Mechanisms in photodynamic therapy: part one—-photosensitizers, photochemistry and cellular localization

Singlet oxygen (1O2) is unique amongst reactive oxygen species formed in cells in that it is an excited state molecule with an inherent upper lifetime of 4 micros in water. Whether the lifetime of 1O2 in cells is shortened by reactions with cellular molecules or reaches the inherent maximum value is still unclear. However, even with the maximum lifetime, the diffusion radius is only approximately 220 nm during three lifetimes (approximately 5% 1O2 remaining), much shorter than cellular dimensions indicating that the primary reactions of 1O2 will be subcellularly localized near the site of 1O2 formation. This fact has raised the question of whether spatially resolved cellular responses to 1O2 occur, i.e. whether responses can be initiated by generation and reaction of 1O2 at a particular subcellular location that would not have been produced by 1O2 generation at other subcellular sites. In this paper, we discuss examples of spatially resolved responses initiated by 1O2 as a function of distance from the site of generation of 1O2. Three levels are recognized, namely, a molecular level where the primary oxidation product directly modifies the behavior of a cell, an organelle level where the initial photo-oxidation products initiate mechanisms that are unique to the organelle and the cellular level where mediators diffuse from their site of formation to the target molecules that initiate the response. These examples indicate that, indeed, spatially resolved responses to 'O2 occur in cells.

https://bioone.org/journals/photochemistry-and-photobiology/volume-82/issue-5/2006-04-14-IR-874/Spatially-Resolved-Cellular-Responses-to-Singlet-Oxygen/10.1562/2006-04-14-IR-874.pdf

Spatially resolved cellular responses to singlet oxygen

https://estudogeral.sib.uc.pt/bitstream/10316/5382/1/filee00c9afa87bb4f27a59fc5d1eb3e9829.pdf

Intracellular signaling mechanisms in photodynamic therapy.

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.

https://www.mdpi.com/1422-0067/16/9/20523/pdf

Photodynamic Efficiency: From Molecular Photochemistry to Cell Death

This review traces the development and study of the second-generation photosensitizer 5,10,15,20-tetra(m-hydroxyphenyl)chlorin through to its acceptance and clinical use in modern photodynamic (cancer) therapy. The literature has been covered up to early 2011.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.2011.00986.x

Temoporfin (Foscan®, 5,10,15,20-tetra(m-hydroxyphenyl)chlorin)--a second-generation photosensitizer

Intracellular photosensitiser localisation significantly influences the mechanism of response to photodynamic therapy (PDT), since the primary sites of damage are closely related to the specific sensitiser distribution Foscan subcellular localisation in the MCF-7 human adenocarcinoma cell line has been studied by means of confocal microscopy and microspectrofluorometry The fluorescence topographic profiles recorded after cells costained with Foscan and organelle-specific fluorescent probes revealed that Foscan presents low localisation in lysosomes and a weak accumulation in mitochondria Alternatively, the Foscan fluorescence topographic profile turned out to colocalise perfectly with that obtained for the endoplasmic reticulum (ER) and the Golgi apparatus The patterns of fluorescence derived from confocal microscopy studies were consistent with predominant localisation of Foscan in these organelles Furthermore, evaluation of enzymatic activity of selected organelles immediately after laser light irradiation (650 nm) indicated the Golgi apparatus and ER as the primary damaged sites resulting from Foscan-mediated PDT in the MCF-7 cell line To our knowledge, this is the first study to demonstrate unambiguously that the ER and the Golgi apparatus are preferential sites of Foscan accumulation

/pdf/endoplasmic-reticulum-and-golgi-apparatus-are-the-3dv4v4mq6t.pdf

Santus R

Papers

Endoplasmic reticulum and Golgi apparatus are the preferential sites of Foscan localisation in cultured tumour cells.