There are many photosensitizers that are presently in their advanced stages of clinical development. All compounds being studied share characteristics that are required of an ideal photosensitizer.

Tissue specificity of a photosensitizer is vital to PDT. Compounds have been selected based upon their ability to be targeted to specific tissue or ability to be loosely bonded to unreactive compounds that can be targeted. Non toxicity of the compound is also essential. Due to restrictions in accessibility of today’s light delivering systems and the depth that this light can penetrate tissue has provided yet another indirect requirement of photosensitizers. Wavelengths which diffuse through the tissue most effectively are 640 nm and 700-800 nm and can penetrate to a depth of 2-3 mm and 5-6 mm respectively. Therefore the compounds of interest must be able to absorb wavelengths within this range of the visible spectrum. Upon being activated the photosensitizer should not dissociate or cause any undesired side effects.

The efficiency of a photosensitizer is measured via molar absorption coefficient (e). The molar absorption coefficient “(formerly known as the molar extinction coefficient), is a property of a molecule undergoing an electronic transition” (3). It is a fixed constant and is unique to every molecule. The Beer-Lambert law; A= e c l, relates molar absorptivity e to Absorbance A (or optical density), molar concentration c and length l of the sample cell (with respect to a cuvette length in a lab). Molecules with a higher molar absorption coefficient are desirable for PDT.

All compounds have the ability to absorb light, but what makes photosensitizers unique is the method by which they decay to their ground state. Energy E of a specific wavelength can be described by E = h c / lamda, where h is Plank’s constant, c is the speed of light and lamda is a single wavelength. The relationship that wavelength shares with energy allow molecules to become electronically excited when exposed to light (at specific wavelengths). Once in this excited state excess energy can be expressed through two possible transitions, spin-allowed transitions or via spin-prohibited transitions. (2) Spin allowed transitions encompass internal conversion; A method of lowering energy by means conversion into heat (kinetic energy) through molecular vibration, rotations and collision with other local molecules.(1) Spin allowed transitions also include fluorescence which follow vibrational relaxation of the excited molecule. The second type of transition, spin-prohibited transition is of particular interest and is fundamental to the concept of PDT. Spin prohibited transitions involve relaxation of an excited molecule via phosphorescence and more importantly by intersystem crossing. Intersystem crossing is method by which an activated molecule reaches a new electronic state (triplet state) which is highly reactive and can trigger photochemical reactions. What makes photosensitizers unique is that they have a higher probability of reaching this reactive triplet state.

Photochemical reactions are expressed by photosensitizers through two types of mechanisms; known as Type I and Type II reactions. “Type I reactions involve an electron/hydrogen transfer directly from the photosensitizer, producing ions, or electron/hydrogen abstraction from a substrate molecule to form free radicals.” (4) Once these radicals have been produced they will react rapidly with oxygen thus producing a highly reactive form of oxygen species. Type II reactions involve the excitation of the oxygen molecule to the singlet oxygen state which is highly reactive. Both mechanisms are responsible for cell death. The singlet oxygen species is extremely toxic to cells because it reacts with amino acids, unsaturated lipids and other cellular components. For purposes of PDT the effects that photosensitizers have on mitochondria are important. Mitochondria are vital to cell functions because they provide the energy for them to transpire in the form of ATP. Photosensitizers once excited cause decoupling of respiration and phosphorylation thus hindering ATP synthesis in mitochondria. Without the aid of ATP cells functions cease and cells, tissue dies. Cells that manage to detect that the toxic singlet oxygen species release prostoglandins to restrict blood flow thus causing the mitochondria to starve and die, again cells and tissue die.

The success of PDT is dependant on the targeting ability of the photosensitizer. Tissue specificity between normal and neoplastic tissue (abnormal growth of tissue; a tumor) is largely determined by the photosensitizer used. The mechanism by which the photosensitizer achieves localization in targeted tissues is not well understood. Recent hypotheses suggest that “greater proliferative rates of neoplastic cells, poor lymphatic drainage, leaky vasculature, or some more specific interation between the photosensitizer and marker molecules on neoplastic cells” (1) may be the cause. One of the more popular beliefs is that low-density lipoproteins (LDL) may interact with photosensitizers. It has been observed that cancerous and neovascular endothelial cells have a higher concentration of LDL receptors. A possible explanation for this phenomenon is that cancerous cells exhibit an increased rate of cell proliferation (1) thus their membranes are immature and collect cholesterol (including LDL) from blood plasma to build cell membranes. Because of the high probability of contact with LDL, photosensitizers will naturally accumulate in neoplastic tissue.