Photosensitizers in clinical PDT
Section snippets
Historical perspectives
Treatment using light and light activated compounds are referenced in ancient times, and were used to treat a wide variety of disorders and malaise [1], [2], [3]. Of particular note were salves placed on cutaneous tumors that were then exposed to sunlight with good response. The 1903 Nobel Prize was awarded to Niels Finsen for his work on phototherapy. Finsen discovered that light treatment could control skin manifestations of tuberculosis, a very common ailment at that time [4]. Similarly
Ideal photosensitizers
In order to critique clinically available photosensitizers, one must have some sort of ideal for comparison. However, the ideal photosensitizer would vary from clinicians to purists. We believe the guidelines that follow are clinically relevant.
Guidelines
(1) Toxicity One does not want a toxic chemical, otherwise chemotherapeutic agents could be used. Further, metabolism of the photosensitizer should not create new toxic byproducts. (2) Mutagenicity/carcinogenicity The photosensitizer should not cure one disease only to create another. (3) Elimination Removal of the photosensitizer from the patient should be of clinical utility. One may want to retreat a patient without re-administering the photosensitizer, so half-life may be of consequence. (4)
Fluorescence
Having a photosensitizer assist in therapy is an important concept. Light energy brought to the photosensitizer can go through several distinct pathways. For therapy, one wants the pathway that creates a photodynamic reaction although other pathways can be clinically useful. A pathway for fluorescence is extremely beneficial. Employing fluorescence one can define and adjust the treatment fields. The tumor bed will light up, as will other regions containing malignant cells. This could easily
Dosimetry
Dosimetry is an alien concept to most clinicians. However, dosimetry is the single most important and least understood aspect of photodynamic therapy in general and photosensitizers in particular. While this paper’s focus is on clinical photosensitizers, dosimetry truly is the alpha and omega of PDT. Dosimetry allows for a homogeneous or non-homogeneous dose distribution over the region requiring PDT and also evaluates in a quantitative fashion dosing of normal tissues. Clearly, the ideal light
Clinical photosensitizers
Many products can behave as photosensitizers and new ones are regularly discovered; however, very few have made it to clinical trial and even fewer are readily commercially available. We will examine the photosensitizers on the market, based on published peer-reviewed papers. Table 1 lists the current clinical photosensitizers and their manufacturers.
Photosensitizing families
Photosensitizers can be categorized by direct chemical structure and come from several broad families. Table 2 outlines the photosensitizers families discussed in this review. The first family discovered is based on hematoporphyrin (Hp) and its derivatives. After purification and manipulation hematoporphyrin derivative (HpD) is transformed into commercial products variously called Photofrin®, Photosan, Photocan, etc. [21]. These products are composed of differing fractions of porphyrin
The generation gap
The porphyrins are generally called first generation photosensitizers. Sometimes first generation labels photosensitizers developed in the 1970s and early 1980s, which by the way are the porphyrins. Second generation photosensitizers refer more to porphyrin derivatives or synthetics made from the late 1980s on. Third generation photosensitizers take available drugs and then modify them with antibody conjugates, built in photo bleaching capability, biologic conjugates, etc. [37]. Dividing drugs
Hematoporphyrin derivative (HpD)
Photofrin® (HpD) is commercially available from Axcan Pharma, Inc. and has the longest clinical history and patient track record. Fig. 1 shows the molecular structure for Photofrin®. The photosensitizer is actually a proprietary combination of monomers, dimers, and oligomers derived from chemical manipulation of hematoporphyrin [38]. The complex mixture is required for clinical activity. Similarly named photosensitizers derived by similar or different means from hematoprophyrins are also
Temoporfin
Foscan® is a member of the chlorin family with a number of interesting clinical characteristics that have brought it to the forefront of newer photosensitizers [24], [105], [106]. Fig. 3 shows the molecular structure for Foscan®. However, many of the purported benefits of this photosensitizer are also potentially significant drawbacks. As a number of patients have been treated, some conclusions may be made, but only time and additional follow-up will allow for true assessment. However, it is
Dyes
Harking back to the days of Raab, dyes have been a fertile ground in which to develop photosensitizers. In fact, many of the dyes used in ink are efficacious photosensitizers. Most of the activity for clinical photosensitizers in the dye family, come from phthalocyanines and their relatives, the naphthocyanines [141]. These structures are active in the 650–850 nm range and activate at energies around 100 J/cm2. Most dyes are hydrophobic requiring delivery agents for clinical use such as a
Conclusion
The current family of photosensitizers on the market are—depending on your opinion—not selective or too selective, not efficient or too efficient, not pure or too pure, not able to penetrate deeply or able to penetrate too much, and the list goes on. Despite these drawbacks, successful PDT is possible not only on a variety of conditions, but under a variety of conditions. Once clinicians and scientists can speak the language of the photosensitizer, this drug will be able to screen for a medical
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