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Metastatic lesions are usually multiple and resistant to conventional therapies, jeopardizing successful
[4]
surgical resection, chemo and radiation treatment .

Light has been known to provide a therapeutic potential for several thousands of years. Over 3000 years ago,
[5]
since the Ancient, Indian and Chinese civilizations it has been used for the treatment of various diseases
mainly in combination with reactive chemicals, for example to treat conditions like vitiligo, psoriasis and
[6]
skin cancer . After 1895 with the discovery of the phototherapy, which rendered Niels Ryberg Finsen the
Nobel prize in Physiology/Medicine in 1903 in recognition of his work on the treatment of diseases, and in
particular on the treatment of lupus vulgaris by means of concentrated light rays, many studies with the use
[7]
of light and chemicals emerged .

Photodynamic therapy (PDT) is currently being used as an alternative treatment for the control of malignant
diseases [8-10] . It is based in the uptake of a photosensitizer (PS) molecule which, upon being excited by light
in a determined wavelength, reacts with oxygen and generates oxidant species (radicals, singlet oxygen,
triplet species) in target tissues, leading to cell death [11,12] . PDT cytotoxic properties have been established to
be due to the oxidation of a large range of biomolecules in cells, including nucleic acids, lipids, and proteins,
leading to severe alteration in cell signaling cascades or in gene expression regulation [13,14] . Like all the newly
proposed treatments, there is still place for improvements and lots of resources have been invested in this
field recently. In this review, we set out to perform a broad up-date on PDT and it implication in cancer
research and treatment. We have covered topics going from the photochemical mechanisms involved, the
different cell death mechanisms being triggered by a myriad of photosensitizers up to the more recent
reported preclinical studies and on-going clinical trials.

PHOTOCHEMICAL PRINCIPLES AND COMPONENTS OF PDT
As previously stated, PDT involves the photosensitized oxidation of biomolecules which can be separated in
two mechanisms. In Type I, light energy passes from excited molecules to biomolecules through electron/
hydrogen transfer (radical mechanism) in direct-contact reactions [Figure 1] and culminates in specific
damage to biomolecules and in the initiation of radical chain reactions. On the other hand, in the Type
II mechanism, the excitation energy is transferred to molecular oxygen ( O ), resulting in the formation
3
2
1
of singlet oxygen (O ), which is extremely electrophilic, being capable of causing damage to membranes,
2
proteins and DNA [Figure 1]. Direct contact reactions usually cause more severe damage in biomolecules,
but also cause photodegradation of the PS, while diffusive species are important to replenish the PS. By
either mechanism, the formation of triplet excited species is the key step in terms of performance of the PS.
Both tricyclic phenotiazinium salts and macrocyclic poly-pyrroles (porphyrins and derivatives) compounds
generate, reasonable amounts of triplets upon electronic excitation, being therefore PSs commonly used
[15]
for PDT . There is no doubt that the outcome of PDT critically depends on the intrinsic efficiency of the
PS. Even when the search for new PS remains mostly focused in the synthesis of compounds that produce
singlet oxygen with greater efficiency, there are many factors needed to be considered including aggregation
[15]
and photodegradation .
Damages to proteins and membranes are of particular importance for PDT in order to optimize the
cytotoxic efficiency to the process. Indeed, PSs displaying a higher degree of accumulation in cell and/or
organelles membranes are usually more cytotoxic [16,17] . The mechanism by which photosensitized oxidations
[18]
on lipids cause membranes to leak out, has been recently described . In generic terms, changes in
phospholipids occur due to lipid peroxidation, which are reactions that are initiated as a consequence of the
formation of free radicals and singlet oxygen. After this starting point, the process becomes autocatalytic,
leading to the formation of hydroperoxides and other byproducts. Figure 2 summarizes the main steps in
photo-induced membrane damage. The first one usually involves the “ene” reaction between the lipid (LH)