Intrinsic and acquired resistance to photodynamic therapy with 5-Aminolevulinic acid

5-Aminolevulinic acid (5-ALA) has been approved by the FDA for photodynamic therapy (PDT) and tumor fluorescence imaging of very common and highly morbid human diseases including the skin cancer, bladder cancer and high-grade gliomas. As a prodrug, 5-ALA on its own has neither photosensitizing activity for PDT nor fluorescent property for tumor fluorescence imaging. It needs to enter the cell after oral or topical administration and undergo metabolism in the heme biosynthesis pathway to produce protoporphyrin IX (PpIX) in the mitochondria, which is the active drug with strong photosensitizing activity and red fluorescence upon light activation. Despite the wide clinical applications of 5-ALA-based therapies, tumors may exhibit intrinsic and acquired resistance to the treatment, resulting in heterogeneous treatment responses, disease recurrences and even treatment failures. Strategies to overcome intrinsic and acquired resistance to PDT with 5-ALA will be discussed.