Photosensitizers in clinical PDT

https://doi.org/10.1016/S1572-1000(04)00007-9Get rights and content

Abstract

Photosensitizers in photodynamic therapy allow for the transfer and translation of light energy into a type II chemical reaction. In clinical practice, photosensitizers arise from three families—porphyrins, chlorophylls, and dyes. All clinically successful photosensitizers have the ability to a greater or lesser degree, to target specific tissues or their vasculature to achieve ablation. Each photosensitizer needs to reliably activate at a high enough light wavelength useful for therapy. Their ability to fluoresce and visualize the lesion is a bonus. Photosensitizers developed from each family have unique properties that have so far been minimally clinically exploited. This review looks at the potential benefits and consequences of each major photosensitizer that has been tried in a clinical setting.

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) ToxicityOne 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/carcinogenicityThe photosensitizer should not cure one disease only to create another.
(3) EliminationRemoval 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

References (148)

  • H Kostron et al.

    Photodynamic therapy in neurosurgery: a review

    J Photochem Photobiol B

    (1996)
  • W.E Grant et al.

    Photodynamic therapy of oral cancer: photosensitization with systemic aminolevulinic acid

    Lancet

    (1993)
  • R Waidelich et al.

    Whole bladder PDT with 5-ALA and a white light source

    Urology

    (2003)
  • D.M Pariser et al.

    Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial

    J Am Acad Dermatol

    (2003)
  • P Jichlinski et al.

    Hexyl aminolevulinate fluorescence cystoscopy: new diagnostic tool for photodiagnosis of superficial bladder cancer—a multicenter study

    J Urol

    (2003)
  • L Gossner et al.

    Photodynamic therapy: successful destruction of gastrointestinal cancer after oral administration of aminolevulinic acid

    Gastrointest Endosc

    (1995)
  • I.A Barbazetto et al.

    Treatment of choroidal melanoma using photodynamic therapy

    Am J Ophthalmol

    (2003)
  • J.L Sessler et al.

    Texaphyrins: new drugs with diverse clinical applications in radiation and photodynamic therapy

    Biochem Pharmacol

    (2000)
  • R.R Allison et al.

    Photodynamic therapy for the treatment of nonmelanomatous cutaneous malignancies

    Semin Cutan Med Surg

    (1998)
  • R Bonnett et al.

    Porphyrins as photosensitizers

    Ciba Found Symp

    (1989)
  • Dougherty TJ, Henderson BW, Schwartz S, et al. Historical perspective. In: Henderson BW, Dougherty TJ, editors....
  • Finsen NF. Phototherapy. London: Arnold;...
  • O Raab

    On the effect of fluorescent substances on infusoria (in German)

    Z Biol

    (1900)
  • A Jesionek et al.

    On the treatment of skin cancers with fluorescent substances

    Arch Klin Med

    (1905)
  • A Jodlbauer et al.

    On the participation of oxygen in the photodynamic effect of fluorescent substances

    Münch Med Wochenschr

    (1904)
  • H Von Tappeiner et al.

    On the effect of photodynamic (fluorescent) substances on protozoa and enzymes

    Arch Klin Med

    (1904)
  • Schmid R. The porphyrias. In: Stanberg JB, Wyngaarden JB, Fredrickson DB, editors. The metabolic basis of inherited...
  • T.J Dougherty et al.

    Photoradiation therapy for the treatment of malignant tumors

    Cancer Res

    (1978)
  • Drabkin DL. Selected landmarks in the history of porphyrins and their biologically functional derivatives. In: Dolphin...
  • G.A Wagnieres et al.

    In vivo fluorescence spectroscopy and imaging for oncological applications

    Photochem Photobiol

    (1998)
  • A Gillenwater et al.

    Fluorescence spectroscopy: a technique with potential to improve the early detection of aerodigestive tract neoplasia

    Head Neck

    (1998)
  • K Svanberg et al.

    Laser-based spectroscopic methods in tissue characterization

    Ann N Y Acad Sci

    (1998)
  • R Richards-Kortum et al.

    Quantitative optical spectroscopy for tissue diagnosis

    Annu Rev Phys Chem

    (1996)
  • D.R Braichotte et al.

    Optimizing light dosimetry in photodynamic therapy of early stage carcinomas of the esophagus using fluorescence spectroscopy

    Lasers Surg Med

    (1996)
  • K.R Diamond et al.

    Quantification of fluorophore concentration in tissue-simulating media by fluorescence measurements with a single optical fiber

    Appl Opt

    (2003)
  • Hu XH, Feng Y, Lu JQ, et al. Modeling of type II photodynamic therapy process in a heteregeneous tissue phantom. Phys...
  • T.H Foster et al.

    Oxygen consumption and diffusion effects in photodynamic therapy

    Radiat Res

    (1991)
  • R Bonnett et al.

    HpD—a study of its components and their properties

    Adv Exp Med Biol

    (1983)
  • D Kessel et al.

    Probing the structure and stability of the tumor-localizing derivative of hematoporphyrin by reductive cleavage with LiAlH4

    Cancer Res

    (1987)
  • R Bonnett et al.

    Hydroporphyrins of the meso-tetrahydroxyphenyl porphyrin series as tumors photosensitizers

    Biochem J

    (1989)
  • J.W Winkelman et al.

    Neurotoxicity of tetraphenylporphinesulfonate TPPS4 and its relation to photodynamic therapy

    Photochem Photobiol

    (1987)
  • J.G Levy et al.

    Photodynamic therapy of malignancies with benzoporphyrin derivative monoacid ring A

    Proc Soc Photo-Opt Instrum Eng

    (1994)
  • W Hausman

    The photodynamic action of plant extracts containing chlorophyll

    Biochem Z

    (1907)
  • R Bonnett

    Photosensitizers of the porphyrin and phthalocyanine photodynamic therapy

    Chem Soc Rev

    (1995)
  • R Bonnett

    New photosensitizers for the photodynamic therapy of tumors

    Proc Soc Photo-Opt Instrum Eng

    (1994)
  • W.G Roberts et al.

    In vitro characterization of monoaspartylchlorin e6 for photodynamic therapy

    J Natl Cancer Inst

    (1988)
  • Allen R, Kessel D, Tharratt RS, et al. Photodynamic therapy of superficial malignancies with NPe6 in man. In: Spinelli...
  • A.R Morgan et al.

    New photosensitizers for photodynamic therapy: combined effect of metallopurpurin derivatives and light on transplantable bladder tumors

    Cancer Res

    (1988)
  • J.G Moser

    Bacteriopheophorbide ester as a sensitizer

    SPIE

    (1993)
  • E.F Stradnadko et al.

    Photodynamic therapy of cancer: five year clinical experience

    Proc Soc Photo-Opt Instrum Eng

    (1997)
  • Cited by (893)

    View all citing articles on Scopus
    View full text