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dos Santos et al. J Cancer Metastasis Treat 2019;5:25 I http://dx.doi.org/10.20517/2394-4722.2018.83 Page 15 of 20

Cholangiocarcinoma Porfimer sodium Observational 30/Dec/18 200 NCT01524146
Esophageal Adenocarcinoma, Early any Observational Jan/22 400 NCT00587314
Lung Cancer Porfimer sodium Observational 30/Dec/24 1000 NCT01842555
Lung Cancer any Observational 15/Dec/23 1000 NCT03589456
Neoplastic Disease any Observational Jul/21 400 NCT02159742
Prostate Cancer any Observational 01/Mar/20 200 NCT03492424
*HPPH stands for 2-1[Heyloxyethyl]-2-Devinylpyropheophorbide-a

photodynamic cell death by necrosis and selective time- and dose dependent phototoxic effects on MCF-7
cells but little damage to non-tumorigenic cells. The micelles inhibited the generation of cellular colonies as
well as migration of tumor cells indicating possible capacity to prevent the recurrence of breast cancer and
to minimize the chances of cell spreading and thus the formation of metastases [129] .

Although PDT is based on the preferential accumulation in the tumor tissue, this selectivity is not absolute
and some damage can occur to the surrounding tissue. Thus, a deeper understanding of the molecular
mechanisms involved in drug delivery and specific targeting of tumors should contribute to the development
of more specific technologies to deliver light and/or drugs to the tumor site and also to minimize resistance
to PDT. Accordingly, the development of new PS targeting specific tumor sites have led to the modality of
[130]
targeted-PDT . Another approach consists the photochemical delivery of drugs through photochemical
internalization (PCI), a modified form of PDT. PCI is actually a light-controlled drug-delivery alternative in
which light activation enables spatiotemporal specificity and control of the intracellular drug release [131-133] .
Moreover the potential of PCI to circumvent the resistance and increase the efficacy of a variety of
anticancer agents, have been demonstrated in several tumor models including approaches to overcome PDT-
resistance in breast cancer cells [133,134] . Since identifying cellular resistance mechanisms by understanding the
differences in cell response at the molecular level is of fundamental importance to improving the protocol
and to increase the success of the therapy [135] , we have recently shown that breast cancer cells are differently
affected by methylene blue (MB) concentrations at the same light dose in MB-PDT and that non-malignant
[26]
human breast cells are significantly more resistant to the therapy compared to the malignant ones . One
more example of how the use of a targeting agent would ideally improve the selectivity of PDT for the
tumor tissue has been shown in a recent study. By using polyethylene glycol-coated, folate conjugated,
benzoporphyrin derivative-loaded liposomes for PDT treatment of breast cancer cells, the researchers have
reported that these liposomes are targeted for are greater uptake into TNBC cancer cells [136] . Therefore,
focusing on the molecular differences of cell death mechanisms induced by PDT, starting with an optimized
PS choice and conditions of its delivery and activation, will certainly provide valuable clues for the
development of new therapeutic strategies aiming at improving the efficacy of PDT against cancer cells [7,15] .

CONCLUSION
The challenges in fighting the disease rely on intrinsic tumor resistance properties, molecular heterogeneity,
and metastasis. Considering all the information provided one can conclude that there are almost no doubts
that one relevant advantage of PDT over other cancer treatments is the possibility of generating less side
effects to the patients.

In summary, in this review we have explored and presented a broad up-date on the use of PDT as a
therapeutic approach in the treatment of primary cancer as well as metastasis. We have covered several
topics ranging from the photochemical mechanisms involved, the different cell death mechanisms being
triggered by several photosensitizers up to the more recent-on-going clinical trials. Additionally, we
have presented a significant amount of information underscoring the relevance of PDT as an alternative
therapeutic approach capable of inducing several mechanisms of cell death, some of them simultaneously.