Photodynamic therapy in cancer treatment - an update review

Anc��ly Ferreira Dos Santos, Daria Raquel Queiroz De Almeida, Leticia Ferreira Terra, Maur��cio S. Baptista, Leticia Labriola
2019 Journal of Cancer Metastasis and Treatment  
Cancer remains a worldwide health problem, being the disease with the highest impact on global health. Even with all the recent technological improvements, recurrence and metastasis still are the main cause of death. Since photodynamic therapy (PDT) does not compromise other treatment options and presents reduced long-term morbidity when compared with chemotherapy or radiotherapy, it appears as a promising alternative treatment for controlling malignant diseases. In this review, we set out to
more » ... rform a broad up-date on PDT in cancer research and treatment, discussing how this approach has been applied and what it could add to breast cancer therapy. We 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-on-going clinical trials. Metastatic lesions are usually multiple and resistant to conventional therapies, jeopardizing successful surgical resection, chemo and radiation treatment [4] . Light has been known to provide a therapeutic potential for several thousands of years. Over 3000 years ago, since the Ancient, Indian and Chinese civilizations it has been used for the treatment of various diseases [5] mainly in combination with reactive chemicals, for example to treat conditions like vitiligo, psoriasis and skin cancer [6] . 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 of light and chemicals emerged [7] . Photodynamic therapy (PDT) is currently being used as an alternative treatment for the control of malignant diseases [8] [9] [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 ( 3 O 2 ), resulting in the formation of singlet oxygen ( 1 O 2 ), which is extremely electrophilic, being capable of causing damage to membranes, 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 for PDT [15] . 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 and photodegradation [15] . 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 on lipids cause membranes to leak out, has been recently described [18] . 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)
doi:10.20517/2394-4722.2018.83 fatcat:7i6gchnanzggzkcl4ykgqfv5na