5.01] ALA or MAL for photodynamic therapy and fluorescence diagnosis?

Abstract

Aminolevulinic acid (ALA) is the precursor of the potent photosensitizer protoporphyrin IX (PpIX) in the heme biocycle. If ALA is given externally to cells, they generate PpIX in excess, which cannot be quickly converted to the end product heme and therefore remains available as sensitizer for a limited time. During this time, the accumulated PpIX may be irradiated with red light of a wavelength of 635 nm provided by lasers, lamps or LED sources in the presence of oxygen. Due to the relatively low bioavailability of the ALA molecule, ester derivatives with different lengths of the aliphatic side chains were designed. As soon as ALA esters are taken up by the cell, they are hydrolyzed into the active form by enzymes and processed in the same way as ALA. Both ALA and ALA methyl ester (MAL) are used for fluorescence detection (FD) in a variety of (pre)malignant and non-malignant diseases for diagnosis and for fluorescence-guided resection. Both administration forms are applied in photodynamic therapy (PDT) of (pre)malignant lesions in the fields of dermatology, urology, neurosurgery, otorhinolaryngology, gynecology and gastroenterology. ALA is approved as Levulan® for actinic keratoses (EU, US), and MAL (or Metvix®) for actinic keratoses, basal cell carcinoma and Bowen's disease (EU). The most common side effect of ALA- as well as MAL-PDT is pain, burning or stinging discomfort at the site of treatment. The use of ALA and MAL against microbial infections is currently investigated. In addition, immunological effects by ALA-PDT are reported. By evaluating the literature, several advantages of MAL over ALA are found, such as facilitated crossing of the stratum corneum and cell membranes, higher selectivity (e.g. in solar keratoses), increased PpIX formation leading to higher fluorescence and photodynamic efficiency, less pain, less systemic effects after local treatment and faster clearance from the cells. Based on a comparative study of literature it will be analyzed, whether PDT with ALA esters shows the expected advantage over ALA-PDT.