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Page 4 of 20 dos Santos et al. J Cancer Metastasis Treat 2019;5:25 I http://dx.doi.org/10.20517/2394-4722.2018.83

(LOOH) and another L•. The propagation phase comprises the initiation of a new oxidation chain by the
peroxyl radical (LOO•) and the decomposition of the lipid hydroperoxides into other intermediate radicals.
In light-induced reactions, formation of alkoxides is catalyzed by direct contact reactions between the triplet
photosensitizer, the lipid double bond and the lipid hydroperoxide, leading to chain breakage by -scission.
This process leads to the formation of lipid truncated aldehydes and further products, which are molecules
responsible for starting of the leakage process. This explains successful results as well as opens possibilities
for cellular targeting strategies that will be discussed below.

RESEARCH IN PDT
Photosensitizers and photocytotoxicity mechanisms
The PS is one of the three crucial elements of PDT, apart from light and oxygen. Due to their photochemistry
properties and uptake efficiency currently only a few PSs have official approval worldwide and are being used
clinically. Related to cancer treatment, PS approved or in clinical trial are listed on Table 1. In particular, Porfimer
sodium (Photofrin), mTHPC (Foscan), NPe6 (Laserphyrin), SnEt2 (Purlytin), Visudyne (Veteporfin) and
Motexafin lutetium (LuTex) are clinically or preclinically applied for breast cancer [19-21] . These photosensitizers
have shown selectivity towards tumor cells and are ideal for cellular and vascular-targeted PDT. Moreover
their interference with cytoprotective molecular responses constitutes an area of growing interest [22,23] .
[24]
Other compounds such as porphyrin precursors [e.g., aminolevulinic acid (ALA)] , phenothiazines (e.g.,
[28]
[27]
methylene blue) [25,26] , cyanines (e.g., merocyanine, indocyanine green) , hypericin , and xanthenes
[29]
(e.g., Rose Bengal) have been considered as good candidates as PS used for PDT.
Several studies have been performed over the last decades in order to better characterize PS efficacy and
selectivity. Some of them have focused on the development of agents with higher absorption wavelengths,
allowing deeper penetration of illuminating sources and thus the depths at which tumor cells can be
targeted, the so-called second-generation PSs. Third-generation PSs have recently emerged aiming mainly
at targeting strategies, such as antibody-directed PS and PS-loaded nanocarriers. These approaches were
developed in order to increase the power and efficiency of PDT and have allowed the broadening of the types
[36]
of diseased tissues that could be treated .

Besides the PSs photoactive capacity, which enables it as a therapeutic agent upon light activation, their
autofluorescence is also an important characteristic. Indeed, PS’s fluorescence confers them imaging
properties to be used for detection of pre-cancer lesions and early malignancies, as well as tumor margins.
Furthermore, this property can be used for the identification of remaining dysplastic tissue upon surgical
tumor resections, and to monitor the progress of the PDT treatment. Thus the combination of imaging,
detection and therapeutic properties confers them the characteristics of theranostic agents [36,37] . PS 5-ALA,
which is a prodrug enzymatically converted during heme synthesis to the active PS agent protoporphyrin
IX, displays theranostic properties and has brought important knowledge in PDT research and treatment
[24]
field. Additionaly, in clinical trials 5-ALA has already shown clinical benefit in different types of tumors .

PDT is considered to be involved in at least three main mechanisms of tissue destruction. The first one
is the ability to directly kill cells through the action of damaging reactive chemical species generated by
PS excitation. Direct phototoxic effect of PDT involves irreversible photodamage to specific targets, such
[38]
as membranes and organelles as discussed in the previous section. The extent of the damage as well as
the cell death mechanisms involved are dependent on the PS type, concentration, subcellular localization,
energy applied and also on the intrinsic resistance characteristics of each tumor type. When perturbations
of the intracellular and/or extracellular microenvironment are too intense, cells can die following a complete
[39]
breakdown of the plasma membrane (necrosis morphology) or elicit specific cell death mechanisms .
Additionally, PDT tumor destruction can also involve the damage of the tumor vasculature, thereby