Reconstructing the intracellular pH microenvironment for enhancing photodynamic therapy

Acidic tumor microenvironments, characterized by weak acidity outside the cell (pH similar to 6.5-7.0), have been revealed as a potential therapeutic target with specific acid-responsible materials. However, the intracellular pH of tumor cells is still slightly alkaline (pH similar to 7.2-7.4), which is not conducive for nanomaterials that respond to acid but should destroy intracellular substances. Here, we proposed a new strategy for reconstructing the intracellular pH microenvironment to enhance photodynamic therapy. Nanomaterials (UCNP@ZIF + TPP + PA) were designed with an NaYF4:Yb:Tm (UCNP) inner core coated by a porous zeolitic imidazolate framework (ZIF-8) outside for photoacid (PA) and acid-responsive porphyrin (TPP) co-loading. Upon 980 nm laser irradiation, the emission light of UCNP activates PA for H+ release, which achieves reconstruction of the intracellular pH environment. In this new acid condition, TPP becomes protonated (TPP-H+), which reduces its aggregation by enhancing its water solubility, and in turn increases singlet oxygen (O-1(2)) production for enhanced tumor killing. Both in vitro and in vivo experiments have proved that UCNP@ZIF + TPP + PA could reconstruct the intracellular pH environment and enhance therapeutic effect of photodynamic therapy (PDT). Reconstructing the intracellular pH by using light is of great significance for acid-responsive nanosystems to destroy intracellular substances and treat tumors. The results also signify the use of such acid-responsive materials for several other disease therapies.