Bioorthogonal reaction-mediated photosensitizer–peptide conjugate anchoring on cell membranes for enhanced photodynamic therapy†

Abstract

Photodynamic therapy (PDT), utilizing a photosensitizer (PS) to induce tumor cell death, is an effective modality for cancer treatment. PS–peptide conjugates have recently demonstrated remarkable antitumor potential in preclinical trials. However, the limited cell membrane binding affinity and rapid systemic clearance have hindered their transition to clinical applications. To address these challenges, we investigated whether in vivo covalent chemistry could enhance tumor accumulation and potentiate antitumor efficacy. Specifically, we synthesized a PS–peptide conjugate termed P-DBCO-Ce6, with chlorin e6 (Ce6) and dibenzocyclooctyne (DBCO) conjugated to a negatively charged short peptide. By employing metabolic glycoengineering and bioorthogonal reactions, P-DBCO-Ce6 achieves covalent bonding to the cell membrane, enabling prolonged retention of the PS on the cell surface and the in situ generation of reactive oxygen species (ROS) on cell membranes to kill tumor cells. In vivo studies demonstrated a 3.3-fold increase in tumor accumulation of the PS through bioorthogonal reactions compared to the control group, confirming that click chemistry can effectively enhance PS tumor accumulation. This approach allows for the effective elimination of tumors with a single treatment. The improved efficiency of this strategy provides new insights into the design of PDT systems for potential clinical applications.