Biomedical Engineering Reference
In-Depth Information
180 J/cm
2
; 200 ± 40 mW/cm
2
) (14). After 6 months, the authors
found higher histopathologic response with the higher light
dose, ranging from 69% at 60 J/cm
2
to 93% at 180 J/cm
2
.
No signifi cant systemic adverse events were observed and 65%
of tumors were judged to have good-to-excellent cosmesis at
24 months.
In 1990, Kennedy and colleagues (15) introduced the fi rst
topical porphyrin derivative, known as 5-
processes leads to the generation of tumor-specifi c immune
cells (34,35), which represents a unique feature of PDT and a
major advantage over conventional anticancer therapy (34).
topical photosensitizers
Aminolevulinic Acid /Methyl Aminolevulinate
5-
-ALA is a hydrophilic, low-molecular weight molecule
within the heme biosynthesis pathway (17,36). ALA is consid-
ered a prodrug (37). In vivo, it is converted to PpIX, a photosen-
sitizer in the PDT reaction. In the USA, ALA is available as a
20% topical solution manufactured under the name Levulan®
Kerastick (DUSA Pharmaceuticals, Inc., Wilmington, Massa-
chusetts, USA). FDA-approved since 1999, Levulan is approved
for the treatment of nonhyperkeratotic AKs in conjunction with
a blue light source, such as the Blu-U (DUSA Pharmaceuticals,
Inc.) (38). It is supplied as a cardboard tube housing two sealed
glass ampules, one containing 354 mg of
δ
-ALA, which is a
natural precursor of protoporphyrin IX (PpIX) in the heme
pathway. Therefore, ALA is the prodrug photosensitizing agent
with the ability to penetrate the stratum corneum of the skin
and be absorbed by actinically damaged skin cells as well as
pilosebaceous units, whereas PpIX is the photosensitizer.
Exogenous ALA-forming PpIX is rapidly cleared from the
body, reducing the potential for phototoxicity to days instead
of several months.
Later, lipophilic ALA ester derivatives were developed, show-
ing stronger porphyrin fl uorescence and better tumor selectiv-
ity, most likely because of better penetration through cellular
membranes compared with the hydrophilic ALA (16).
δ
-ALA hydrochloride
powder and the other 1.5 mL of solvent (22). The separate com-
ponents are mixed within the cardboard sleeve just prior to use.
Esters of ALA [methyl ester methyl aminolevulinate (MAL)]
are lipophilic derivatives of the parent molecule. Their chemi-
cal structure provides increased lipophilicity, allowing supe-
rior penetration through cellular lipid bilayers compared with
ALA (18,39). MAL is available as a 16.8% cream in a 2 g tube
and is produced under the name of Metvixia® (Galderma, SA,
Switzerland; PhotoCure ASA, Norway). Since 2004, Metvixia®
and the CureLight BroadBand (Model CureLight 01) were
FDA-approved for the treatment of nonhyperkeratotic AKs of
the face and scalp in immunocompetent patients. Metvixia®
can be used in conjunction with the Aktilite CL128 lamp
(Galderma, SA, Switzerland; PhotoCure ASA, Norway) as well.
MAL may offer better tumor selectivity (39-42) and less
pain (42,43) during PDT with less patient discomfort (43)
compared with ALA.
δ
mechanism of pdt
PDT Mechanism of Action
PDT involves the activation of a photosensitizer by light in the
presence of an oxygen-rich environment. Topical PDT involves
the application of ALA or its methylated derivative (MAL) to
the skin for varying periods. This leads to the conversion of ALA
to PpIX, an endogenous photactivating agent. PpIX accumu-
lates in rapidly proliferating cells of premalignant and malig-
nant lesions (17), as well as in melanin, blood vessels, and
sebaceous glands (18). Upon activation by a light source and in
the presence of oxygen, the sensitizer (PpIX) is oxidized, a pro-
cess called “photobleaching” (19). During this process, free
radical oxygen singlets are generated, leading to selective
destruction of tumor cells by apoptosis without collateral dam-
age to surrounding tissues (20,21). Selective destruction of
malignant cells is due in part to their reduced ferrochelatase
activity, leading to excessive accumulation of intracellular PpIX
(22). In vitro research suggests that any remaining malignant
cells following PDT have reduced survival (23).
Although the precise mechanisms (at a cellular level) under-
lying the effi cacy of topical PDT in the treatment of NMSC are
not fully known, both apoptosis (24,25) and necrosis (26,27)
have been described, with their respective importance being
related to intracellular localization of the photosensitizer and
illumination parameters. In addition to direct damage of neo-
plastic cells, vascular injury plays an important role for the
tumor destruction (28-30), particularly with systemic photo-
sensitizers. Oxygen radicals produced during the photodynamic
process decrease the barrier function of endothelial cells, expos-
ing the vascular basement membrane that leads to the activa-
tion of platelets and polymorphonuclear leukocytes (31,32),
resulting in arteriolar vessel constriction, thrombus formation,
and blood fl ow stasis causing indirect tumor cell kill (28,29). In
addition, the impairment of vascular functions activates acute-
phase proteins (proteinases, peroxidases, complement factors,
and cytokines), resulting in massive accumulation of neutro-
phils and macrophages (32,33) that will contribute to the
destruction of tumor tissue. The establishment of immune
response against the treated malignancy by infl ammatory
Light Irradiation
A range of light sources can be used for topical PDT, including
lasers, pulsed light sources, fi ltered xenon arc and metal halide
lamps, fl uorescent lamps and LEDs. However, certain laser and
light sources are predictably chosen for PDT activation. Their
wavelengths correspond closely with the four absorption peaks
along the porphyrin curve. The Soret band (400-410 nm), with
a maximal absorption at 405-409 nm, is the highest peak along
this curve for photoactivating PpIX. Smaller peaks designated as
the “Q bands” exist at approximately 505-510 nm, 540-545 nm,
580-584 nm, and 630-635 nm (Fig. 10.1) (17,18,36). There are
advantages and disadvantages to exploiting the wavebands in
either the Soret or Q bands for PDT. The Soret band peak is 10-
to 20-fold larger than the Q bands, and blue light sources are
often used to activate PpIX within this portion of the porphyrin
curve, however, longer wavelengths found within the Q bands
produce a red light that penetrates more deeply and can be used
to treat NMSC up to a thickness of 2-3 mm (44), but necessi-
tates higher energy requirements (17,36).
Light Sources
Light sources utilized in PDT can be categorized in a variety of
ways, including incoherent versus coherent sources, or by
color (and wavelengths) emitted. Incoherent light is emitted as
noncollimated light and is provided through broadband
