Editorial New Applications of Photodynamic Therapy in...

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013, Article ID 161362, 3 pageshttp://dx.doi.org/10.1155/2013/161362

EditorialNew Applications of Photodynamic Therapy inBiomedicine and Biotechnology

Kristjan Plaetzer,1 Mark Berneburg,2 Tobias Kiesslich,3,4 and Tim Maisch5

1 Laboratory of Photodynamic Inactivation of Microorganisms, Department of Materials Science and Physics,University of Salzburg, Hellbrunnerstraße 34, 5020 Salzburg, Austria

2 Department of Dermatology, Eberhard Karls University, Liebermeisterstraße 25, 72076 Tuebingen, Germany3Department of Internal Medicine I, Paracelsus Medical University and Salzburger Landeskliniken (SALK),Muellner Hauptstrasse 48, 5020 Salzburg, Austria

4 Institute of Physiology and Pathophysiology, Paracelsus Medical University, Strubergasse 21, 5020 Salzburg, Austria5 Department of Dermatology, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany

Correspondence should be addressed to Kristjan Plaetzer; [email protected]

Received 23 April 2013; Accepted 23 April 2013

Copyright © 2013 Kristjan Plaetzer et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Photodynamic procedures are based on the light-induced,photosensitizer-mediated overproduction of reactive oxygenspecies for removal of harmful or unwanted cells/pathogens.With approvals for various applications by health agenciesin most industrial countries, Photodynamic Therapy (PDT)represents the method of choice for treatment of age-relatedmacular degeneration and is appreciated as minimally inva-sive therapeutic procedure to treat skin, esophageal, head andneck, lung, and bladder cancers with high cure rates, lowside effects, and excellent cosmetic outcome. Beingmotivatedby the success of PDT in management of various humandiseases, new and very promising applications of this proce-dure are being identified and explored by the PDT researchcommunity. So, for example, Photodynamic Inactivation ofmicroorganisms (PDI) has the potential to avert the severethreat of increasing antimicrobial resistance. This specialissue presents a collection of papers dealingwith novel photo-sensitizers with improved photochemical and photophysicalproperties, alternatives to (single) photon excitation of thephotoactive drug, new clinical targets of photodynamicprocedures, and innovative reviews on crucial aspects, whichsubstantiate the success of Photodynamic Therapy and Pho-todynamic Inactivation.

In a research paper entitled “Hydrogen bond acceptorsand additional cationic charges in methylene blue derivatives:

photophysics and antimicrobial efficiency,” A. Felgentrageret al. report on the synthesis and photodynamic efficiency ofsix novel methylene blue derivatives with highly polar and/orhydrophilic groups. Based on a systematic analysis of singletoxygen formation in combination with the absorbed lightenergy and on investigations of the phototoxicity towardsStaphylococcus aureus and Escherichia coli, a structure-activi-ty relationship has been drawn from a chemical point of view.The data presented in this study demonstrate that hydrogenacceptor bond moieties and additional tertiary charges inthe substituent have a positive influence on the overallantimicrobial efficacy ofmethylene blue derivatives, resultingin a convincing inactivation of viable Gram (+) or Gram (−)bacteria up to 7 log units.

Conjugates of nanoparticles and photosensitizers rep-resent a very promising new generation of photoactivesubstances. The correlation of the size of purpurin-18-N-methyl-D-glucamine gold nanoparticles and the respectivephotodynamic activity is described by B. Lkhagvadulam etal.’s “Size-dependent photodynamic activity of gold nanopar-ticles conjugate of water soluble purpurin-18-N-methyl-D-glucamine”. The authors demonstrate that the PDT efficiencyof photosensitizer-nanoparticle conjugates against A549 lungcancer cells is higher when compared to the unbound pho-tosensitizer because of the increased internalization of the PS

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into the target cells using the size effect.The highest photody-namic activity is reported to be associated with rather biggerconjugates with a diameter of about 60 nm.

Y-.S. Chou et al.’s “Photo-induced antitumor effect of 3,6-Bis(1-methyl-4-vinylpyridinium) carbazole diiodide” evalu-ated the photo-induced antitumor effect of 3,6-bis(1-methyl-4-vinylpyridinium) carbazole diiodide (BMVC) in a lungtumor cell line (TC-1) and the corresponding in vivomurinemodel (TC-1 cell tumors in C57BL/6 mice). BMVC is ableto induce a phototoxic effect in TC-1 cells at light fluencesgreater than 40 J/cm2 and significantly reduced the tumorgrowth rate in vivo following fine-needle interstitial lightillumination of the photosensitizer. Immunohistochemistrystudies showed that the microvascular density was lower notonly in the PDT group but also in animals, which receivedlight only (without photosensitizer).Therefore, the antivascu-lar effect might be partially attributed to mild hyperthermiainduced by the laser illumination.

The study of V. Ziegler et al. entitled “Photosensitizeradhered to cell culture microplates induces phototoxicity incarcinoma cells” discusses the phototoxic effect of adherenceof photosensitizers on the surfaces of cell culturemicroplates.Using two rather lipophilic and two hydrophilic substancescurrently employed in PDT, the authors show that lipophilicphotosensitizer molecules adhered to microplates are able toinduce cytotoxicity in A431 human epidermoid carcinomacells upon illumination, independently of whether the pho-toactive molecule relocalizes from the surface into cells ornot. This effect is negligible for hydrophilic photosensitizers.The ability of plastic materials to (reversibly) store photo-sensitizers might, according to V. Ziegler et al. represent anew approach for photosensitizer delivery or development ofantimicrobial coatings.

Inactivation of microorganisms within skin or tissuebased on photosensitizers activated by illumination may becomplicated by the relatively low penetration depth of visiblelight. As an alternative to light illumination, F. Nakonechny etal.’s “Sonodynamic excitation of rose bengal for eradication ofGram-positive and Gram-negative bacteria” excited the pho-tosensitizer Rose Bengal with 28 kHz ultrasound. The resultspresented in the study demonstrate for the first time thatthe novel “sonodynamic” activation of Rose Bengal is able toreduce the number of viable Staphylococcus aureus andEscherichia coli by up to 4 log units. Sonodynamic treatmentrepresents a promising approach for curing internal infec-tions and sterilization.

In a comprehensive review article entitled “Innovativestrategies to overcome biofilm resistance” by A. Taraszkiewiczet al. strategies to combat bacterial microfilms are discussed.If organized in biofilms (e.g., in or on humans), bacteria aremuch more resistant to antimicrobial therapies, includingPhotodynamic Inactivation. The authors suggest two inno-vative approaches to increase the bactericidal effect of PDI,namely, the employment of enzymes that affect the biofilmor a combination of PDI with antibiotics, plant extracts,or other biofilm disrupting substances. Application of PDItogether with enzymes specific for microbial structuresmight furthermore increase the selectivity of phototoxicity

and/or allow for the usage of lower photosensitizer concen-trations.

Patients suffering from the genetically induced skin dis-order epidermolysis bullosa (EB) are exposed to an increasedskin tumor risk. P. Larisch et al.’s “In vitro analysis of photo-sensitizer accumulation for assessment of applicability of fluo-rescence diagnosis of squamous cell carcinoma of epidermolysisbullosa patients” investigated the applicability of fluorescencediagnosis of hypericin and endogenous protoporphyrin IXusing an in vitro model system, consisting of different (EB)skin cell lines exposed to normal and proinflammatory con-ditions. A proinflammatory milieu simulated by addition ofTNF-alpha appeared not to influence photosensitizer accu-mulation in skin cells. Carcinoma cells of recessive dystrophicEB showed lower hypericin or PpIX-induced fluorescencethan nonmalignant recessive dystrophic EB cells. Furtherexperiments will be necessary to evaluate the possible appli-cation of fluorescence diagnosis for early cancer detection ofEB patients.

Two-photon absorption is a nonlinear optical process,by which two photons are absorbed simultaneously, thusallowing for doubling the wavelength of excitation of a givenphotosensitizer in PDT, thereby increasing the penetrationdepth of the PDT illumination light in tissue and allowingfor treatment of thicker malignancies. In this issue, K. Ogawaand Y. Kobuke through their paper “Two-photon photo-dynamic therapy by water-soluble self-assembled conjugatedporphyrins” review a set of studies on two-photon PDT withwater-soluble and self-assembling conjugated porphyrins.Based on data of two-photon cross section values obtainedby open-aperture Z-scan measurements, singlet oxygen pro-duction and phototoxicity towards cancer cells in vitro, theconjugated porphyrins are suggested as candidates for two-photon PDT agents.

In the paper entitled “Killing effect of Ad5/F35-APE1siRNA recombinant adenovirus in combination with hemato-porphrphyrin derivative-mediated photodynamic therapy onhuman nonsmall cell lung cancer,” L. Xia and coworkers reporton the PDT efficiency and the molecular mechanism of cyto-toxicity of the Ad5/F35-APE1 siRNA recombinant adenovirusin combination with hematoporphyrin derivative (HpD) inA549 human lung adenocarcinoma cells. Infection of cancercells with the Ad5/F35-APE1 siRNA recombinant adenovirussignificantly reduced the HpD-PDT-induced expression ofthe APE1 protein and could therefore enhance the pho-tokilling of HpD-mediated PDT.

Three papers discuss the interconnection between PDTand the host’s immune response. The methodology reportentitled “Effective combination of photodynamic therapy andimiquimod 5% cream in the treatment of actinic keratoses: threecases” of L. Held et al. evaluate the therapeutic effect of com-bining PDT using 5-aminolevulinic-acid-(ALA-) inducedPPIX as photosensitizer with imiquimod 5% cream for theclinical treatment of actinic keratoses. Imiquimod is knownto regulate the level of cytokines and thereby to influencethe immune response and was applied to the treatment areatwo weeks after PDT. Although a rather small population ofpatients was part of the pilot study, the results are promisingand should be studied in subsequent larger clinical trials:

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PDT followed by imiquimod treatment was well toleratedand combination of both improved the reduction of actinickeratoses, as demonstrated by the authors.

Photodynamic treatment of actinic keratoses and non-melanoma skin cancer in solid organ transplant recipients aswell as alternatives to PDT are reviewed by C. Wlodek et al.’s“Use of photodynamic therapy for treatment of actinic keratosesin organ transplant recipients”. It is well known that long-termimmunosuppressive medication performed on organ trans-plant recipients increases the risk to develop skin cancersand/or their precursors.The authors present PDT as efficient,safe, and well-tolerated treatment option for these malignan-cies in immunosuppressed patients but point out that earlyand numerous treatments on a regular basis are necessary toobtain an optimal response and to prevent development ofnew actinic keratoses.

E. Panzarini et al. in their paper “Immunogenic cell death:can it be exploited in photodynamic therapy for cancer?” reviewthe undoubted key role of the immune response triggered byPDT for the control of cancer cells revival after an antitumortreatment. By elucidating the role of damage associatedmolecular patterns (DAMPs) at the crossroad between can-cer cell death and immunogenicity in PDT, the convinc-ing advantage of PDT over several other cancer treatmentoptions, which is to potentially elicit a specific antitumorimmunity, is discussed.

The process of scientific development of new applicationsof PDT is still highly active and viable. The finalizing contri-bution of this special issue is therefore an invitation to otherresearchers to join the successful photodynamic community.T. Kiesslich and coworkers in the paper entitled “A compre-hensive tutorial on in vitro characterization of new photosensi-tizers for photodynamic antitumor therapy and photodynamicinactivation of microorganisms” present a comprehensivetutorial on the initial experimental procedures in vitro, whichhelp to identify possible applications of newly synthesizedphotosensitizers in the frame of PDT/PDI. The article coversa detailed description of the experimental approach to thecharacterization of the photochemical and photophysicalproperties of a photosensitizer, its uptake kinetics into cells,intracellular localization, and photodynamic action in both,tumor cells and microorganisms. The authors hope that thespecial issue on PDT in general and the tutorial article inparticular will help to stimulate the efforts to expand theconvincing benefits of photodynamic procedures within bothestablished and new fields of applications.

Acknowledgments

The guest editors are grateful to all referees who devotedconsiderable time and effort to maintain the high scientificstandard of this special issue by their excellent and construc-tive comments on the papers.

Kristjan PlaetzerMark BerneburgTobias Kiesslich

Tim Maisch

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