history of photodetection and photodynamic therapy, The

Photochemistry and Photobiology, Nov 2001 by Ackroyd, Roger, Kelty, Clive, Brown, Nicola, Reed, Malcolm

Although such immediate effects are important to the initial ablation of the tumor mass PDT has been reported to have an effect on the immune system. It can both activate and suppress the response. The inflammatory process is characterized by the release of a wide range of inflammatory mediators with recruitment of leukocytes after PDT and amplification of their activity. The induction of an acute inflammatory response and the generation of tumor-specific immunity also play a decisive role in achieving long-term control (82,83).

All of these principles are reviewed more extensively in several review articles (71,72,80,84).

ALTERNATIVE PHOTOSENSITIZING AGENTS

USED IN PDT

The majority of photosensitive molecules have a heterocyclic ring structure similar to that of chlorophyll or hemoglobin. Light energy is captured in the form of photons and the energy is transferred to other molecules resulting in the liberation of short-lived energetic species that interact with biological systems and produce tissue damage (1). An ideal photosensitizer must be biologically stable, photochemically efficient, selectively retained in the target tissue relative to surrounding normal tissue and should have minimal toxicity other than to the treated area.

The majority of photosensitizers are derivatives of hematoporphyrin, a synthetic porphyrin synthesized from heme. In 1983, Dougherty (85) demonstrated that crude hematoporphyrin contains a range of different porphyrins and, when converted to HpD by acetylation further porphyrins are produced, such as protoporphyrin and hydroxyethylvinyldeuteroporphyrin. The following year he proposed that the active component of HpD was composed of two porphyrin units linked by an ether bond (86). The chemical formula bis-1-[3(1-hydroxy-ethyl)deuteroporphyrin-8-yl] ethyl ether (I) was proposed, and the compound was given the abbreviated name dihematoporphyrin ether (DHE). Further analytical studies by Kessel et al. (87) and Dougherty (51) suggested that the active component of HpD comprised a mixture of porphyrin rings, between 5 and 8, linked by a number of ether and ester bonds. Although the exact nature of this compound is still controversial, the active component of HpD has retained the name DHE. It is available commercially as "Photofrin(R)" (porfimer sodium, Axcan Pharma, Montreal, Canada), a heterogenous mixture of porphyrins, many of which are not active as tumor sensitizers.

Although Photofrin is the most commonly used photosensitizer it has significant side effects. Therefore, major effort has been invested in the development of new sensitizers. In particular, there was a need for new compounds that absorbed light at longer wavelengths to assist tissue penetration, greater PDT efficiency, selective tissue localization and self-limiting minor skin photosensitivity. To this end many other sensitizers have been described.

Phthalocyanines

These compounds have a structure similar to hematoporphyrin. Instead of four pyrrole units linked by methine carbon atoms, a ring of four isoindole units are linked by nitrogen atoms. In 1986, Bown and coworkers (88) at the National Medical Laser Center in London showed that aluminum chlorophthalocyanine sulfonate (A1SPc) produces more prolonged photosensitization than HpD, but less skin sensitivity in ambient light. A subsequent study by Chan et al (89) demonstrated that A1SPc produces less toxicity on exposure to ambient light but greater toxicity on exposure to red light when compared with HpD. Further studies by the same group, using A1SPc-induced PDT in the treatment of rat bladder tumors, demonstrated that the drug is eliminated from the deeper muscle layers more quickly than the superficial layers of the bladder wall leading to an increased concentration in the mucosa and lamina propria at 24 h. It has since been proposed that this may potentially be exploited to produce a superficial necrosis without underlying muscle damage following light administration (90).