof Southern University of Science and Technology, Second Clinical Medical College of Jinan University,Shenzhen 518020, Guangdong, P. R. China. [3]NMPA Key Laboratory for Research and Evaluation of DrugMetabolism and Guangdong Provincial Key Laboratory of New Drug Screening and Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern MedicalUniversity, Guangzhou 510515, P. R. China. [7]State Key Laboratory forQuality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Instituteof Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, P. R. China. [8]State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, Kaifeng 475004, Henan,P. R. China. [9]Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou646000, Sichuan, P. R. China

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