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Page 4 of 15 Girotti et al. J Cancer Metastasis Treat 2020;6:52 I http://dx.doi.org/10.20517/2394-4722.2020.107

Figure 1. 5-Aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Utilization of PpIX for
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photodynamic therapy (PDT) or fluorescence-guided surgery (FGS) is illustrated. PBG: porphobilinogen; FECH: ferrochelatase; PpIX:
3
1
1
ground state porphyrin; PpIX: singlet excited state porphyrin; PpIX: triplet excited state porphyrin; O 2 : photogenerated singlet oxygen
which accounts, at least in part, for the greater PDT susceptibility of the former. Moreover, unlike normal
brain, malignant brain typically loses most of its blood-brain barrier function, allowing ALA access via
the blood stream. In some tumors, including glioblastomas, this PpIX buildup is augmented by partial
downregulation of ferrochelatase (FECH), the enzyme that inserts ferrous iron into PpIX to give heme [40,41] .
In ALA-based PDT [Figure 1], relatively intense red light elevates ground state PpIX to a singlet excited
3
1
state ( PpIX), much of which undergoes intersystem crossing to a long-lived triplet ( PpIX). Energy
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transfer from the latter to O gives O , a non-radical ROS, whereas indirect reaction could give free radical
2
2
ROS, as indicated above. In addition to sensitizing cytotoxic PDT reactions, ALA-induced PpIX can be
used diagnostically to define tumor boundaries. In this case, low intensity blue light (~400 nm) generates
1
significant PpIX, which, upon decay to ground state, releases red fluorescent light. Many oncologists,
particularly those treating difficult glioblastomas, have exploited this property for fluorescence-guided
[42]
surgery (FGS), i.e., for clear demarcation of tumor boundaries before surgical resection [Figure 1] . When
applied carefully, using a surgical fluorescence microscope, FGS can greatly improve procedural accuracy
by limiting inadvertent removal of non-tumor tissue [42-44] . Thus, ALA-induced PpIX has the advantage of
serving as a surgical guide on the one hand and PDT sensitizer on the other hand. In addition to being
used individually, FGS and PDT are often run sequentially, the latter to eradicate any residual tumor cells
[44]
after the former is carried out . Various pharmacologic approaches have been used for improving both
[44]
FGS and PDT efficacy, e.g., FECH inhibitors or iron chelators to further elevate ALA-induced PpIX
levels. ALA-based FGS and PDT are rapidly becoming the new standards of care for the management of
malignant brain tumors.