Toward Precise Antitumoral Photodynamic Therapy Using a Dual Receptor‐Mediated Bioorthogonal Activation Approach

Abstract Targeted delivery and specific activation of photosensitizers can greatly improve the treatment outcome of photodynamic therapy. To this end, we report herein a novel dual receptor‐mediated bioorthogonal activation approach to enhance the tumor specificity of the photodynamic action. It involves the targeted delivery of a biotinylated boron dipyrromethene (BODIPY)‐based photosensitizer, which is quenched in the native form by the attached 1,2,4,5‐tetrazine unit, and an epidermal growth factor receptor (EGFR)‐targeting cyclic peptide conjugated with a bicycle[6.1.0]non‐4‐yne moiety. Only for cancer cells that overexpress both the biotin receptor and EGFR, the two components can be internalized preferentially where they undergo an inverse electron‐demand Diels–Alder reaction, leading to restoration of the photodynamic activity of the BODIPY core. By using a range of cell lines with different expression levels of these two receptors, we have demonstrated that this stepwise “deliver‐and‐click” approach can confine the photodynamic action on a specific type of cancer cells.