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REVIEW

Photodynamic therapy for

cancer: Principles
Brian C Wilson PhD

BC Wilson. Photodynamic therapy for cancer: Principles. Can Le traitement photodynamique contre
J Gastroenterol 2002;16(6):393-396. le cancer
The principles of photodynamic therapy (PDT), using drugs RÉSUMÉ : Les principes du traitement photodynamique (TPD), faisant
(photosensitizers) that are activated by light to become cytotoxic, appel à des médicaments (photosensibilisants) activés par la lumière pour
provide the basis for understanding the current and potential devenir cytotoxiques, permettent d’en comprendre les applications cli-
future clinical applications in gastroenterology, general oncology niques actuelles et potentielles en gastroentérologie, en oncologie et dans
and other specialities. The properties of photosensitizers are key d’autres spécialités. Les propriétés des photosensibilisants sont essentielles
to their biological efficacy, while lasers and optical fibres allow à leur efficacité biologique, tandis que les lasers et les fibres optiques per-
convenient and flexible light delivery for endoscopic use. PDT mettent de fournir de la lumière avec rapidité et flexibilité en cas d’endos-
has several distinct and unique advantages, both as a stand-alone copie. Le TPD possède plusieurs avantages distincts et uniques, tant à titre
treatment and in combination with other established modalities. de traitement autonome qu’en combinaison avec d’autres modalités
The current limitations are also recognized, as is the need for rig- établies. Ses limites actuelles sont également reconnues, de même que le
orous randomized trials of this emerging technology. The fluores- besoin de procéder à des essais aléatoires rigoureux au sujet de cette tech-
cence of many photosensitizers may be useful, either for nologie émergente. La fluorescence de nombreux photosensibilisants peut
(endoscopic) diagnosis or for PDT treatment guidance and mon- être utile au diagnostic (endoscopique) ou à l’orientation et à la surveil-
itoring. lance du TPD.

Key Words: Cancer; Fluorescence; Laser; Optical fibre; Photo-

dynamic therapy; Photosensitizer

hotodynamic therapy (PDT) is the therapeutic use of A photon of light of an appropriate wavelength is
P drugs (photosensitizers) that are activated by light (1-3).
There are three main steps leading from light absorption by
absorbed by the photosensitizer molecule, raising it to a
short-lived (singlet) excited state. The molecule can then
the photosensitizer to the therapeutic outcome. Figure 1 undergo internal rearrangement to a longer lived (triplet)
shows a typical energy level diagram for photosensitizer state, which exchanges energy with molecular oxygen to
activation. produce highly active singlet oxygen (1O2). The photosen-

This review is based on a presentation made at the 13th International Course on Therapeutic Endoscopy, Toronto, Ontario, October 11 to 14, 2000
Department of Medical Biophysics, Ontario Cancer Institute/University of Toronto, Toronto, Ontario
Correspondence and reprints: Dr Brian Wilson, Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute,
Princess Margaret Hospital, 610 University Avenue, Room 7-417, Toronto, Ontario M5G 2M9. Telephone 416-946-2952, fax 416-946-6529,
e-mail [email protected]
Received for publication April 23, 2001. Accepted April 23, 2001

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Wilson

Figure 1) Energy level diagram for photodynamic therapy via genera-

tion of singlet oxygen (1O2)

Figure 2) Absorption (extinction) spectra of three photosensitizers.

TABLE 1 AlPcSn Aluminumchlorosulphonated phthalocyanine; mTHPC Meso-
Examples of photodynamic therapy drugs tetra(hydroxyphenyl) porphyrin
Class Examples Commercial drug
Porphyrins HpD Photofrin* (Axcan
Pharma, Canada)
Protoporphyrin IX Levulan* (DUSA, USA)
BPD-MA Vertofrin* (QLT
Phototherapeutics,
Canada)
mTHPC Foscan* (Biolitec,
Germany)
Purpurins Tin etiopurpurin Purlytin* (Miravant, USA)
Phthalo- AlPcSn –
cyanines
Texafrins Lutetium texafrin Lutrin* (Pharmacyclics, USA)
Chlorins Chlorin-e6 NPe6* (Nippon Chemical, Japan)
*Currently in clinical trials. AlPcSn Aluminumchlorosulphonated phthalocya-
nine; BPD-MA Benzoporphyrin derivative; HpD Hematoporphyrin derivative; Figure 3) Typical penetration depths of light in tissue ranging from high
mTHPC Meso-tetra(hydroxyphenyl) porphyrin
to low pigmentation, as a function of wavelength

sitizer returns to the ground state, where it may undergo fur- the photophysics, photochemistry and photobiology of
ther activation cycles. 1O2 is highly reactive and produces PDT (4). The concept of light-activated drug therapy has
the photobiological and clinical response. An alternative also been extended to several other medical conditions in
decay path for the excited drug is to emit longer wavelength addition to solid tumour destruction, and there has been
fluorescent light that can be used for tumour detection and parallel development of fluorescence diagnostics. A partial
localization, or for monitoring the PDT treatment. list of current PDT drugs is given in Table 1.
In the 1960s, hematoporphyrin derivative was discov- Except for the ‘prodrug’ 5-aminolevulinic acid (ALA),
ered, leading to reports of tumour detection by its fluores- these current PDT drugs are all photosensitizers.
cence. In the mid-1970s, tumour eradication was Administration of ALA increases heme synthesis, the
demonstrated in animal models, and the first patient studies penultimate step of which is the accumulation of a photo-
were reported shortly thereafter. The first governmental sensitizer, protoporphyrin IX (PpIX). PpIX tissue selectivity
approvals for the use of PDT with hematoporphyrin deriva- depends on the rates of PpIX synthesis and conversion to
tive (in its purified commercial form, Photofrin [Axcan heme, while the tissue selectivity of the other photosensi-
Pharma, Canada]) took place in 1993 in Canada, and this tizers relies on their pharmacokinetics and binding. Some
treatment has since been approved in the United States, drugs also require a delivery vehicle, such as lipid emulsions
Europe and Japan for a variety of malignant solid tumours or liposomes, for in vivo administration, due to poor water
and dysplasias. In the past decade, there have been major solubility. Typically, the tumour to normal host tissue selec-
advances in new photosensitizers, improved light sources, tivity of photosensitizers is less than about 5:1, but addi-
delivery and dosimetry equipment, and in understanding tional selectivity is gained through the targeting of the

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Photodynamic therapy for cancer

activation light. In most cases, the photosensitizer is admin- emitting diodes, generally are used either in ‘open beam’
istered intravenously (and the dose is expressed in mg of configuration or may be coupled into fibre bundles of a few
drug/kg body weight). ALA may also be given orally or top- millimetres in diameter.
ically. The transport of the light from the source to the patient
One objective for solid tumour therapy has been to is a crucial step in PDT. Endoscopy requires fibre optic
increase the photosensitizer activation wavelength to delivery, while interstitial activation involves placing opti-
increase the penetration depth of the light in tissue and, cal fibres directly into the tumour. Although a simple
hence, the treatment depth or volume. Several absorption cleaved-tip fibre can be used, the power density at the tip
spectra are shown in Figure 2, while Figure 3 shows the gen- can be very high, causing tissue heating. Microlens-tipped
eral wavelength dependence of light penetration in tissue. fibres may be used for irradiating tissue surfaces, and fibres
For very superficial disease, such as Barrett’s esophagus, use with scattering tips are available, as either an isotropic point
of short-wavelength light (eg, blue light) may be advanta- or a line source. The latter come in lengths of about 5 mm
geous. Note that the treatment depth (ie, depth of necrosis) to 10 cm, either rigid or flexible. Multiple fibres can be used
is typically three to five times the light penetration depth. interstitially to treat larger tissue volumes, with typical
1O has a very short lifetime due to its reactivity; there- spacings of 5 to 10 mm. With cylindrical diffusing fibres,
2
fore, the biochemical damage, primarily lipid peroxidation, the light ‘dose’ may be expressed in terms of light energy
occurs very close to the site of photosensitizer localization, delivered per cm length of fibre, rather than per cm2 of tis-
usually cell membranes. If the concentration of 1O2 is high sue surface area, in cases where the latter is not well defined
enough, then cell death occurs, by either necrosis or apop- (eg, for interstitial treatments) or is difficult to measure.
tosis. In tissue, both direct killing of (tumour) cells and For endoscopic irradiation, microlens and diffusing-tip
damage to blood vessels from killing of endothelial cells, fibres may be placed via the instrument channel.
leading to ischemic tissue death, may occur, and immuno- Specialized irradiators include line fibres incorporated into
logical effects may also contribute to tumour response. a cylindrical balloon, which, when inflated, centres the
In most clinical treatments to date, a single drug and source along the lumen. The balloon surface can be masked
light dose have been used. Treatment ‘fractionation‘ has to limit the treatment to be only partially circumferential.
also been investigated, either by repeating the complete The general advantages of PDT for solid tumour therapy
drug-light cycle or by using multiple light doses for a single are as follow.
drug administration. Rapid on-off light sequences can • It has double selectivity (drug and light), while
increase the tumour response by allowing oxygen to be either drug or light therapy alone has no effect.
replenished in cases where the rate of 1O2 production
exceeds the oxygen perfusion rate in the tissue. • It can be given before, after or adjuvantly with other
Many photosensitizers are photobleached by light irradi- standard therapies, including surgery, radiation and
ation, ie, the concentration of photoactive drug falls as the chemotherapy, with no known contraindications.
drug is destroyed in the photochemical reactions. For some • There is excellent healing of normal host tissue, with
photosensitizers, photobleaching leads to the generation of preservation of the collagen structure.
a photoproduct that may absorb light at a different wave-
length and may be photoactive. • It may be repeated without inducing tumour
PDT involves a combination of drugs and devices. The resistance or normal tissue hypersensitivity.
latter include light sources, light delivery systems and • It has minimum side effects, except for skin
instruments for light, drug and oxygen dosimetry. With photosensitivity, which requires the patient to
most photosensitizers, the delivered light ‘dose’ (fluence) take moderate precautions against bright light.
required is substantial – typically around 100 J/cm2. This is With Photofrin, this sensitivity can persist for several
expressed as the incident energy per unit area of tissue sur- weeks, but the effect is greatly reduced with many
face. For example, to treat a lesion with a surface area of second-generation drugs, both in severity and in
10 cm2 in 15 min requires a total delivered power of about duration.
1 W, within a narrow wavelength band, to overlap with the
photosensitizer absorption. • By selection of the drug, delivery vehicle and
There are two main classes of light source – laser and drug-light time interval, different tissue components
nonlaser. Lasers can be coupled efficiently to single optical can be targeted and different mechanisms of action
fibres for endoscopic, intraoperative or interstitial light invoked for therapeutic gain.
delivery. Recently, compact diode lasers have become avail-
able with adequate power for many PDT applications, and The current limitations of PDT are as follow.
are replacing the earlier wavelength-tunable argon dye or • It cannot easily be used for large tumour masses.
potassium titanyl phosphate (KTP)-dye systems. However, The penetration of even longer wavelength light
each operates at a single wavelength, so that multiple limits the effective depth of treatment to typically
sources are required for use with different drugs. Nonlaser 5 to 10 mm. Multiple interstitial optical fibres can
sources, which include wavelength-filtered lamps and light- increase the treated volume.

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Wilson

• The optimum drug and light doses, and after PDT light irradiation can be used to check that the
drug-light time interval may vary from patient target tissue has been adequately and uniformly irradiated
to patient or lesion to lesion, so that standardized and/or to assess the fraction of drug bleached.
protocols may not achieve the maximum response
rates. REFERENCES
1. Buskard NA, Wilson BC. The use of photodynamic therapy in cancer.
• Extensive preclinical and clinical trials are needed Semin Oncol 1994;21(Suppl 15):1-3.
for each new photosensitizer and/or indication. 2. Dougherty TJ, Gomer CJ, Henderson BW, et al. Photodynamic
therapy. J Natl Cancer Inst 1998;90:889-905.
Many PDT photosensitizers are fluorescent (5). Fluores- 3. Dougherty TJ. Photodynamic therapy. J Clin Laser Med Surg
1996;14:219-348.
cence measurements can be made in vivo either point by 4. Fisher AMR, Murphree AL, Gomer CJ. Clinical and preclinical
point or by imaging. The target tissue to be treated by PDT photodynamic therapy. In: Puliafito CA, ed. Laser Surgery and
can be localized using this fluorescence. The photosensi- Medicine. New York: Wiley-Liss, 1996:339-68.
5. Wagnieres GA, Star WM, Wilson BC. In vivo fluorescence
tizer uptake and kinetics can also be determined. spectroscopy and imaging for oncological applications. Photochem
Monitoring of photosensitizer photobleaching during or Photobiol 1998;68:603-32.

396 Can J Gastroenterol Vol 16 No 6 June 2002

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