Solid-phase Synthesis of Folate–Chlorin Conjugates for Selective Photodynamic Therapy and the Effect of Linker Variation

Here, we evaluated the effect of linkers conjugating a chlorin-based photosensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), and folic acid to target cancer cells. Folate–HPPH conjugates with peptide, polyethylene glycol (PEG), peptoid, or 7-aminoheptanoic acid (AHA) linkers were synthesized on a solid-phase and evaluated for photodynamic therapy (PDT) efficacy. Compared to free HPPH, the folate-linker-HPPHs were effectively internalized into tumor cells and exhibited superior PDT effect upon irradiation. Tumor-targeting PDT efficacy was influenced by linker variation, with in vitro photocytotoxicities of peptide > PEG > AHA > peptoid, paralleling water solubility of the linkers. Thus, linker choice significantly affects targeted PDT efficacy providing useful information for linker design.