A pH‐Responsive Layered Double Hydroxide (LDH)–Phthalocyanine Nanohybrid for Efficient Photodynamic Therapy

A pH‐responsive nanohybrid (LDH–ZnPcPS₄), in which a highly hydrophilic zinc(II) phthalocyanine tetra‐α‐substituted with 4‐sulfonatophenoxy groups (ZnPcPS₄) is incorporated with a cationic layered double hydroxide (LDH) based on electrostatic interaction, has been specially designed and prepared through a facile co‐precipitation approach. ZnPcPS₄ is an excellent singlet‐oxygen generator with strong absorption at the near‐infrared region (692 nm) in cellular culture media, whereas the photoactivities of ZnPcPS₄ were remarkably inhibited after incorporation with the LDH. The nanohybrid is essentially stable in aqueous media at pH 7.4; nevertheless, in slightly acidic media of pH 6.5 or 5.0, ZnPcPS₄ can be efficiently released from the LDH matrix, thus leading to restoration of the photoactivities. The nanohybrid shows a high photocytotoxicity against HepG2 cells as a result of much more efficient cellular uptake and preferential accumulation in lysosomes, whereby the acidic environment leads to the release of ZnPcPS₄. The IC₅₀ value of LDH–ZnPcPS₄ is as low as 0.053 μM , which is 24‐fold lower than that of ZnPcPS₄. This work provides a facile approach for the fabrication of photosensitizers with high photocytotoxicity, potential tumor selectivity, and rapid clearance character.