Cascade In Situ Self‐Assembly and Bioorthogonal Reaction Enable the Enrichment of Photosensitizers and Carbonic Anhydrase Inhibitors for Pretargeted Cancer Theranostics

• Published in: Angewandte Chemie International Edition Vol. 63; no. 4; pp. e202314039 - n/a
• Main Authors: Wen, Xidan, Zeng, Wenhui, Zhang, Junya, Liu, Yili, Miao, Yinxing, Liu, Shaohai, Yang, Yanling, Xu, Jing‐Juan, Ye, Deju
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 22.01.2024; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Alkaline phosphatase; Antigens; Bioorthogonal Reaction; Cancer; Carbonic anhydrase; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic anhydrases; Catalysis; Cell Line, Tumor; Cell membranes; Chemistry; Chemistry, Multidisciplinary; Cycloaddition Reaction; Cyclooctanes; Dephosphorylation; Enrichment; Fluorescence; Hypoxia; Irradiation; Microparticles; Multimodal Imaging; Nanoparticles; Nanoparticles Regrowth; Neoplasms - diagnostic imaging; Neoplasms - drug therapy; Pharmacology; Photodynamic Therapy; Photosensitizing Agents - pharmacology; Photosensitizing Agents - therapeutic use; Physical Sciences; Precision Medicine; Radiopharmaceuticals; Regrowth; Science & Technology; Self-Assembly; Tumor cells; Tumors; DESIGN; VIVO; Bioorthogonal Reaction; Self-Assembly; TUMOR; HYPOXIA; CHALLENGES; PROBES; Multimodal Imaging; NANOPARTICLES; PRODRUG; Photodynamic Therapy; EFFICIENT; Nanoparticles Regrowth
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202314039

We report here a tumor‐pretargted theranostic approach for multimodality imaging‐guided synergistic cancer PDT by cascade alkaline phosphatase (ALP)‐mediated in situ self‐assembly and bioorthogonal inverse electron demand Diels–Alder (IEDDA) reaction. Using the enzymatic catalysis of ALP that continuously catalyses the dephosphorylation and self‐assembly of trans‐cyclooctene (TCO)‐bearing P‐FFGd‐TCO, a high density of fluorescent and magnetic TCO‐containing nanoparticles (FMNPs‐TCO) can be synthesized and retained on the membrane of tumor cells. They can act as ‘artificial antigens’ amenable to concurrently capture lately administrated tetrazine (Tz)‐decorated PS (775NP‐Tz) and carbonic anhydrase (CA) inhibitor (SA‐Tz) via the fast IEDDA reaction. This two‐step pretargeting process can further induce FMNPs‐TCO regrowth into microparticles (FMNPs‐775/SA) directly on tumor cell membranes, which is analyzed by bio‐SEM and fluorescence imaging. Thus, efficient enrichment of both SA‐Tz and 775NP‐Tz in tumors can be achieved, allowing to alleviate hypoxia by continuously inhibiting CA activity and improving PDT of tumors. Findings show that subcutaneous HeLa tumors could be completely eradicated and no tumor recurred after irradiation with an 808 nm laser (0.33 W cm−2, 10 min). This pretargeted approach may be applied to enrich other therapeutic agents in tumors to improve targeted therapy. A two‐step tumor‐pretargeted approach for multimodal imaging‐guided cancer theranostics via cascade alkaline phosphatase (ALP)‐mediated in situ self‐assembly and bioorthogonal inverse electron demand Diels–Alder (IEDDA) reaction enhances the accumulation of carbonic anhydrase inhibitors (SA‐Tz) and photosensitizers (775NP‐Tz) at the tumor site, efficiently alleviating hypoxic tumors and augmenting synergistic PDT efficacy in vivo.