Mechanisms in photodynamic therapy: part one-photosensitizers, photochemistry and cellular localization

Abstract

The use of non-toxic dyes or photosensitizers (PS) in combination with harmless visible light that is known as photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as a tumor therapy, some of its most successful applications are for non-malignant disease. In a series of three reviews we will discuss the mechanisms that operate in the field of PDT. Part one discusses the recent explosion in discovery and chemical synthesis of new PS. Some guidelines on how to choose an ideal PS for a particular application are presented. The photochemistry and photophysics of PS and the two pathways known as Type I (radicals and reactive oxygen species) and Type II (singlet oxygen) photochemical processes are discussed. To carry out PDT effectively in vivo, it is necessary to ensure sufficient light reaches all the diseased tissue. This involves understanding how light travels within various tissues and the relative effects of absorption and scattering. The fact that most of the PS are also fluorescent allows various optical imaging and monitoring strategies to be combined with PDT. The most important factor governing the outcome of PDT is how the PS interacts with cells in the target tissue or tumor, and the key aspect of this interaction is the subcellular localization of the PS. Examples of PS that localize in mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes are given. Finally the use of 5-aminolevulinic acid as a natural precursor of the heme biosynthetic pathway, stimulates accumulation of the PS protoporphyrin IX is described.

Figure 1

Structures of PS either clinically approved or in trials.

Figure 2

Graphical illustration of the photophysical and photochemical mechanisms of PDT.

Figure 3

Optical window in tissue. Absorption spectra of important tissue chromophores such as water, oxy- and deoxyhemoglobin and melanin are plotted on a logarithmic scale.

Figure 4

Scanning laser confocal fluorescence microscope images of cells loaded with PS (red fluorescence) and organelle specific green fluorescent probes. (A and B) J774 macrophage cells that have been incubated with a lysosomal-targeted photosensitizer–protein conjugate with (A) lysotracker green and (B) mitotracker green. (C and D) J774 cells that were incubated with BPD and (C) lysotracker green and (D) mitotracker green. Scale bar is 10 μm.

Figure 5

ALA-induced PPIX. Schematic illustrating the interaction of the heme biosynthesis pathway with exogenous ALA to give intracellular PPIX. Abbreviations are ALA-D: ALA dehydratase; ALA-S: ALA synthetase; Coprogen III: coproporphyrinogen III; CPO: coproporphyrinogen oxidase; FCH: ferrochelatase; HMB: hydroxymethylbilane, PBG-D: porphobilinogren deaminase; protogen III: protoporphyrinogen; PPO: protoporphyrinogen oxidase; Urogen III: uropor-phyrinogen III; UCS: uroporphyrinogen cosynthase, UGD: uroporphyrinogen decarboxylase.