{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yan J"],"funding":["Natural Science Foundation of China grant","Jiangsu Province Key Research and Development Program grant","Jiangsu Provincial Medical Key Discipline grant"],"pagination":["1323"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12632142"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["23(1)"],"pubmed_abstract":["<h4>Background</h4>Although antibody-conjugated drugs have achieved success in clinical practice for cancer treatment, challenges remain in developing a highly efficient drug delivery system with specific accumulation in tumors and reduction in side effects. With improved pharmacokinetics, strong covalent bonding and quick binding reactions, a pre-targeting approach via molecular pairs represents an attractive platform for two-step delivery system construction.<h4>Methods</h4>Bioinformatics and immunohistochemistry assays were performed to assess Claudin-6 (CLDN6) as a highly specific tumor target in solid tumors. A phage-displayed library was used to screen and optimize anti-CLDN6 designed ankyrin repeat proteins (DARPins), which were incorporated into a two-step delivery system based on SpyTag/SpyCatcher. Fluorescent staining, flow cytometry and near-infrared imaging were performed to assess the tumor-targeting ability and biodistribution of this delivery system. The cytotoxic drug, Monomethyl auristatin E (MMAE), was conjugated with the delivery system to evaluate its anti-tumor efficacy and safety profile.<h4>Results</h4>Anti-CLDN6 DARPins exhibited specific binding to CLDN6<sup>+</sup> cancer cells with high affinity instead of negative cells in vitro, ex vivo and in vivo. The DARPins-based two-step delivery system improved background clearance with a high signal-to-noise ratio, enhancing the specific accumulation of payloads in tumors. The cytotoxic drug delivered via the two-step system appeared superior to the one-step approach in IC50, biodistribution, and tumor growth inhibition.<h4>Conclusions</h4>Our study presented the de novo design of a two-step drug delivery system targeting Claudin-6 with enhanced anti-tumor efficacy and improved biosafety. These findings highlighted the potential of this approach to enhance the efficacy of tumor-targeting therapies and reduce adverse effects, paving the way for more effective cancer treatments."],"journal":["Journal of translational medicine"],"pubmed_title":["De novo design of a two-step approach targeting Claudin-6 for enhanced drug delivery to solid tumors."],"pmcid":["PMC12632142"],"funding_grant_id":["ZDXK202233","BE2023654","82272811"],"pubmed_authors":["Lei L","Yan J","Shao J","An M","Liu Q","Wei X","Li R","Li L","Zhao Y","Guo J","Liu B","Chen X","Wang Y","Zhong L","Liu F","Yu X","Chen T"],"additional_accession":[]},"is_claimable":false,"name":"De novo design of a two-step approach targeting Claudin-6 for enhanced drug delivery to solid tumors.","description":"<h4>Background</h4>Although antibody-conjugated drugs have achieved success in clinical practice for cancer treatment, challenges remain in developing a highly efficient drug delivery system with specific accumulation in tumors and reduction in side effects. With improved pharmacokinetics, strong covalent bonding and quick binding reactions, a pre-targeting approach via molecular pairs represents an attractive platform for two-step delivery system construction.<h4>Methods</h4>Bioinformatics and immunohistochemistry assays were performed to assess Claudin-6 (CLDN6) as a highly specific tumor target in solid tumors. A phage-displayed library was used to screen and optimize anti-CLDN6 designed ankyrin repeat proteins (DARPins), which were incorporated into a two-step delivery system based on SpyTag/SpyCatcher. Fluorescent staining, flow cytometry and near-infrared imaging were performed to assess the tumor-targeting ability and biodistribution of this delivery system. The cytotoxic drug, Monomethyl auristatin E (MMAE), was conjugated with the delivery system to evaluate its anti-tumor efficacy and safety profile.<h4>Results</h4>Anti-CLDN6 DARPins exhibited specific binding to CLDN6<sup>+</sup> cancer cells with high affinity instead of negative cells in vitro, ex vivo and in vivo. The DARPins-based two-step delivery system improved background clearance with a high signal-to-noise ratio, enhancing the specific accumulation of payloads in tumors. The cytotoxic drug delivered via the two-step system appeared superior to the one-step approach in IC50, biodistribution, and tumor growth inhibition.<h4>Conclusions</h4>Our study presented the de novo design of a two-step drug delivery system targeting Claudin-6 with enhanced anti-tumor efficacy and improved biosafety. These findings highlighted the potential of this approach to enhance the efficacy of tumor-targeting therapies and reduce adverse effects, paving the way for more effective cancer treatments.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Nov","modification":"2026-06-05T17:14:08.828Z","creation":"2026-05-19T03:11:44.744Z"},"accession":"S-EPMC12632142","cross_references":{"pubmed":["41267074"],"doi":["10.1186/s12967-025-07316-2"]}}