Photodynamic Efficiency: From Molecular Photochemistry to Cell Death

Abstract

Photodynamic therapy (PDT) is a clinical modality used to treat cancer and infectious diseases. The main agent is the photosensitizer (PS), which is excited by light and converted to a triplet excited state. This latter species leads to the formation of singlet oxygen and radicals that oxidize biomolecules. The main motivation for this review is to suggest alternatives for achieving high-efficiency PDT protocols, by taking advantage of knowledge on the chemical and biological processes taking place during and after photosensitization. We defend that in order to obtain specific mechanisms of cell death and maximize PDT efficiency, PSes should oxidize specific molecular targets. We consider the role of subcellular localization, how PS photochemistry and photophysics can change according to its nanoenvironment, and how can all these trigger specific cell death mechanisms. We propose that in order to develop PSes that will cause a breakthrough enhancement in the efficiency of PDT, researchers should first consider tissue and intracellular localization, instead of trying to maximize singlet oxygen quantum yields in in vitro tests. In addition to this, we also indicate many open questions and challenges remaining in this field, hoping to encourage future research.

Keywords: cell death; photodynamic therapy; photooxidation; photosensitization; subcellular localization.

Figure 1

Main routes and initial products of singlet oxygen and radical mediated photooxidations (for details on the products formed, refer to citations in the main text). Abbreviations: PS: photosensitizer; ISC: intersystem crossing; A: substrate for electron transfer reactions.

Figure 2

Biological outcomes of photodynamic therapy (PDT) associated with the amount of reactive species that are generated and possible targets of photooxidation. Note that it is not necessary to damage all targets together to trigger cell death. (A) High PDT-doses in organelles and photodamage of plasma membrane cause ATP depletion, resulting in non-programmed cell death (necrosis); (B) production of reactive species in mitochondria and/or damage to protein B-cell lymphoma 2 (Bcl-2) causes the release of cytochrome c and other apoptogenic factors, which classically trigger the caspases cascade, resulting in apoptosis. Photodamaging endoplasmic reticulum (ER) and lysosomes can also converge to mitochondrial damage, resulting in apoptosis; (C) low PDT-doses in organelles (mitochondria, ER and lysosomes) may activate autophagic process in an unbalanced manner (too much induction or flux inhibition), resulting in autophagic cell death. The inhibition of the mammalian target of rapamycin (mTOR) complex by photooxidation can also trigger autophagy as a cell death pathway.

Figure 2

Biological outcomes of photodynamic therapy (PDT) associated with the amount of reactive species that are generated and possible targets of photooxidation. Note that it is not necessary to damage all targets together to trigger cell death. (A) High PDT-doses in organelles and photodamage of plasma membrane cause ATP depletion, resulting in non-programmed cell death (necrosis); (B) production of reactive species in mitochondria and/or damage to protein B-cell lymphoma 2 (Bcl-2) causes the release of cytochrome c and other apoptogenic factors, which classically trigger the caspases cascade, resulting in apoptosis. Photodamaging endoplasmic reticulum (ER) and lysosomes can also converge to mitochondrial damage, resulting in apoptosis; (C) low PDT-doses in organelles (mitochondria, ER and lysosomes) may activate autophagic process in an unbalanced manner (too much induction or flux inhibition), resulting in autophagic cell death. The inhibition of the mammalian target of rapamycin (mTOR) complex by photooxidation can also trigger autophagy as a cell death pathway.

Figure 3

Possible outcomes of the interaction between photosensitizers (PSes) and binding sites of macromolecules or particles, considering triplet excited states deactivation pathways: (A) stabilization of the monomeric form of the PS and formation of singlet oxygen by energy transfer; (B) stabilization of the dimeric species, favoring the dye–dye mechanism; and (C) binding of the PS to a pocket inaccessible to oxygen, raising the probability of electron transfer pathways.

Figure 4

Proposed main steps that should happen with the photosensitizer (PS) in order to achieve cell death.