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INNOSC Theranostics and
Pharmacological Sciences The biochemical and biophysical guide for photodynamic therapy

when the PS is in the triplet state. In the first process, achieve the desired therapeutic effect, certain conditions
the PS removes an electron from a reducing molecule in must be met, influencing each of these aspects. PDT
its vicinity. Molecules that donate electrons include, for reduces the number of clonogenic cancer cells through
example, tyrosine in proteins, guanine in nucleic acids, or direct photodamage; however, this event does not lead
tryptophan. This electron transfer creates a pair of radical to the complete eradication of pathological cells. This
anions and radical cations. In an oxygen-rich environment, limitation arises from serveral factors, one of which is the
the PS radical anion transfers its electron to molecular heterogeneous distribution of the PS within the tumor.
oxygen, generating a superoxide anion, which effectively Another key factor is the availability of oxygen in the tissue
restores the PS to its original state. The superoxide anion being treated. Limited oxygen availability can restrict the
can act as a reducing agent or as a monovalent oxidant. direct killing of cancer cells (Figure 2). These constraints
Although it does not directly interact with lipids, nucleic give rise to two primary mechanisms: photochemical
acids, or carbohydrates, the superoxide can oxidize small oxygen consumption and the direct impact of PDT on
molecules such as leucoflavins, sugar tautomers, sulfates, tissue microcirculation. The amount of oxygen available
tetrahydroflavins, and catecholamines. Superoxide radical during PDT depends on the photobleaching of the PS. As
reaction with other biologically relevant radicals may the PS is reduced, the rate of oxygen consumption during
lead to the formation of potentially toxic, cell-damaging therapy also decreases. Fractionating the delivered light
products. In biological systems, the most common phenol is crucial, as it allows the tissue to reoxygenate during
is the amino acid tyrosine. When the superoxide reacts with breaks in illumination. Furthermore, PDT-induced
nitric oxide, a strong oxidant, peroxynitrite, is produced, microcirculation damage, particularly when higher doses
which can react with carbon dioxide and bicarbonates to of PSs such as Photofrin are used, disrupts oxygen delivery
form nitrosoperoxycarbonate. The carbonate radical anion to tissues. Vascular mechanisms of PDT vary significantly
is a single-electron oxidizer that can remove electrons with different PSs. For instance, PDT with Photofrin leads
from tyrosine and tryptophan. In addition, superoxide can to vasoconstriction, leakage of macromolecules from
oxidize protein clusters, such as enzymes involved in the vessels, leukocyte adhesion, and clot formation, all of
Krebs cycle and dehydratases. Disruption of these clusters, which are associated with platelet activation and the release
particularly the iron-sulfur [4Fe-4S] clusters, can have of thromboxane. PDT can also induce vasoconstriction
harmful effects. First, it impairs aerobic energy production by inhibiting the production or release of nitric oxide
and biosynthetic pathways by inactivating Krebs cycle by the endothelium. Damage to the normal vascular
enzymes. Second, it generates hydroxyl radicals, that system surrounding the tumor can significantly hinder
is, strong oxidants, through the Fenton reaction, where the effectiveness of PDT. Studies have shown that cancer
released iron from the [4Fe-4S] clusters acts as a catalyst for cannot be effectively treated when the tissue surrounding
hydrogen peroxide. The iron ions, in their reduced form, the tumor is damaged during PDT. Recent research
bind to anionic molecules, such as nucleic acids, proteins, suggests that treatment with a high fluence rate inhibits
lipids, and other cellular components. The stable hydrogen tumor cure. However, no differences in tumor perfusion or
peroxide can diffuse through membranes and react with oxygenation were observed between treatments with low
iron bound to biomolecules, generating highly reactive or high fluency. These findings indicate that the protection
hydroxyl radicals. The radicals can damage cells at the site provided by the normal vascular system around the tumor
where they are formed. In the second process, the energy is a crucial factor in the long-term control of cancerous
of the PS is transferred to molecular oxygen, which, in its tissue during PDT (Table 1). To optimize the efficacy of
ground state, is a triplet. The transfer of energy excites one PDT, it is important to regularly monitor parameters such
of the two unpaired electrons into a high-energy orbital, as the concentration of the PS in the tissues, the rate of
causing a spin flip, which converts oxygen into a singlet. photobleaching, blood oxygen levels, and blood flow. 3
Singlet oxygen ( O ) is considered the main destructive
1
2
agent in PDT. While biological systems have enzymatic 4. Literature search method
defenses against superoxide, there are no developed Articles for this review were retrieved from online databases
antioxidant enzymes to remove O , likely due to its short (PubMed/MEDLINE) using the following search terms:
1
2
lifespan. 4 “photodynamic therapy,” “PDT,” and “photosensitizers.”
3. Mechanisms of cancer cell destruction in 5. Results
PDT The total number of articles identified was 92 and the

PDT targets cancer cells, specifically their microcirculation, number included in the current review is 45. In this paper,
as well as the functioning of the host’s immune system. To only studies in English are selected. The first cited here

Volume 8 Issue 2 (2025) 18 doi: 10.36922/itps.4559