Overcoming Solubility and Aggregation: Water-Soluble Porphyrins in Modern Phototherapy

Abstract Photodynamic therapy (PDT) is a minimally invasive cancer treatment that works through the combined use of photosensitizers (PS), light, and molecular oxygen to generate reactive oxygen species. Several porphyrin-based photosensitizers have been clinically developed for PDT, with Photofrin being one of the most commonly used photosensitizers for tumor destruction. Several of the limitations associated with using porphyrins as photodynamic therapeutic agents include weak absorption in the therapeutic window, prolonged skin phototoxicity after photosensitizer administration, and variable composition. Porphyrins remain among the most extensively studied classes of PSs for PDT and aPDT (antimicrobial photodynamic therapy) because of their favorable photophysical characteristics. However, many photosensitizers have limited utility because of poor water solubility, aggregation in biological media, or suboptimal cellular uptake. In response to these challenges, recent efforts have increasingly emphasized rational molecular design to improve intrinsic water solubility while simultaneously enhancing their therapeutic performance. Although significant progress has been made with nanomaterials and hybrid systems, discrete water-soluble porphyrins remain a valuable molecular basis for the development of photosensitizers for both PDT and aPDT. Recent work on water-soluble porphyrin-based photosensitizers is discussed in the context of PDT, antimicrobial PDT, and selected theranostic applications, with emphasis on emerging strategies for their further development.