Biomedical Engineering Reference
In-Depth Information
10
Photodynamic therapy
Mitchel P. Goldman and Ane B.M. Niwa Massaki
introduction
Aminolevulinic acid (ALA) was the fi rst photosensitizer
prodrug to be approved by the US Food and Drug Administra-
tion (FDA) for use in topical photodynamic therapy (PDT).
Since its approval over a decade ago, many aspects of
ALA-PDT have been examined. Studies investigating the
treatment of nonhyperkeratotic actinic keratoses (AKs) with
ALA-PDT have led to advances in treatment. Incubation times
of ALA have decreased, multiple light sources have been used
to elicit the reaction, and cosmetic benefi ts of treatment have
been discovered. In the discussion that follows, background on
topical 5-ALA and methyl aminolevulinic acid (MAL), the
most commonly used agents in topical PDT, is provided.
In addition, clinical studies regarding the treatment of AKs,
nonmelanoma skin cancer (NMSC), acne, and photorejuvena-
tion are summarized. There is now growing interest in the use
of PDT for other skin tumors, such as lymphoma, as well as for
nononcological indications, such as psoriasis, localized sclero-
derma, viral warts, onichomycosis, and many other dermato-
logical conditions. Finally, a practical guide for treatment is
provided for the reader to optimize treatment while avoiding
common pitfalls of treatment.
of hematoporphyrins were required for photosensitization,
resulting in subsequent severe phototoxic reactions.
A new photosensitizer hematoporphyrin purifi ed derivative
(HPD) was presented in 1978 by Dougherty and colleagues (6)
that successfully treated cutaneous malignancies using red
light as the primary light source. HPD was a complex mixture
of porphyrin subunits and byproducts. A complete or partial
response in 111 of 113 malignant lesions, including carcino-
mas of the breast, colon, prostate, squamous cell, basal cell,
and endometrium; malignant melanoma; mycosis fungoides;
chondrosarcoma; and angiosarcoma, was observed with sys-
temic HPD (dose of 2.5 or 5.0 mg/kg).
Subsequently, other studies (7,8) using a purifi ed hematopor-
phyrin derivative, known as Photofrin (porfi mer sodium), were
conducted and Photofrin received approvals for PDT of selected
stages of lung, esophageal, gastric, and cervical cancer in several
European countries and Japan. Therefore systemic HPD became
the standard for PDT research. However, practical use in der-
matology was diffi cult due to the cutaneous accumulation of
porphyrin-based photosensitizing drugs and their slow clear-
ance leading to prolonged photosensitivity (4-6 weeks).
Second-generation photosensitizers were then developed,
consisting of several synthetic purifi ed compounds that have
been proposed as potentially useful for anticancer PDT.
Successful treatment of multiple NMSCs has been reported
(6,9-11) using those synthetic purifi ed systemic photosensitiz-
ers, including chlorine derivatives (benzoporphyrin derivative-
monoacid ring A,
N
-aspartyl-chlorin e6, Tin etiopurpurin,
lutetium texapyrin, porphines, and phthalocyanines (chloro-
aluminum phthalocyanine tetrasulfonate and silicon phthalo-
cyanine). Those compounds present strong light absorption at
660-850 nm range, allowing deeper penetration of tissue by
the activating light as compared with porphyrins, which exhibit
a maximum absorption in the Soret band (360-400 nm)
followed by four smaller peaks between 500 and 635 nm (Q
bands) (12). Furthermore, rapid drug accumulation in neo-
plastic tissue (1-8 hours after intravenous administration)
enabled patients to be treated in the same day. In view of low
accumulation levels in normal skin and rapid drug elimina-
tion, those synthetic compounds also presented mild photo-
sensitivity for a few days after administration, although
cutaneous reaction occurring one or more months after
PDT was still possible (13). A randomized multicenter phase II
study conducted at four North American university-based
dermatology clinics evaluated 54 patients with 421 multiple
NMSC treated with vertoporfi n (benzoporphyrin derivative
monoacid ring A)-PDT (intravenous dose 14-18 mg/m
2
)
using red light-emitting diode (LED) (688 ± 10 nm; 60, 120, or
history
In 1900, Raab (1) fi rst noted that paramecia cells
(Paramecium
caudatum)
were unaffected when exposed to acridine orange
or light, but when exposed to both at the same time, they died
within 2 hours. In 1904, Von Tappeiner and Jodblauer (2) were
the fi rst to use the term “photodynamic effect” to an oxygen-
consuming reaction process in protozoa after aniline dyes were
applied with fl uorescence. In 1905, topical 5% eosin was suc-
cessfully used as a photosensitizer with artifi cial light to treat
NMSCs, lupus vulgaris, and condylomata lata in humans by
Jesionek and Von Tappeiner (3). The authors theorized that
the eosin was incorporated into cells and triggered a cytotoxic
reaction when exposed to a light source and oxygen.
Most photosensitizers used in PDT are derivatives of hemato-
porphyrin, an endogenous porphyrin that was fi rst synthesized
from heme in the mid-19th century. In 1913, Meyer-Betz (4)
was the fi rst to demonstrate the “photodynamic effect” in vivo
after he injected himself with hematoporphyrin and noticed
that the areas exposed to light became swollen and painful.
Unfortunately, the phototoxic reaction lasted for 2 months.
In 1942, Auler and Banzer (5) demonstrated the ability of hema-
toporphyrin to concentrate more in certain dermatologic
tumors than in their surrounding tissues. Histological analysis
also showed that tumors were necrotic, confi rming the photo-
dynamic response of hematoporphyrin. However, large doses
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