APPLICATION OF THE PHOTODYNAMIC THERAPY

IN MEDICINE AND DENTISTRY

Literature Review on Photodynamic and Antimicrobial Photodynamic Therapy

Zuzanna Oruba

, Maria Chomyszyn-Gajewska

and Wojciech Macyk

Department of Periodontology and Oral Medicine, Jagiellonian University, Montelupich 4, 31-155, Kraków, Poland

Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Kraków, Poland

Keywords: Photodynamic therapy, Antimicrobial photodynamic therapy, Periodontitis.

Abstract: Photodynamic therapy (PDT) is recently being recognized as an attractive, non-invasive and alternative

treatment method for precancerous lesions and superficial cancers. PDT has many advantages when

compared with conventional treatment modalities. It has also been used for the photoinactivation of

microbes. There is an increasing interest in the practical application of antimicrobial photodynamic therapy

(aPDT) in many branches of dentistry, especially in periodontology, for the management of such conditions

as chronic periodontitis or periimplantitis. The aim of the present paper was to discuss the application of

photodynamic therapy in medicine and dentistry. The results of many so far published studies seem to be

very promising indicating at the same time that further research is needed to establish the optimal protocol

for effective photodestruction of tumor cells and microorganisms.

1 INTRODUCTION

Photodynamic therapy (PDT) is a medical treatment

that utilizes light to activate a photosensitizing agent

in the presence of oxygen. It is a noninvasive and

painless medical procedure with relatively little side

effects. Its use in medicine and dentistry is becoming

widespread.

2 PRINCIPLE OF

PHOTODYNAMIC THERAPY

Photodynamic therapy (PDT) involves three agents,

i.e. photosensitizer, light and oxygen. The

administration of a photosensitizer is followed by

irradiation with the light of a specific wavelength

(Takasaki et al., 2009). Upon photon absorption a

molecule of the photosensitizer gets activated and

transforms from its ground state (S

) into an excited

singlet state (S

). The lifetime of the singlet state is

in the nanosecond timescale (Stochel et al., 2009,

chapter 17), which is too short to react with other

molecules. From this state the drug may decay back

to the ground state by emitting fluorescence or by

internal conversion with energy lost as heat.

However, to obtain a therapeutic photodynamic

effect, the molecule of the photosensitizer must

undergo electron spin conversion to its triplet state

). The lifetime of the triplet state is in the

microsecond to millisecond range (Soukos and

Goodson, 2011). The molecule in its triplet state can

again reach the ground state (in the case of light

emission the process is called phosphorescence) or it

can react further with oxygen according to two

different types of mechanisms (Scheme 1) (Soukos

and Goodson, 2011). Type I reaction involves

electron-transfer reaction between the

photosensitizer triplet state and a substrate (O

When oxygen participates in this process reactive

oxygen species (ROS) (superoxide, hydroxyl radical,

hydrogen peroxide) are produced. They are harmful

to cell membrane integrity and cause irreparable

biological damage. In the type II reaction the

molecule of a photosensitizer in the triplet state

transfers its energy directly to oxygen to form

singlet oxygen (

) which is highly reactive and

induces oxidative cell damage (Takasaki et al., 2009;

Stochel et al., 2009, chapter 17; Soukos and

Goodson, 2011).

190

Oruba Z., Chomyszyn-Gajewska M. and Macyk W..

APPLICATION OF THE PHOTODYNAMIC THERAPY IN MEDICINE AND DENTISTRY - Literature Review on Photodynamic and Antimicrobial

Photodynamic Therapy.

DOI: 10.5220/0003775501900195

In Proceedings of the International Conference on Biomedical Electronics and Devices (BIODEVICES-2012), pages 190-195

ISBN: 978-989-8425-91-1

 2012 SCITEPRESS (Science and Technology Publications, Lda.)

Scheme 1: Two types of mechanisms governing the

photodynamic process. ROS are placed in rectangles; Ph –

a photosensitizer in its singlet (S) or triplet (T) state.

2.1 PDT in the Treatment of Cancer

Photodynamic therapy is a relatively new treatment

modality of localized cancers. Upon administration

of a photosensitizer and its illumination, tumor cells

are being directly killed as a result of oxidative

damage (necrosis and apoptosis). Additionally, the

vasculature of the tumor and surrounding tissues are

damaged, resulting in indirect tumor cells death of

hypoxia and starvation (Stochel et al., 2009, chapter

17); (Triesscheijn et al., 2006). The ideal

photosensitizer for the use in oncology should

possess the following properties: chemical purity,

high binding affinity for tumor cells and low for host

cells, non-toxicity in the dark, minimal risk of

promoting mutagenic processes, high absorption

coefficient within the phototherapeutic window

(620-1000 nm) and as low as possible in the range of

400-600 nm to avoid skin sensitivity to solar

irradiation after drug administration, high quantum

yield of excited triplet state generation (the

efficiency of PDT depends on photophysical

properties of this state) (Stochel et al., 2009, chapter

17). Following photosensitizers are currently

approved for the clinical use: Photofrin (porfimer

sodium), Levulan (5-aminolevulinic acid), Metvix

(methyl ester of ALA), mTHPC (meso-tetra-

hydroxyphenyl-chlorin) (Triesscheijn et al., 2006).

PDT had been applied clinically in the treatment of

bladder cancer, skin cancer, Bowen’s disease, head

and neck cancer, esophageal cancer, Barrett’s

esophagus, endobronchial cancer, actinic keratoses

(Triesscheijn et al., 2006); (Overholt et al., 2007).

In dental surgery, PDT has been applied in the

treatment of oral leukoplakia, a premalignant lesion

of the oral mucosa with a rate of malignant

transformation of 0.1-17% (Spinola Ribeiro et al.,

2010). Upon PDT with the use of ALA as a

photosensitizer in combination with red light, all

authors noted high response-to-treatment rate and a

very low recurrence rate in a long-term observation

(Spinola Ribeiro et al., 2010). Lin et al. (2010)

reported excellent outcomes of PDT in the treatment

of other oral precancerous lesions – oral verrucous

hyperplasia (OVL) and oral erythroleukoplakia

(OEL) (Lin et al., 2010). Upon the use of PDT with

20% ALA irradiated with 635 nm laser light, a

complete response for 100% of OVL lesions and

95% of OEL was achieved after an average of 3.6

and 3.4 treatment sessions, respectively. The authors

concluded, that for oral precancerous lesions ALA-

PDT is one of the best treatments of choice.

2.2 Photodynamic Antimicrobial

Chemotherapy (PACT)

The principle of PACT (also known as antimicrobial

photodynamic therapy, aPDT) is similar to PDT.

Photosensitizers and light (visible or UV) are used in

order to induce phototoxic response, usually via an

oxidative damage (Stochel et al., 2009, chapter 18).

In PACT, the photosensitizer should basically

possess properties similar to those expected for

PDT, with a high binding affinity for

microorganisms, broad spectrum of action and a low

propensity for selecting resistant bacterial strains

(Soukos and Goodson, 2011). The differences in

susceptibility of gram-positive and gram-negative

bacteria have been reported (Takasaki et al., 2009;

Usacheva et al., 2001). Gram-positive bacteria are

generally susceptible to photoinactivation. Gram-

negative bacteria seem to be more resistant to

PACT, mostly because of their additional outer

membrane which decreases the permeability and

reduces the photosensitizer uptake (Takasaki et al.,

2009). Moreover, the surface of gram-negative

bacteria cells is negatively charged, which makes

anionic and neutral photosensitizers ineffective

(Stochel et al., 2009, chapter 18). However,

phenothiazinium dyes (methylene blue and toluidine

blue), which are most commonly used in PACT,

bear pronounced cationic charge and thanks to the

electrostatic interaction can bind to the outer

membrane of both gram-negative and gram-positive

bacteria and penetrate bacterial cells (Soukos and

Goodson, 2011); (Usacheva et al., 2001). Reactive

oxygen species generated upon illumination of the

photosensitizer are lethal to bacteria by oxidizing

cell membrane (lipid peroxidation) causing its

decomposition, followed by destruction of nucleic

acids and proteins (Stochel et al., 2009, chapter 18).

2.3 PACT in Dentistry

2.3.1 Dental Caries

Dental caries is the result of tooth-hard tissue

demineralization in the presence of acids secreted by

supragingival biofilm bacteria (Streptococcus and

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191

Lactinobacillus species) (Soukos and Goodson,

2011). Up to 10-fold reduction of the viability of S.

mutans, the main cariogenic bacteria, was achieved

by toluidine blue mediated PACT, even when the

organisms were embedded in a collagen matrix

mimicking carious dentin (Burns et al., 1995). The

susceptibility of cariogenic bacteria was confirmed

by other authors (Williams et al., 2004). PACT may

be useful in the prevention of caries, management of

early carious lesions and disinfection of carious

cavities before restoration.

2.3.2 Endodontics

The success of the endodontic treatment relies on the

elimination of infection from the root canal system.

The conventional means to achieve it is to perform

chemo-mechanical debridement and irrigation with

disinfectant solutions, like sodium hypochlorite

(NaOCl). However, anatomical complexity of the

root canal system (isthmuses, ramifications,

presence of dentinal tubules) makes complete

removal of bacteria with standard procedures and

medicaments almost impossible (Soukos and

Goodson, 2011). Therefore, the adjunctive

antimicrobial PDT (aPDT) has been employed to

eliminate residual root canal bacteria in many

studies, the results of which seem to be very

promising. The combined use of red light and

methylene blue results in reduction of Enterococcus

faecalis viability by 40 – 97% in the experimentally

infected root canals of extracted human teeth (Foschi

et al., 2007; Silbert et al., 2000; Soukos et al., 2006).

The results of in vivo studies conducted by Bonsor,

Nichol, Reid and Pearson (2005 and 2006) point that

PACT is as effective in root canal system

disinfection as conventional chemo-mechanical

techniques (instrumentation with NaOCl/citric acid

irrigation) (Bonsor et al., 2005; Bonsor et al., 2006).

These authors highlighted also, that aPDT is more

biocompatibile than conventional irrigants. It was

confirmed by Xu et al. (2009), who reported that

although some of the light energy applied to the root

canal escapes from the root apex (<10%), methylene

blue-mediated aPDT is harmless to osteoblasts in the

periapical region. This is not the case for sodium

hypochlorite, which is highly toxic and damages

cells of the periapical tissues (Xu et al., 2009).

2.3.3 Periodontology

Periodontology deals with the diseases of

periodontium (gum, alveolar bone and periodontal

ligament). Chronic periodontitis, the most common

periodontal disease, which refers to approximately

48% of the population (Albandar, 2005) and is a

major cause of tooth loss (Bakrami et al., 2008), is

characterized by a progressive destruction of the

periodontium’s fibers and alveolar bone, resulting in

following clinical symptoms: pathological pockets

or gum recessions, attachment loss, bony defects,

bleeding, hypermobility of the teeth and eventually

tooth loss. Following gram-negative anaerobes are

considered the most harmful for periodontium and

are isolated from the deepest periodontal pockets

and sites with severe bone loss: Porphyromonas

gingivalis, Tanerella forsythia and Treponema

denticola (so called ‘red complex’ according to

Socransky) (Socransky and Haffajee, 2002).

The effective treatment of the periodontal disease

is of a great importance also when general health is

considered, as the relationship between periodontal

disease and several systemic disorders, e.g.

cardiovascular disease, diabetes mellitus,

rheumatoid arthritis, cerebral infarction or

hypertension was proved (Detert et al., 2010;

Seymour et al., 2003; Lagervall et al., 2003).

Effective bacteria eradication is the basis of

periodontal treatment. Standard non-surgical

treatment procedures, like supra- and subgingival

plaque removal, have to be accompanied with some

additional antimicrobial means, like the

administration of antibiotics. However, the use of

antibiotics, delivered systemically or locally, apart

from many other side effects, promotes the

emergence of resistant bacterial strains, which,

according to WHO, is becoming a threatening

problem in healthcare worldwide. From this

standpoint, new and effective antimicrobial

approaches are urgently needed to be introduced.

The interest in use of PACT in periodontology is

considerable. Its effectiveness against

periopathogens has been proved in many in vitro

studies: with the use of toluidine blue (TBO) or

methylene blue (MB) as photosensitizers and a light

wavelength of approximately 632 nm emitted by a

He-Ne laser, significant reductions in the viability of

bacteria were observed (Bhatti et al., 2002; O’Neil et

al., 2002; Chan and Lai, 2003). Matevski et al.

determined optimal PACT parameters for the

effective photoinactivation of P. gingivalis in terms

of light intensity (25 mW/cm

), light dose (10 J/cm

)

and TBO concentration (12.5 µmol/ml) and applied

them for inactivation of P. gingivalis resuspended in

blood or serum to mimic actual periodontal pocket

conditions. Interestingly, in the presence of blood or

serum, the decline in bacteria viability was still

statistically significant, but there was a large

decrease in effectiveness compared with

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blood/serum-free suspensions. Blood and serum

appeared to partially protect P. gingivalis from

PACT. This effect can be explained by a lowered

light penetration through blood and serum (due to

light absorption and scattering by these media) and

by scavenging of photogenerated reactive oxygen

species through oxidation of blood/serum organic

components.

The susceptibility of P. gingivalis to PDT was

also confirmed in animal model study conducted by

Koemerik et al. (2003). Upon the use of 1 mg/ml of

TBO in combination with increasing light doses (6,

12, 24 and 48 J) in rats previously infected with P.

gingivalis, no viable bacteria were detected. After

irradiation, histological examination was carried out.

No adverse effects of PACT on the periodontal

tissues were observed. Even with the highest

concentration of TBO (1 mg/ml) and the highest

light dose tested (48 J) no ulcer on epithelium or

inflammation of the connective tissue were detected.

The authors evaluated the alveolar bone levels of the

maxillary molars by morphometric and radiographic

methods. The results showed that with the use of

TBO concentration of 0.1 and 1 mg/ml in

combination with 48 J of laser light, the bone loss

was significantly reduced in comparison with the

control group that did not receive PACT (Koemerik

et al., 2003). The biodistribution of topically applied

TBO on the gingival tissues was also examined. It

was demonstrated that the photosensitizer penetrated

throughout the epithelium. This fact may have very

advantageous clinical implications, as conventional

periodontal debridement fails to eliminate

pathogenic bacteria that are placed in the soft

tissues. In the study conducted by Fernandes et al.

(2009) PACT was applied as an adjunctive treatment

to scaling and root planning (SRP) to

immunosuppressed and non-immunosuppressed rats

with experimentally ligature-induced periodontitis in

mandibular molars. In rats that received PDT, the

periodontal ligament was found to be intact, with

parallel collagen fibers, lack of an inflammatory

infiltrate and thick alveolar bone, which was not the

case for rats treated only with SRP or SRP and TBO

with no irradiation (Fernandes et al., 2009).

The outcomes of in vivo studies are, however,

divergent. Some authors reported that adjunctive

PACT has a positive effect on periodontal

parameters contributing to the statistically

significant decrease of bleeding and probing depths

and gain of clinical attachment in comparison with

conventional treatment (SRP) (Braun et al., 2008).

In comparison, Polansky, Haas, Heschl and Wimmer

(2009) concluded, that PACT does not provide

additional benefits to conventional periodontal

treatment, although visibly larger reductions of

bleeding indices were seen among the patients that

received PACT than in the control group, however

these differences turned out to be statistically

insignificant (Polansky et al., 2009). Similar results

were obtained by other authors (Chondros et al.,

2009). The differences in the outcomes of in vitro

and in vivo studies indicate that more detailed

research is needed in this field.

2.3.4 Periimplantitis

Periimplantitis is an inflammatory condition that

affects soft and hard tissues surrounding an

osseointegrated dental implant and may lead to its

failure. The causative flora is similar to that one

responsible for the development of periodontal

disease (A. actinomycetemcomitans, P. gingivalis, P.

intermedia) (Takasaki et al., 2009). In an animal

split-mouth study, Shibli et al. (2006) compared

histometrically the outcomes of conventional

periimplantitis management (debridement + guided

bone regeneration) with those of conventional

management combined with TBO-mediated PACT

in dogs with ligature-induces periimplantitis. The

use of PACT resulted in a greater bone gain – the

mean percentage of re-osseointegration was 31-41%

for the test group and 0-14% for the control group

(Shibli et al. 2006). Haas, Baron, Doertbudak and

Watzek (2000) used TBO-mediated PACT in

combination with soft laser (906 nm) as an adjunct

to autogenous bone augmentation in 17 patients with

periimplantitis. The mean radiographic bone gain 4

months after the procedure was 2 mm (maxilla – 2.5

mm; mandible – 1.9 mm), what can be considered as

an excellent clinical outcome (Haas et al., 2000).

2.3.5 Soft Tissue Therapy

The effectiveness of PACT in the treatment of

recurrent herpes labialis (RHL) was also

investigated (Sperandio et al., 2009). Great clinical

outcomes were achieved for treating already

established RHL vesicles, compared to conventional

treatment with the use of antiviral compounds.

Patients reported an immediate pain relief after the

procedure. No recurrence was observed in a 6-month

period (Sperandio et al., 2009).

2.4 Towards Increased Effectiveness

The reduced susceptibility of P. gingivalis and other

periopathogens to PACT in vivo can be explained by

the fact, that periodontitis is a biofilm-related

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193

infection. The penetration of the photosensitizer

solution into the bacterial biofilm is decreased in

comparison to the suspensions of bacteria used in in

vitro studies. Therefore, to enhance the effectiveness

of PACT, the development of novel delivery and

targeting approaches may be required. One strategy

to improve the targeting was proposed by Bhatti et

al. (2000). The authors used a conjugate of TBO and

murine monoclonal antibody (Ab-TBO) to

specifically target P. gingivalis in the presence of S.

sanguis or human gingival fibroblasts (HGFs) in

vitro. It was demonstrated that with the use of Ab-

TBO conjugate a high selectivity and efficiency in

the killing of P. gingivalis can be achieved. Such an

approach could enable the killing of important

periopathogens without collateral damage either to

host tissues or to the normal oral microflora.

3 CONCLUSIONS

PDT and PACT are non-invasive, relatively

inexpensive, painless to the patient with little or no

side-effects. The outcomes of presented in vitro and

in vivo studies are very promising. However, more

research is still needed in this field for optimizing

the protocol of clinical application, improving

specific targeting of tumor cells and bacteria and

introducing new groups of photosensitizers.

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