although the most common side effect of clinically approved PDT
sensitizers is persistent skin photosensitivity and this is related
to a poor distribution between the tumor and skin. For example,
Photofrin and Foscan lead to skin photosensitivity that may last
from 4 to 6 weeks after treatment ( 102 ). Improved biodistribution
may reduce skin photosensitivity and when associated with a high
tumor-to-muscle tissue ratio it may also avoid unwanted side
effects in the tissues surrounding the tumor. Favorable pharmaco-
kinetics, namely, a circulation time in the organism that is suffi-
ciently long to take advantage of the good biodistribution of
porphyrin derivatives but sufficiently short for satisfactory clear-
ance, is also critical for the success of a PDT sensitizer. Finally,
most sensitizers are hydrophobic and require drug formulations
with organic solvents that are an additional burden to the organ-
ism. Preference for biocompatible sensitizers with low or negative
logPOWmust be balanced with the evidence for higherin vitro
PDT efficacy of more lipophilic sensitizers, presumably due to bet-
ter intracellular localizations (107,109,110).
Many examples of tumor regressions in mice with implanted
tumors are available in the literature.Table VII results from
an effort to select studies with efficient sensitizers that also
reported tumor-to-skin and tumor-to-muscle tissue ratios. These
ratios are not relevant for Stakel and H 2 DOHPTMB because
irradiation of the tumors was made starting immediately or
15 min after the intravenous injection of the sensitizers, respec-
tively (85,113). The use of these sensitizers and of Tookad is
not based on their selectivity toward tumor versus normal
tissues. Rather, PDT with these sensitizers targets vascular
effects. In fact, it was shown that there is no significant penetra-
tion of Tookad in the tissues, and its mechanism is based on the
differential response of tumor and normal vasculature to Tookad-
PDT ( 114 ). The photosensitizer in Table VII with the largest
tumor-to-skin ratio is H 2 TClPBOH, and this is expected to mini-
mize skin photosensitivity. Additionally, more than 90% of this
sensitizer is cleared from the blood in 24 h, which are very favor-
able pharmacokinetics. The stability of this bacteriochlorin due
to the presence of electron-withdrawing substituents and the sol-
ubility in biocompatible vehicles introduced by the sulfophenyl
groups are key factors for the success of this sensitizerin vivo.
These factors complement the spectroscopic and photochemical
properties discussed earlier, namely, the strong absorption of
the bacteriochlorin core in the phototherapeutic window, the fast
intersystems crossing to the triplet due to the internal heavy-
atom effect, the long-lived triplet state, and the efficient forma-
tion of both singlet oxygen and superoxide ion. The tumor growth
226 LUIS G. ARNAUT