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.

ΔΨm: mitochondrial transmembrane inner potential; AAU: autophagy arbitrary units; ATG5, autophagy related 5; ATG7: autophagy related 7; BAF: bafilomycin A; BSA: bovine serum albumin; CASP3: caspase 3; CF: carboxyfluorescein; CTSB: cathepsin B; CVS: crystal violet staining; DCF: dichlorofluorescein; DCFH: 2',7'-dichlorodihydrofluorescein; DMMB: 1,9-dimethyl methylene blue; ER: endoplasmic reticulum; HaCaT: non-malignant immortal keratinocyte cell line from adult human skin; HP: hydrogen peroxide; LC3B-II: microtubule associated protein 1 light chain 3 beta-II; LMP: lysosomal membrane permeabilization; LTG: LysoTracker™ Green DND-26; LTR: LysoTracker™ Red DND-99; 3-MA: 3-methyladenine; MB: methylene blue; mtDNA: mitochondrial DNA; MitoSOX™: red mitochondrial superoxide probe; MTDR: MitoTracker™ Deep Red FM; MTO: MitoTracker™ Orange CMTMRos; MT-ND1: mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1; MTT: methylthiazolyldiphenyl-tetrazolium bromide; O: singlet oxygen; OH hydroxil radical; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PBS: phosphate-buffered saline; PI: propidium iodide; PDT: photodynamic therapy; PS: photosensitizer; QPCR: gene-specific quantitative PCR-based; Rh123: rhodamine 123; ROS: reactive oxygen species RTN: rotenone; SQSTM1/p62: sequestosome 1; SUVs: small unilamellar vesicles; TBS: Tris-buffered saline.

Mobilization of specific mechanisms of regulated cell death is a promising alternative to treat challenging illness such as neurodegenerative disease and cancer. The use of light to activate these mechanisms may provide a route for target-specific therapies. Two asymmetric porphyrins with opposite charges, the negatively charged TPPS2a and the positively charged CisDiMPyP were compared in terms of their properties in membrane mimics and in cells. CisDiMPyP interacts to a larger extent with model membranes and with cells than TPPS2a, due to a favorable electrostatic interaction. CisDiMPyP is also more effective than TPPS2a in damaging membranes. Surprisingly, TPPS2a is more efficient in causing photoinduced cell death. The lethal concentration on cell viability of 50% (LC50) found for TPPS2a was ~3.5 (raw data) and ~5 (considering photosensitizer incorporation) times smaller than for CisDiMPyP. CisDiMPyP damaged mainly mitochondria and triggered short-term phototoxicity by necro-apoptotic cell death. Photoexcitation of TPPS2a promotes mainly lysosomal damage leading to autophagy-associated cell death. Our data shows that an exact damage in lysosome is more effective to diminish proliferation of HeLa cells than a similar damage in mitochondria. Precisely targeting organelles and specifically triggering regulated cell death mechanisms shall help in the development of new organelle-target therapies.

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