Sustained Endocytosis Inhibition via Locally‐Injected Drug‐Eluting Hydrogel Improves ADCC‐Mediated Antibody Therapy in Colorectal Cancer
Abstract The epidermal growth factor receptor (EGFR) is a validated therapeutic target for RAS/RAF wild‐type colorectal cancer (CRC). However, monoclonal antibody‐based anti‐EGFR therapies such as cetuximab have limited effectiveness. Herein, it is identified that EGFR internalization is associated...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202407239 |
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| author | Chong Wu Xiaoting Liu Rong Liu Shiyao Song Zi‐Fan Zheng Yilin Zeng Yong Mei Jing‐Yang Zhang Qijia Duan Run Lin Jin‐Zhi Du Weiling He |
| author_facet | Chong Wu Xiaoting Liu Rong Liu Shiyao Song Zi‐Fan Zheng Yilin Zeng Yong Mei Jing‐Yang Zhang Qijia Duan Run Lin Jin‐Zhi Du Weiling He |
| author_sort | Chong Wu |
| collection | DOAJ |
| description | Abstract The epidermal growth factor receptor (EGFR) is a validated therapeutic target for RAS/RAF wild‐type colorectal cancer (CRC). However, monoclonal antibody‐based anti‐EGFR therapies such as cetuximab have limited effectiveness. Herein, it is identified that EGFR internalization is associated with poor treatment response and prognosis in patients with CRC, based on a retrospective analysis of patients treated with cetuximab. It is further demonstrated that the endocytosis inhibitor prochlorperazine (PCZ) can move EGFR, which is hidden inside the cell, to the cell surface to improve therapeutic antibody binding. Thus, a thermosensitive hydrogel co‐loaded with cetuximab and PCZ (Gel@Cmab/PCZ) is constructed for sustained inhibition of endocytosis and effective cetuximab delivery. Peritumoral injection of Gel@Cmab/PCZ shows strong antitumor efficacy in subcutaneous and orthotopic CRC tumor models and completely abrogated liver metastasis when combined with chemotherapy. In a humanized patient‐derived xenograft model, a single injection of Gel@Cmab/PCZ with one‐third of the conventional cetuximab dose achieved 91% tumor growth inhibition, which promoted NK cell infiltration into tumor tissues and their antibody‐dependent cell‐mediated cytotoxicity effect. This study represents a novel strategy to boost the monoclonal antibody‐mediated anti‐tumor response in CRC. |
| format | Article |
| id | doaj-art-1d5dcc9f55014bce99dea0df70149aad |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-1d5dcc9f55014bce99dea0df70149aad2025-08-20T02:34:31ZengWileyAdvanced Science2198-38442025-01-01122n/an/a10.1002/advs.202407239Sustained Endocytosis Inhibition via Locally‐Injected Drug‐Eluting Hydrogel Improves ADCC‐Mediated Antibody Therapy in Colorectal CancerChong Wu0Xiaoting Liu1Rong Liu2Shiyao Song3Zi‐Fan Zheng4Yilin Zeng5Yong Mei6Jing‐Yang Zhang7Qijia Duan8Run Lin9Jin‐Zhi Du10Weiling He11Department of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaSchool of Medicine South China University of Technology Guangzhou Guangdong 510006 ChinaDepartment of Pediatrics, The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Radiology, The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaSchool of Biomedical Sciences and Engineering, Guangzhou International Campus South China University of Technology Guangzhou Guangdong 511442 ChinaSchool of Medicine South China University of Technology Guangzhou Guangdong 510006 ChinaDepartment of Radiology, The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaSchool of Medicine South China University of Technology Guangzhou Guangdong 510006 ChinaDepartment of Gastrointestinal Surgery The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaAbstract The epidermal growth factor receptor (EGFR) is a validated therapeutic target for RAS/RAF wild‐type colorectal cancer (CRC). However, monoclonal antibody‐based anti‐EGFR therapies such as cetuximab have limited effectiveness. Herein, it is identified that EGFR internalization is associated with poor treatment response and prognosis in patients with CRC, based on a retrospective analysis of patients treated with cetuximab. It is further demonstrated that the endocytosis inhibitor prochlorperazine (PCZ) can move EGFR, which is hidden inside the cell, to the cell surface to improve therapeutic antibody binding. Thus, a thermosensitive hydrogel co‐loaded with cetuximab and PCZ (Gel@Cmab/PCZ) is constructed for sustained inhibition of endocytosis and effective cetuximab delivery. Peritumoral injection of Gel@Cmab/PCZ shows strong antitumor efficacy in subcutaneous and orthotopic CRC tumor models and completely abrogated liver metastasis when combined with chemotherapy. In a humanized patient‐derived xenograft model, a single injection of Gel@Cmab/PCZ with one‐third of the conventional cetuximab dose achieved 91% tumor growth inhibition, which promoted NK cell infiltration into tumor tissues and their antibody‐dependent cell‐mediated cytotoxicity effect. This study represents a novel strategy to boost the monoclonal antibody‐mediated anti‐tumor response in CRC.https://doi.org/10.1002/advs.202407239antibody‐dependent cell‐mediated cytotoxicitycolorectal cancerendocytosis inhibitionepidermal growth factor receptorhydrogeltargeted therapy |
| spellingShingle | Chong Wu Xiaoting Liu Rong Liu Shiyao Song Zi‐Fan Zheng Yilin Zeng Yong Mei Jing‐Yang Zhang Qijia Duan Run Lin Jin‐Zhi Du Weiling He Sustained Endocytosis Inhibition via Locally‐Injected Drug‐Eluting Hydrogel Improves ADCC‐Mediated Antibody Therapy in Colorectal Cancer Advanced Science antibody‐dependent cell‐mediated cytotoxicity colorectal cancer endocytosis inhibition epidermal growth factor receptor hydrogel targeted therapy |
| title | Sustained Endocytosis Inhibition via Locally‐Injected Drug‐Eluting Hydrogel Improves ADCC‐Mediated Antibody Therapy in Colorectal Cancer |
| title_full | Sustained Endocytosis Inhibition via Locally‐Injected Drug‐Eluting Hydrogel Improves ADCC‐Mediated Antibody Therapy in Colorectal Cancer |
| title_fullStr | Sustained Endocytosis Inhibition via Locally‐Injected Drug‐Eluting Hydrogel Improves ADCC‐Mediated Antibody Therapy in Colorectal Cancer |
| title_full_unstemmed | Sustained Endocytosis Inhibition via Locally‐Injected Drug‐Eluting Hydrogel Improves ADCC‐Mediated Antibody Therapy in Colorectal Cancer |
| title_short | Sustained Endocytosis Inhibition via Locally‐Injected Drug‐Eluting Hydrogel Improves ADCC‐Mediated Antibody Therapy in Colorectal Cancer |
| title_sort | sustained endocytosis inhibition via locally injected drug eluting hydrogel improves adcc mediated antibody therapy in colorectal cancer |
| topic | antibody‐dependent cell‐mediated cytotoxicity colorectal cancer endocytosis inhibition epidermal growth factor receptor hydrogel targeted therapy |
| url | https://doi.org/10.1002/advs.202407239 |
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