Abstract

Photodynamic therapy (PDT) is a noninvasive, highly selective method for the treatment of diseases characterized by uncontrolled cell proliferation. It was clinically approved more than 30 years ago. PDT involves the selective uptake of a photosensitizer (PS) by neoplastic tissue, which is able to produce reactive oxygen species (ROS) upon irradiation with visible or near-infrared (NIR) light. ROS induce destruction of target cells and damage of tumor-associated vasculature and activate an antitumor immune response, leading to tumor regression. The execution of this process is attained by different mechanisms, including host immune responses and activation of cell death pathways: apoptosis and necrosis.

Introduction

Photodynamic therapy (PDT) is a minimally invasive modality used in the treatment of a variety of cancers and benign diseases (table 1). It was originally used in the management of a small number of selected tumors [25] and has expanded to areas of application as diverse as dermatology [4,54] and cosmetics [84,85], immunology [17], ophthalmology [63,80], cardiology [89,92], urology [8] and dentistry [45,61]. Furthermore, PDT has been successfully used against antibiotic-resistant bacteria [3,81], for the treatment of viral [16,87] and fungal infections [11,73,74], for the inactivation of pathogens in blood products [88], for water sterilization [7,58] and for disinfection [10,59]. The photodynamic process is also used for drug delivery and the release of endocytosed molecules in the cytosol [5,6].

Photosensitizers and photodynamic reaction

The destruction of target cells in PDT is achieved by activation of a light-absorbing photosensitizer (PS) with visible or near-infrared light (figure 1).

The activated PS is excited to its singlet state, and, after intersystem crossing to the triplet state, PS transfers its energy to molecular oxygen and generates reactive singlet oxygen (type II reaction), or reacts directly with biomolecules (type I reaction), forming reactive oxygen species (ROS): superoxide anion, hydroxyl radical, hydrogen peroxide. ROS mediate oxidative damage of intracellular structures, causing cell death via apoptosis or necrosis [12,68], vascular shutdown, induction of an antitumour immune response, and the consequent destruction of the tumor [2]. Because the PS is effective only in the presence of light, generalized toxicity in PDT is avoided by illuminating only the specific area. Unfortunately the ROS also switch on a stress response of cancer cells that helps them to deal with the PDT-induced oxidative stress (repair and survival pathway).

The majority of currently used PSs (table 2) are cyclic tetrapyrrolic molecules – porphyrins and their analogs, chlorins, phthalocyanines, etc. – and their characteristics have been thoroughly reviewed [71]. The first clinically approved PS was Photofrin, a hematoporphyrin derivative, widely used in clinical PDT [90]. Shortcomings of Photofrin [70] stimulated research of compounds which can meet the requirements for an ideal PS [77]. Researchers succeeded in several aspects: synthesis of stable PSs absorbing red and NIR light (650–800 nm), which allow for better tissue penetration [18,19,93]; better pharmacokinetics for faster elimination from the body and reduction of side effects; and selectivity – increasing the target/healthy tissue ratio [2,60,78,82]. In further improvement of PSs, priority was given to the targeting of the PS to particular cellular organelles, increasing PS uptake and shifting absorbance to longer light wavelengths. Key elements in PDT are illumination and optical properties of tissues that determine the depth and efficacy of the treatment. Light absorption by endogenous chromophores, such as hemoglobin and melanin, limit light penetration at wavelengths <650 nm, whereas light penetration is reduced due to absorption by water at wavelengths over 1,300 nm. The first study involved the natural pigments bacteriochlorins and bacteriopurpurins, with strong absorption of NIR light (720–850 nm) [39], but revealed that they are photounstable and permit limited chemical modifications [38,66]. Recently developed new synthetic bacteriochlorins are more stable and demonstrate improved pharmacokinetics and high PDT efficacy [18,19,20,38,93].

Cell responses

The PS is preferentially taken up and retained by tumor cells, and its subcellular localization determines the sites of primary damage and influences the way of cell death [43]. Generally speaking, mitochondrially localized PSs induce programmed cell death (apoptosis), whereas lysosomally localized ones can cause either a necrotic or an apoptotic response [42,64]. A dose-dependent apoptosis to necrosis shift has been found for most PSs [27,75].

Depending on morphology, enzymatic activity and immunologic responses, the cell death mode is designated as either programmed or non-programmed [50]. Apoptosis is the standard programmed cell death characterized by nuclear and membrane degradation [26]. It is triggered by specific signals that lead to the activation of cascade pathways and result in degradation of nucleic and polypeptide materials and a suicidal outcome. Apoptosis involves a family of caspases – cysteine aspartyl proteases – that stimulate other effector agents to disassemble cellular contents.

Affected cells round off and wind up communication with adjacent cells, their plasma membranes fragment and phosphatidylserines translocate to the outer layers. Other changes follow: cross-linkage and polymerization of proteins, chromatin condensation, nuclear fragmentation by cation-dependent endonuclease and, finally, fragmentation into apoptotic bodies and removal. Mitochondrial membranes’ increased permeability and the release of apoptogenic substances, such as cytochrome C, characterize the intrinsic pathway of apoptosis. The extrinsic pathway involves the activation of cell membrane death receptors, such as tumor necrosis factor receptor 1 (TNFR1) or Fas/CD95 [26,41,44].

Generally, PSs with a predilection for mitochondrial accumulation and causing Bcl-2 protein destruction are inducers of apoptosis [67]. For example, silicon phthalocyanine (PC-4) was proven to promote apoptosis of malignant CD4+ CD7− T-lymphocytes by destruction of Bcl-2 [53]. Similarly, in breast cancer cells a metallo-PC- -mediated PDT led to apoptosis, with the predominance of apoptotic cells after PDT, nuclear fragmentation and increased expression of Bcl-2, DNA fragmentation factor alpha (DFFA1) and caspase 2 (CASP2) genes [62]. Another way for apoptotic cell death induction is the transfer of calcium ions (Ca2+) from endoplasmic reticulum to mitochondria, causing calcium overload in mitochondria. That leads to morphological changes and apoptosis in a nonnuclear and Ca2+-dependent manner [33]. Additionally, PDT has the ability to induce cell damage in the presence of an increased level of intracellular Ca2+, which appears to be p53 dependent [32].

Necrosis is defined as accidental and non-programmed cell death, characterized by an inflammatory response and the absence of signals associated with apoptosis. A necrotic response can be stimulated by stress factors such as infectious pathogens, toxins and trauma [50,55]. It was found that signal transduction and catabolic reactions of the necrotic pathway are initiated by toll-like receptors (TLR) and the death domain [14]. Seven types of necrotic pathways have been recognized, but the sequence of events is common for all, including oncosis (swelling of the nucleus and mitochondria and cytoplasm vacuolization), membrane permeability, lysosomal perforation, movement of calcium ions across the endoplasmic reticulum and calpain (a family of calcium- -dependent, non-lysosomal cysteine proteases) activation, followed by degradation of cell components and induction of the inflammatory response [15].

PCs leading to cell membrane disintegration and local depletion of oxygen and nutrients would stimulate cell death mainly by necrosis [67]. Liposomal aluminum chloro-phthalocyanine (AlClPC) mediated PDT led to 90% necrotic cell death and disruption of blood vessels, in both in vitro and in vivo studies using an oral cancer cell line [56,57]. Another evident increase of necrotic- -related cell death was observed in the case of application of phthalocyanine tetra-sulfonated zinc [76].

The relative uptake and subcellular localization are dependent on particular chemical features of PC. Neutral PCs show more diffuse localization and tend to be primarily localized in the Golgi apparatus in the perinuclear area, whereas ionic PCs are initially collected in lysosomes. The cationic (ahead of the neutral) PCs seem to be more effective than the anionic ones. Following irradiation, PCs undergo relocalization, which is charge dependent, and this demonstrated that the secondary localization site is more important in predicting the outcome of any PC-mediated PDT [91].

Worth mentioning, a promising strategy for more effective PDT is the use of two combined PSs. Simultaneous administration of two chemically different PSs – zinc(II)-phthalocyanine (ZnPc) and the cationic porphyrin meso-tetrakis(4-N-methylpyridyl)porphine (TMPyP) – in three cell lines (HeLa, HaCaT and MCF-7) provided synergistic cure rates compared to standard PDT. Moreover, depending on the light dose, changes from predominant apoptosis (without cell detachment) to predominant necrosis were detected [1].

Immune responses

Non-specific immune response in PDT

PDT-induced oxidative damage affects mainly the membranes and cytoplasm of tumor cells, tumor vasculature, and other stromal elements. The local host response develops as acute inflammation [46], triggered by release of cytoplasmic components, vasoactive agents and activation of the complement cascade. This acute inflammation is expressed by the secretion of cytokines, leukocyte chemoattractants, growth factors, and other regulators, leading to infiltration of the tissue with neutrophils, macrophages, mastocytes, and natural killer (NK) cells [24].

Among cytokines (interleukins [IL-1β, IL-6, IL-10], tumor necrosis factor [TNF], granulocyte-colony stimulating factor [G-CSF]) and chemokines (murine chemokines [KC], macrophage-inflammatory protein-2 [MIP-2]) induced by the photodynamic reaction, IL-1β seems to be the most important [35]. Neutralization of IL-1β reduces the efficacy of PDT, whereas no significant effects are observed with anti-IL-6 and anti-TNFalpha antibodies [83]. Furthermore, PDT combined with recombinant cytokines (G-CSF, GM-CSF, and TNF) is more effective [23,34,51]. Also anti-inflammatory cytokines such as IL-10 and transforming growth factor beta (TGF-β) improve PDT outcomes [46].

The first cells invading PDT-treated tumor sites are neutrophils. Depletion of neutrophils in mouse and rat models impairs the efficacy of antitumor PDT [22,47]. Macrophages infiltrating the tumor bed also play a role in the PDT-induced response. Inactivation of macrophages with silica particles decreases cure rates in mice, while macrophage-activating GM-CSF or vitamin D3-binding protein improves PDT antitumor effects [49,51]. Another major element of the non-specific immune response is NK cells. The response to a suboptimal PDT dose is significantly reduced by NK cell depletion [37].

Innate immune cells encounter released tumor antigens (including oxidatively modified ones) and molecules known as damage-associated molecular patterns (DAMPs) or cell death-associated molecular patterns (CDAMPs) [24]. DAMPs and CDAMPs serve as warning signals and promote inflammatory responses to cell stress, injury, or death. DAMPs bind to pattern recognition receptors (PRRs) of infiltrating leukocytes and stimulate antigen-presenting cells (APCs). DAMPs released from PDT-treated tumor cells are considered to be key players in the immunogenicity of tumor cells. The best known PDT-induced DAMPs are the heat-shock protein family (HSP), adenosine triphosphate (ATP), high mobility group box-1 (HMGB-1), and calreticulin (CRT) [29,31].

Specific immune response in PDT

It has been noted that the adaptive immune response is influenced by PDT-mediated inflammation [9]. The intermediaries between innate and adaptive immune systems are dendritic cells (DCs), the most potent APCs [79]. DC maturation is triggered by PDT-elicited local and systemic inflammation caused by PDT-related oxidative stress and tumor cell apoptotic and necrotic death [30,36,40,52]. Activated and functionally mature DCs that have captured tumor-derived proteins and encounter DAMPs migrate to the secondary lymphoid tissues, where they prime T cells with tumor-associated antigens (TAA) associated with major histocompatibility complex class I and II molecules (MHC).

An effective specific immune response depends on proper selection, proliferation, and differentiation of antigen-specific T lymphocytes into activated effector T cells [72], which infiltrate the tumor site [65]. Several studies accentuate the role of cytotoxic CD8+ T cells in PDT outcome and clinical efficacy [13]. Long-term tumor control after PDT treatment is possible only in immunocompetent mice. However, adoptive transfer of T lymphocytes from naive mice that underwent successful PDT restored antitumor PDT efficacy in immunodeficient ones [37,48]. Moreover, PDT of multifocal angiosarcoma resulted in spontaneous regression of untreated distant tumors [86]. T-cell depletion studies revealed that the CD8+ T-cell population is essential for a successful PDT response, whereas the CD4+ T cell population plays only a supportive role [37]. MHC class I molecules lacking tumors are resistant to a specific immune response since recognition of an antigen complexed with MHC I is necessary for CD8+ T cell activation [21].

Conclusion

Cell death processes lead to elimination of undesirable cells from the organism. The execution of these processes is accomplished by cell senescence, apoptosis and necrosis. The generation of ROS and induction of oxidative responses are essential for these eradicating mechanisms. PDT is an efficient treatment modality selectively inducing oxidative damage in cancer cells. PDT remains an attractive and promising therapeutic strategy in the light of steadily growing knowledge of the interaction between the immune system and tumor cells. It is believed that the unique properties of PDT combined with adjuvant immunotherapy may offer not only simple destruction of the primary tumor but also stimulation of the host immune system to recognize, track down, and ultimately destroy tumor cells that have metastasized to distant regions of the body. Further research is needed, especially in the fields of PS selectivity and tumor cell survival pathways and their inhibitors. Higher PDT efficacy will lead to better disease management and prolonged patient survival.

References

• 1. Acedo P., Stockert J.C., Cañete M., Villanueva A.: Two combinedphotosensitizers: a goal for more effective photodynamic therapyof cancer. Cell Death Dis., 2014; 5: e1122
  Google Scholar
• 2. Agostinis P., Berg K., Cengel K.A., Foster T.H., Girotti A.W., GollnickS.O., Hahn S.M., Hamblin M.R., Juzeniene A., Kessel D., Korbelik M.,Moan J., Mroz P., Nowis D., Piette J., et al.: Photodynamic therapy ofcancer: an update. CA Cancer J. Clin., 2011; 61: 250-281
  Google Scholar
• 3. Arenas Y., Monro S., Shi G., Mandel A, McFarland S, Lilge L.: Photodynamicinactivation of Staphylococcus aureus and methicillin-resistantStaphylococcus aureus with Ru(II)-based type I/type II photosensitizers.Photodiagnosis Photodyn. Ther., 2013; 10: 615-625
  Google Scholar
• 4. Babilas P., Schreml S., Landthaler M., Szeimies R.M.: Photodynamictherapy in dermatology: state of the art. Photodermatol. Photoimmunol.Photomed., 2010; 26: 118-132
  Google Scholar
• 5. Berg K., Folini M., Prasmickaite L., Selbo P.K., Bonsted A., EngesaeterB.Ø., Zaffaroni N., Weyergang A., Dietze A., MaelandsmoG.M., Wagner E., Norum O.J., Høgset A.: Photochemical internalization:a new tool for drug delivery. Curr. Pharm. Biotechnol., 2007;8: 362-372
  Google Scholar
• 6. Berg K., Selbo P.K., Prasmickaite L., Tjelle T.E., Sandvig K., MoanJ., Gaudernack G., Fodstad O., Kjølsrud S., Anholt H., Rodal G.H.,Rodal S.K., Høgset A.: Photochemical internalization: a novel technologyfor delivery of macromolecules into cytosol. Cancer Res.,1999; 59: 1180-1183
  Google Scholar
• 7. Bonnett R., Krysteva M.A., Lalov I.G., Artarsky S.V.: Water disinfectionusing photosensitizers immobilized on chitosan. Water Res.,2006; 40: 1269-1275
  Google Scholar
• 8. Bozzini G., Colin P., Betrouni N., Nevoux P., Ouzzane A., Puech P.,Villers A., Mordon S.: Photodynamic therapy in urology: what can we do now and where are we heading? Photodiagnosis Photodyn.Ther., 2012; 9: 261-273
  Google Scholar
• 9. Brackett C.M., Gollnick S.O.: Photodynamic therapy enhancementof anti-tumor immunity. Photochem. Photobiol. Sci., 2011;10: 649-652
  Google Scholar
• 10. Brovko L.: Photodynamic treatment: a new efficient alternativefor surface sanitation. Adv. Food Nutr. Res., 2010; 61: 119-147
  Google Scholar
• 11. Calzavara-Pinton P., Rossi M.T., Sala R., Venturini M.: Photodynamicantifungal chemotherapy. Photochem. Photobiol. 2012;88: 512-522
  Google Scholar
• 12. Castano A.P., Demidova T.N., Hamblin M.R.: Mechanisms in photodynamictherapy: part one-photosensitizers, photochemistry andcellular localization. Photodiagnosis Photodyn. Ther., 2004; 1: 279-293
  Google Scholar
• 13. Castano A.P., Mroz P., Hamblin M.R.: Photodynamic therapy andanti-tumour immunity. Nat. Rev. Cancer, 2006; 6: 535-545
  Google Scholar
• 14. Cho Y., McQuade T., Zhang H., Zhang J., Chan F.K.: RIP1-dependentand independent effects of necrostatin-1 in necrosis and T cellactivation. PLoS One, 2011; 6: e23209
  Google Scholar
• 15. Christofferson D.E., Li Y., Hitomi J., Zhou W., Upperman C., ZhuH., Gerber S.A., Gygi S., Yuan J.: A novel role for RIP1 kinase in mediatingTNFα production. Cell Death Dis., 2012; 3: e320
  Google Scholar
• 16. Costa L., Faustino M.A., Neves M.G., Cunha A., Almeida A.: Photodynamicinactivation of mammalian viruses and bacteriophages.Viruses, 2012; 4: 1034-1074
  Google Scholar
• 17. Cotter T.G.: Apoptosis and cancer: the genesis of a research field.Nat. Rev. Cancer, 2009; 9: 501-507
  Google Scholar
• 18. Dabrowski J.M., Arnaut L.G., Pereira M.M., Monteiro C.J.,Urbańska K., Simões S., Stochel G.: New halogenated water-solublechlorin and bacteriochlorin as photostable PDT sensitizers: synthesis,spectroscopy, photophysics, and in vitro photosensitizingefficacy. Chem. Med. Chem., 2010; 5: 1770-1780
  Google Scholar
• 19. Dabrowski J.M., Arnaut L.G., Pereira M.M., Urbańska K., StochelG.: Improved biodistribution, pharmacokinetics and photodynamicefficacy using a new photostable sulfonamide bacteriochlorin. Med.Chem. Commun., 2012; 3: 502-505
  Google Scholar
• 20. Dabrowski J.M., Urbanska K., Arnaut L.G., Pereira M.M., AbreuA.R., Simões S., Stochel G.: Biodistribution and photodynamic efficacyof a water-soluble, stable, halogenated bacteriochlorin againstmelanoma. Chem. Med. Chem., 2011; 6: 465-475
  Google Scholar
• 21. Daniels M.A., Jameson S.C.: Critical role for CD8 in T cell receptorbinding and activation by peptide/major histocompatibilitycomplex multimers. J. Exp. Med., 2000; 191: 335-346
  Google Scholar
• 22. de Vree W.J., Essers M.C., De Bruijn H.S., Star W.M., Koster J.F.,Sluiter W.: Evidence for an important role of neutrophils in theefficacy of photodynamic therapy in vivo. Cancer Res., 1996; 56:2908-2911
  Google Scholar
• 23. de Vree W.J., Essers M.C., Koster J.F., Sluiter W.: Role of interleukin 1 and granulocyte colony-stimulating factor in photofrin-basedphotodynamic therapy of rat rhabdomyosarcoma tumors. CancerRes., 1997; 57: 2555-2558
  Google Scholar
• 24. Dolmans D.E., Fukumura D., Jain R.K.: Photodynamic therapyfor cancer. Nat. Rev. Cancer, 2003; 3: 380-387
  Google Scholar
• 25. Dougherty T.J., Gomer C.J., Henderson B.W., Jori G., Kessel D.,Korbelik M,. Moan J., Peng Q.: Photodynamic therapy. J. Natl. Cancer.Inst., 1998; 90: 889-905
  Google Scholar
• 26. Erental A., Sharon I., Engelberg-Kulka H.: Two programmed celldeath systems in Escherichia coli: an apoptotic-like death is inhibitedby the mazEF-mediated death pathway. PLoS Biol., 2012; 10: e1001281
  Google Scholar
• 27. Fabris C., Valduga G., Miotto G., Borsetto L., Jori G., GarbisaS., Reddi E.: Photodensitization with zinc (II) phthalocyanine asa switch in the decision between apoptosis and necrosis. CancerRes., 2001; 61: 7495-500
  Google Scholar
• 28. Firczuk M., Nowis D., Gołąb J.: PDT-induced inflammatory andhost responses. Photochem. Photobiol. Sci., 2011; 10: 653-663
  Google Scholar
• 29. Garg A.D., Krysko D.V., Vandenabeele P., Agostinis P.: DAMPsand PDT-mediated photo-oxidative stress: exploring the unknown.Photochem. Photobiol. Sci., 2011; 10: 670-680
  Google Scholar
• 30. Garg A.D., Krysko D.V., Verfaillie T., Kaczmarek A., Ferreira G.B.,Marysael T., Rubio N., Firczuk M., Mathieu C., Roebroek A.J., AnnaertW., Golab J., de Witte P., Vandenabeele P., Agostinis P.: A novelpathway combining calreticulin exposure and ATP secretion in immunogeniccancer cell death. EMBO J., 2012; 31: 1062-1079
  Google Scholar
• 31. Garg A.D., Nowis D., Golab J., Vandenabeele P., Krysko D.V., AgostinisP.: Immunogenic cell death, DAMPs and anticancer therapeutics:an emerging amalgamation. Biochim. Biophys. Acta, 2010; 1805:53-71
  Google Scholar
• 32. Giorgi C., Bonora M., Missiroli S., Poletti F., Ramirez F.G., MorcianoG., Morganti C., Pandolfi P.P., Mammano F., Pinton P.: Intravitalimaging reveals p53-dependent cancer cell death induced byphototherapy via calcium signaling. Oncotarget, 2015; 6: 1435-1445
  Google Scholar
• 33. Giorgi C., Bonora M., Sorrentino G., Missiroli S., Poletti F., SuskiJ.M., Ramirez F.G., Rizzuto R., Di Virgilio F., Zito E., Pandolfi P.P.,Wieckowski M.R., Mammano F., Del Sal G., Pinton P.: p53 at the endoplasmicreticulum regulates apoptosis in a Ca2+-dependent manner.Proc. Natl. Acad. Sci. USA, 2015; 112, 1779-1784
  Google Scholar
• 34. Gołąb J., Wilczyński G., Zagozdzon R., Stokłosa T., DąbrowskaA., Rybczyńska J., Wasik M., Machaj E., Ołda T., Kozar K., KamińskiR., Giermasz A., Czajka A., Lasek W., Feleszko W., Jakóbisiak M.: Potentiationof the anti-tumour effects of photofrin-based photodynamictherapy by localized treatment with G-CSF. Br. J. Cancer, 2000;82: 1485-491
  Google Scholar
• 35. Gollnick S.O., Evans S.S., Baumann H., Owczarczak B., Maier P.,Vaughan L., Wang W.C., Unger E., Henderson B.W.: Role of cytokinesin photodynamic therapy-induced local and systemic inflammation.Br. J. Cancer, 2003; 88: 1772-1779
  Google Scholar
• 36. Gollnick S.O., Owczarczak B., Maier P.: Photodynamic therapyand anti-tumor immunity. Lasers Surg. Med., 2006; 38: 509-515
  Google Scholar
• 37. Hendrzak-Henion J.A., Knisely T.L., Cincotta L., Cincotta E., CincottaA.H.: Role of the immune system in mediating the antitumoreffect of benzophenothi¬azine photodynamic therapy. Photochem.Photobiol., 1999; 69: 575-581
  Google Scholar
• 38. Huang Y.Y., Balasubramanian T., Yang E., Luo D., Diers J.R., BocianD.F., Lindsey J.S., Holten D., Hamblin M.R.: Stable synthetic bacteriochlorinsfor photodynamic therapy: role of dicyano peripheralgroups, central metal substitution (2H, Zn, Pd), and Cremophor ELdelivery. Chem. Med. Chem., 2012; 7: 2155-2167
  Google Scholar
• 39. Huang Y.Y., Mroz P., Zhiyentayev T., Sharma S.K., BalasubramanianT., Ruzié C., Krayer M., Fan D., Borbas K.E., Yang E., Kee H.L., KirmaierC., Diers J.R., Bocian D.F., Holten D., Lindsey J.S., Hamblin M.R.:In vitro photodynamic therapy and quantitative structure-activityrelationship studies with stable synthetic near-infrared-absorbingbacteriochlorin photosensitizers. J. Med. Chem., 2010; 53: 4018-4027
  Google Scholar
• 40. Jalili A., Makowski M., Switaj T., Nowis D., Wilczynski G.M., WilczekE., Chorazy-Massalska M., Radzikowska A., Maslinski W., BiałyL., Sienko J., Sieron A., Adamek M., Basak G., Mróz P., et al.: Effectivephotoimmunotherapy of murine colon carcinoma induced by thecombination of photodynamic therapy and dendritic cells. Clin.Cancer Res., 2004; 10: 4498-508
  Google Scholar
• 41. Kang R., Zeh H.J., Lotze M.T., Tang D.: The Beclin 1 network regulatesautophagy and apoptosis. Cell Death Differ., 2011; 18, 571-580
  Google Scholar
• 42. Kessel D., Luo Y.: Photodyanmic therapy: a mitochondrial inducerof apoptosis. Cell Death Differ., 1999; 6: 28-35
  Google Scholar
• 43. Kessel D., Luo Y., Deng Y., Chang C.K.: The role of subcellularlocalization in initiation of apoptosis by photodynamic therapy.Photochem. Photobiol., 1997; 65: 422-426
  Google Scholar
• 44. Kim K.S., Cho C.H., Park E.K., Jung M.H., Yoon K.S., Park H.K.:AFM-detected apoptotic changes in morphology and biophysicalproperty caused by paclitaxel in ishikawa and HeLa cells. PLoS One,2012; 7: e30066
  Google Scholar
• 45. Konopka K., Goslinski T.: Photodynamic therapy in dentistry. J.Dental. Res., 2007; 86: 694-707
  Google Scholar
• 46. Korbelik M.: PDT-associated host response and its role in thetherapy outcome. Lasers Surg. Med., 2006; 38: 500-508
  Google Scholar
• 47. Korbelik M., Cecic I.: Contribution of myeloid and lymphoidhost cells to the curative outcome of mouse sarcoma treatment byphotodynamic therapy. Cancer Lett., 1999; 137: 91-98
  Google Scholar
• 48. Korbelik M., Dougherty G.J.: Photodynamic therapy-mediatedimmune response against subcutaneous mouse tumors. Cancer Res.,1999; 59: 1941-1946
  Google Scholar
• 49. Korbelik M., Naraparaju V.R., Yamamoto N.: Macrophage-directedimmunotherapy as adjuvant to photodynamic therapy of cancer.Br. J. Cancer, 1997; 75: 202-207
  Google Scholar
• 50. Kroemer G., Galluzzi L., Vandenabeele P., Abrams J., Alnemri E.S.,Baehrecke E.H., Blagosklonny M.V., El-Deiry W.S., Golstein P., GreenD.R., Hengartner M., Knight R.A., Kumar S., Lipton S.A., Malorni W.,et al.: Classification of cell death. Cell. Death Differ., 2009; 16: 3-11
  Google Scholar
• 51. Krosl G., Korbelik M., Krosl J., Dougherty G.J.: Potentiation ofphotodynamic therapy-elicited antitumor response by localizedtreatment with granulocyte-macrophage colony-stimulating factor.Cancer Res., 1996; 56: 3281-3286
  Google Scholar
• 52. Kushibiki T., Tajiri T., Tomioka Y., Awazu K.: Photodynamic therapyinduces interleukin secretion from dendritic cells. In. J. Clin.Exp. Med., 2010; 3: 110-114
  Google Scholar
• 53. Lam M., Lee Y.J., Deng M., Hsia A.H., Morrissey K.A., Yan C.,Azzizudin K., Oleinick N.L., McCormick T.S., Cooper K.D., Baron E.D.:Photodynamic therapy with the silicon phthalocyanine Pc 4 inducesapoptosis in Mycosis fungoides and sezary syndrome. Adv. Hematol.,2010; 2010: 896161
  Google Scholar
• 54. Lee Y., Baron E.D.: Photodynamic therapy: current evidenceand applications in dermatology. Semin. Cutan. Med. Surg., 2011;30: 199-209
  Google Scholar
• 55. Lemasters J.J.: Dying a thousand deaths: redundant pathwaysfrom different organelles to apoptosis and necrosis. Gastroentrology,2005; 129: 351-360
  Google Scholar
• 56. Longo J.P., de Melo L.N., Mijan M.C., Valois C.R., Joanitti G.A.,Simioni A.R., Tedesco A.C., de Azevedo R.B.: Photodynamic therapymediated by liposomal chloroaluminum-phthalocyanine inducesnecrosis in oral cancer cells. J. Biomater. Tissue Eng., 2013; 3: 148-156
  Google Scholar
• 57. Longo J.P., Lozzi S.P., Simioni A.R., Morais P.C., Tedesco A.C., AzevedoR.B.: Photodynamic therapy with aluminum-chloro-phthalocyanineinduces necrosis and vascular damage in mice tongue tumors.J. Photochem. Photobiol. B., 2009; 94: 143-146
  Google Scholar
• 58. Magaraggia M., Faccenda F., Gandolfi A., Jori G.: Treatment ofmicrobiologically polluted aquaculture waters by a novel photochemicaltechnique of potentially low environmental impact. J. Environ.Monit., 2006; 8: 923-931
  Google Scholar
• 59. Maisch T., Spannberger F., Regensburger J., Felgenträger A.,Bäumler W.: Fast and effective: intense pulse light photodynamicinactivation of bacteria. J. Ind. Microbiol. Biotechnol., 2012; 39:1013-1021
  Google Scholar
• 60. Master A., Livingston M., Sen Gupta A.: Photodynamic nanomedicinein the treatment of solid tumors: perspectives and challenges.J. Control Release, 2013; 168: 88-102
  Google Scholar
• 61. Meisel P., Kocher T.: Photodynamic therapy for periodontal diseases:state of the art. J. Photochem. Photobiol. B., 2005; 79: 159-170
  Google Scholar
• 62. Mfouo-Tynga I., Houreld N.N., Abrahamse H.: Induced cell deathpathway post photodynamic therapy using a metallophthalocyanine photosensitizer in breast cancer cells. Photomed. LaserSurg., 2014; 32: 205-211
  Google Scholar
• 63. Michels S., Schmidt-Erfurth U.: Photodynamic therapy withverteporfin: a new treatment in ophthalmology. Semin. Ophthalmol.,2001; 16: 201-206
  Google Scholar
• 64. Moor A.C.: Signalling pathways in cell death and survival afterphotodynamic therapy. J. Photochem. Photobiol., B., 2000; 57: 1-13
  Google Scholar
• 65. Mroz P., Hashmi J.T., Huang Y.Y., Lange N., Hamblin M.R.: Stimulationof anti-tumor immunity by photodynamic therapy. Expert.Rev. Clin. Immunol., 2011; 7: 75-91
  Google Scholar
• 66. Mroz P., Huang Y.Y., Szokalska A., Zhiyentayev T., Janjua S., NifliA.P., Sherwood M.E., Ruzié C., Borbas K.E., Fan D., Krayer M., BalasubramanianT., Yang E., Kee H.L., Kirmaier C., et al.: Stable syntheticbacteriochlorins overcome the resistance of melanoma to photodynamictherapy. FASEB J., 2010; 24: 3160-3170
  Google Scholar
• 67. Mroz P., Yaroslavsky A., Kharkwal G.B., Hamblin M.R.: Cell deathpathways in photodynamic therapy of cancer. Cancers, 2011;3, 2516-2539
  Google Scholar
• 68. Nowis D., Makowski M., Stokłosa T., Legat M., Issat T., Gołab J.:Direct tumor damage mechanisms of photodynamic therapy. ActaBiochim. Pol., 2005; 52: 339-352
  Google Scholar
• 69. Nowis D., Stokłosa T., Legat M., Issat T., Jakóbisiak M., Gołab J.:The influence of photodynamic therapy on the immune response.Photodiagn. Photodyn. Ther., 2005; 2: 283-298
  Google Scholar
• 70. Nyman E.S., Hynninen P.H.: Research advances in the use oftetrapyrrolic photosensitizers for photodynamic therapy. J. Photochem.Photobiol. B, 2004; 73: 1-28
  Google Scholar
• 71. Ormond A.B., Freeman H.S.: Dye sensitizers for photodynamictherapy. Materials, 2013; 6: 817-840
  Google Scholar
• 72. Palucka K., Banchereau J.: Cancer immunotherapy via dendriticcells. Nat. Rev. Cancer, 2012; 12: 265-277
  Google Scholar
• 73. Paz-Cristobal M.P., Royo D., Rezusta A., Andrés-Ciriano E., AlejandreM.C., Meis J.F., Revillo M.J., Aspiroz C., Nonell S., Gilaberte Y.:Photodynamic fungicidal efficacy of hypericin and dimethyl methyleneblue against azole-resistant Candida albicans strains. Mycoses,2014; 57: 35-42
  Google Scholar
• 74. Pereira Gonzales F., Maisch T.: Photodynamic inactivation forcontrolling Candida albicans infections. Fungal Biol., 2012; 116: 1-10
  Google Scholar
• 75. Plaetzer K., Kiesslich T., Verwanger T., Krammer B:. The modesof cell death induced by PDT: an overview. Med. Laser Application,2003; 18: 7-19
  Google Scholar
• 76. Portilho F.A., Cavalcanti C.E., Miranda-Vilela A.L., EstevanatoL.L., Longo J.P., Santos M.F., Bocca A.L., Martins O.P., Simioni A.R., MoraisP.C., Azevedo R.B., Tedesco A.C., Lacava Z.G.: Antitumor activityof photodynamic therapy performed with nanospheres containingzinc-phthalocyanine. J. Nanobiotechnology, 2013; 11: 41
  Google Scholar
• 77. Pushpan S.K., Venkatraman S., Anand V.G., Sankar J., ParmeswaranD., Ganesan S., Chandrashekar T.K.: Porphyrins in photodynamictherapy: a search for ideal photosensitizers. Curr. Med. Chem.Anticancer Agents, 2002; 2: 187-207
  Google Scholar
• 78. Ricchelli F., Franchi L., Miotto G., Borsetto L., Gobbo S., NikolovP., Bommer J.C., Reddi E.: Mesosubstituted tetra-cationic porphyrinsphotosensitize the death of human fibrosarcoma cells via lysosomaltargeting. Int. J. Biochem. Cell Biol., 2005; 37: 306-319
  Google Scholar
• 79. Schraml B.U., Reis E., Sousa C.: Defining dendritic cells. Curr.Opin. Immunol., 2015; 32: 13-20
  Google Scholar
• 80. Silva J.N., Filipe P., Morlière P., Mazière J.C., Freitas J.P., GomesM.M., Santus R.: Photodynamic therapy: dermatology and ophthalmologyas main fields of current applications in clinic. Biomed. Mater.Eng., 2008; 18: 319-327
  Google Scholar
• 81. Sperandio F.F., Huang Y.Y., Hamblin M.R.: Antimicrobial photodynamictherapy to kill Gram-negative bacteria. Recent. Pat. Antiinfect. Drug Discov., 2013; 8: 108-120
  Google Scholar
• 82. St Denis T.G., Hamblin M.R.: Synthesis, bioanalysis and biodistributionof photosensitizer conjugates for photodynamic therapy.Bioanalysis, 2013; 5: 1099-1114
  Google Scholar
• 83. Sun J., Cecic I., Parkins C.S., Korbelik M.: Neutrophils as inflammatoryand immune effectors in photodynamic therapy-treatedmouse SCCVII tumours. Photochem. Photobiol. Sci., 2002; 1: 690-695
  Google Scholar
• 84. Szeimies R.M., Lischner S., Philipp-Dormston W., Walker T., Hiepe-WegenerD., Feise K., Podda M., Prager W., Kohl E., Karrer S.:Photodynamic therapy for skin rejuvenation: treatment options –results of a consensus conference of an expert group for aestheticphotodynamic therapy. J. Dtsch. Dermatol. Ges., 2013; 11: 632-636
  Google Scholar
• 85. Taub A.F.: Cosmetic clinical indications for photodynamic therapy.J. Cosmet. Dermatol., 2012; 25: 218-224
  Google Scholar
• 86. Thong P.S., Olivo M., Kho K.W., Bhuvaneswari R., Chin W.W., OngK.W., Soo K.C.: Immune response against angiosarcoma following lowerfluence rate clinical photodynamic therapy J. Environ. Pathol.Toxicol. Oncol., 2008; 27: 35-42
  Google Scholar
• 87. Wainwright M.: Local treatment of viral disease using photodynamictherapy. Int. J. Antimicrob. Agents, 2003; 21: 510-520
  Google Scholar
• 88. Wainwright M.: Pathogen inactivation in blood products. Curr.Med. Chem., 2002; 9: 127-143
  Google Scholar
• 89. Waksman R., McEwan P.E., Moore T.I., Pakala R., Kolodgie F.D.,Hellinga D.G., Seabron R.C., Rychnovsky S.J., Vasek J., Scott R.W., VirmaniR.: PhotoPoint photodynamic therapy promotes stabilizationof atherosclerotic plaques and inhibits plaque progression. J. Am.Coll. Cardiol., 2008; 52: 1024-1032
  Google Scholar
• 90. Wolfsen H.C.: Porfimer sodium photodynamic therapy: the longroad to acceptance in America. Photodiagnosis Photodyn. Ther.,2007; 4: 242-243
  Google Scholar
• 91. Wood S.R., Holroyd J.A., Brown S.B.: The subcellular localizationof Zn (II) phthalocyanines and their redistribution on exposure tolight. Photochem. Photobiol., 1997; 65: 397-402
  Google Scholar
• 92. Woodburn K.W., Fan Q., Kessel D., Wright M., Mody T.D., HemmiG., Magda D., Sessler J.L., Dow W.C., Miller R.A., Young S.W.: Phototherapyof cancer and atheromatous plaque with texaphyrins. J.Clin. Laser Med. Surg., 1996; 14: 343-348
  Google Scholar
• 93. Yang E., Diers J.R., Huang Y.Y., Hamblin M.R., Lindsey J.S., BocianD.F., Holten D.: Molecular electronic tuning of photosensitizers toenhance photodynamic therapy: synthetic dicyanobacteriochlorinsas a case study. Photochem. Photobiol., 2013; 89: 605-618
  Google Scholar

Full text