INDIAN JOURNAL OF DENTAL ADVANCEMENTS

J o u r n a l h o m e p a g e : w w w. n a c d . i n

REVIEW

Photodynamic Therapy
Veerendra Nath Reddy1, Rekha Rani K2, Chandana G3, Sangeeta Sehrawat4

Dept. of Periodontics
Panineeya Dental Sciences,
Hyderabad,
Andhra Pradesh, India

Reader1
Professor & HOD2
Sr. Lecturer3
PG Student4

Article Info
Received: 28th July, 2009
Review Completed: 28th August, 2009
Accepted: 29th September, 2009
Available Online: 18th January, 2010
NAD, 2009 - All rights reserved

Abstract:
Photodynamic therapy (PDT ) is a powerful laser-initiated
photochemical reaction, involving the use of a photoactive dye
(photosensitizer) activated by light of a specific wavelength in the
presence of oxygen. This leads to the formation of toxic oxygen
species which can damage proteins, lipids, nucleic acids and other
cellular components. Applications of photodynamic therapy in
dentistry is growing rapidly for as the treatment of oral cancer,
bacterial and fungal infections and photodynamic diagnosis of
malignant transformation of oral lesions. PACT (photodynamic
antimicrobial chemotherapy) has been efficacious in the
management of peri-implantitis, enodontic infections and oral
biofilms such as plaque. The absence of genotoxic and mutagenic
effects, no risk of developing resistance to its antimicrobial action
and increased healing process favors its long-term safety and use.
Thus, PDT represents a novel therapeutic approach in the
management of various dental conditions.
Key words:

INTRODUCTION
Photodynamic therapy (PDT ) matured as
feasible medical technology in 1980s at several
institutions in the world basically as a treatment for
cancer involving 3 components:
1. A photosensitizer
2. A light source
3. Tissue oxygen
The word photodynamics means the application
of dynamics of photons of light on the biological
molecules.1 Employing the same principle we can
describe it as a medical treatment that utilizes light
Address for correspondence:
veerureddy@yahoo.com

46

IJDA, 1(1), 2009

photodynamic therapy, photosensitizers,

photodynamic antimicrobial chemotherapy,
cancer therapy, oral biofilm, periowave.

to activate a photosensitizing agent in the presence

of oxygen. The exposure of the photosensitizer to
light results in the formation of toxic oxygen species,
causing localized photodamage and cell death.
HISTORY
In strict terms photodynamic therapy is as old
as life on earth and a classical example is
photosynthesis by plants. German physician Friedrich
Mayer-Betz performed the first study, with what was
first called photoradiation therapy (PRT ) with
porphyrins in 1913 in humans. But it was John Toth,
who acknowledged the photodynamic chemical
effect of the therapy with early clinical argon dye

Photodynamic Therapy

lasers and renamed it as photodynamic therapy

(PDT). It received even greater interest as Thomas
Dougherty formed the International Photodynamic
Association. Its use first started in dermatology (1992),
then oncology (1995), and recently in microbiology
(1996).
MECHANISM OF ACTION
A photosensitizer is a chemical compound
(usually a dye) that can be excited by light of specific
wavelength (visible or infra-red light). The agent or
its metabolic product is administered (injected or
applied externally) to the patient and gets
accumulated in the targeted tissues (cancer cells).
The tissue is then exposed to the light activating the
dye from its ground singlet state to an excited singlet
state which then undergoes an intersystem crossing
forming a longer lived excited triplet state. In the
presence of endogenous oxygen, an energy transfer
then takes place from this activated agent to the
oxygen molecule forming excited singlet state
oxygen or other reactive oxygen species (ROS),
causing a rapid and selective destruction of the target
tissues. There are two mechanisms for this last
process. Type I reaction involving electron transfer
directly from the photosensitizer producing ions, or
electron/hydrogen removal from a substrate
molecule to form free radicals. These radicals react
rapidly with oxygen, resulting in the production of
highly reactive oxygen species (superoxide, hydroxyl
radicals, and hydrogen peroxide). Type II reactions
producing the electronically excited and highly
reactive state of oxygen known as singlet oxygen.
Usually it involves a contribution from both the
mechanisms.2
It may also mediate tumor destruction indirectly
by vascular damage through photochemical oxygen
consumption or by stimulation of the host response.3
A massive invasion of inflammatory cells during and
after PDT has been observed in murine tumor
models. 4
LIGHT SOURCE:
PDT requires a source of light that activates the
photosensitizer by exposure to low-power visible

Veerendra Nath Reddy, et, al.

light at a specific wavelength. Human tissue

transmits red light efficiently, and the longer
activation wavelength of the photosensitizer results
in deeper light penetration. Consequently, most
photosensitizers are activated by red light between
630 and 700 nm, corresponding to a light
penetration depth from 0. 5 cm (at 630 nm) to 1. 5
cm (at ~ 700 nm).5
We have 3 light systems for the therapy:
1.

Diode laser systems: they are easy to handle,

portable and cost-effective.

2.

Non-coherent light sources: preferred for

treatment of larger areas and include
tungsten filament, quartz halogen, xenon
arc, metal halide and phosphor-coated
sodium lamps.

3.

Non-laser light sources include lightemitting diodes (LED). They are economical,
light weight and highly flexible. 6

PHOTOSENSITIZER:
Requirements of an optimal photosensitizer include
following characteristics:
1.

Highly selective tumor accumulation :

targetibility

2.

Low toxicity and fast elimination from the

skin and epithelium

3.

High quantum yield of singlet oxygen

production in vivo

4.

Cost effectiveness and commercial

availability

5.

High solubility in water, injection solutions,

and blood substitutes

6.

Storage3

The various agents can be grouped under 3

generations. 7 First genetation include photofrin
(most extensively used) and hematoporphyrin
derivatives (HPD). Second generation include 5aminolevulinic acid (ALA), benzoporphyrin
derivatives (BPD), temoporfin (mTHPC) and
talaporphin sodium (LS11). Foscan (mTHPC) is the
most potent amongst them. ALA, is an intrinsic
IJDA, 1(1), 2009

47

Photodynamic Therapy

photosensitizer that is converted in situ to a

photosensitizer, protoporphyrin IX. Topical ALA and
its esters have been used to treat pre-cancer
conditions, and basal and squamous cell carcinoma
of the skin. 8 Third-generation photosensitizers
include currently available drugs that are modified
by targeting with monoclonal antibodies or with
non-antibody-based protein carriers and protein/
receptor systems, and conjugation with a radioactive
tag. Currently only 3 agents have been approved by
FDA - Porfimer sodium, ALA and Vertoporfin. Foscan
is in used only in European countries.
ADVANTAGES OF PDT
Therapy has only localized effects as the
photosenstizer is selectively absorbed at a greater
rate by target tissues, can be performed in outpatient
or day-case settings, is more economical than
radiation and surgical therapy for cancer patients,
shows faster post-op healing with no long term side
effects, less invasive and can be repeated many times
at the same site if needed, unlike radiation.
LIMITATIONS:
Light needed to activate photosensitizer cannot
penetrate more than 1cm of tissue depth using
standard laser and low powered LED technology and
hence is less effective in treatment of large tumors
and metastasis. It may leave many people very
sensitive to light post therapy and cannot be used in
people allergic to porphyrins.
CURRENT STATUS IN DENTISTRY:
It is mainly used as anticancer therapy for head
and neck region including early stage cancers and
early recurrences of the oral cavity and larynx (Tis/
T1/T2)9, oral lichen planus, leukoplakia, verrucous
hyperplasia and some metastatic lesions. Now a days
it is also being employed for the Photodynamic
diagnosis (PDD) of malignant transformation of oral
lesions and treatment of various autoimmune
disorders. A new field has evolved using the principle
of this therapy, the PHOTODYNAMIC ANTIMICROBIAL
CHEMOTHERAPY (PACT) against various viral, fungal
and bacterial infections in the oral cavity. It works
not only on periodontal conditions but also on all
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IJDA, 1(1), 2009

Veerendra Nath Reddy, et, al.

forms of plaque associated conditions (periodontitis

and peri-implantitis)1
PHOTODYNAMIC ANTIMICROBIAL
CHEMOTHERAPY
In recent years, the emergence of antibiotic
resistant strains, such as methicillin resistant
Staphylococcus aureus and vancomycin-resistant
Enterococcus faecalis, stimulated a search for
alternative treatments. PACT has the potential to be
such an alternative, especially for the treatment of
localized infections of the skin and the oral cavity.
Micro-organisms that are killed by PACT include
bacteria, fungi, viruses, and protozoa. The
development of resistance to PACT appears to be
unlikely, since, in microbial cells, singlet oxygen and
free radicals interact with several cell structures and
different metabolic pathways. PACT is equally
effective against antibiotic-resistant and antibioticsusceptible bacteria.10 The photosensitizer can be
delivered to infected areas by topical application,
instillation, interstitial injection, or aerosol delivery.
Photosensitizers used in PACT include: (i)
phenothiazine dyes [Methylene Blue (MB) and
Toluidine Blue O ( TBO; tolonium chloride)]; (ii)
phthalocyanines [aluminum disulphonated
phthalocyanine and cationic Zn(II)-phthalocyanine];
(iii) chlorines [chlorin e6, Sn(IV)chlorin e6, chlorin e62. 5 Nmethyl- d-glucamine (BLC1010)], and polylysine
and polyethyleneimine conjugates of chlorine e6; (iv)
porphyrins (hematoporphyrin HCl, Photofrin, and
ALA); (v) xanthenes (erythrosin); and (vi)
monoterpene (azulene).1
The following bacterias can be destroyed: Total
streptococcus, Actinomyces, Lactobacillus, Prevotella
intermedia, Peptostreptococcus micros, Fusobacterium
nucleatum and Enterococcus faecalis.
PACT can be used for disinfection of tooth
cavities, root canals and periodontal therapy. It also
been recently tested for the treatment of periimplantitis.
EFFECTS OF PACT ON ORAL BIOFILMS:
A wide range of persistent human infections are
due to microbial biofilms. Dental plaque can be

Photodynamic Therapy

defined as the diverse community of microorganisms found on the tooth surface as a biofilm,
embedded in an extra-cellular matrix of polymers
(EMP) of host and microbial origin. Microorganisms
grow in biofilms stuck to a solid surface where they
multiply and form microcolonies. Periodontal
diseases result from accumulation of subgingival
bacterial biofilms on tooth surfaces. Although
mechanical removal of the periodontal pathogens is
the current gold standard of treatment, antibiotics
are also known to be effective. However,
development of resistance in the target organisms
is a problem associated with the use of such drugs.11
Additionally, concerns regarding systemic antibiotics
use include side effects such as pseudomembranous
enterocolitis, superinfection, other gastrointestinal
disorders, and emergence of antibiotic resistance.
Locally delivered antibiotics are an acceptable
alternative for efficacy and are less likely to cause
systemic side effects. However, disadvantages
include inconvenience (because of required change
in oral hygiene habits), cost (repeated treatments),
and usability in relatively small areas in oral cavity
which is not convenient for management of a
generalized disease.12 The use of photoactivatable
compounds or photosensitizers (PS) to cause
photodestruction of oral bacteria has been
demonstrated, indicating that photodynamic
therapy (PDT ) could be a useful alternative to
mechanical means as well as antibiotics in
eliminating periopathogenic bacteria. The
antimicrobial activity of photosensitizers is mediated
by singlet oxygen, which, because of its high chemical
reactivity, has a direct effect on extracellular
molecules. Thus, the polysaccharides present in EMP
of a bacterial biofilm are also susceptible to
photodamage. Such dual activity, not exhibited by
antibiotics, represents a significant advantage of
PACT. Breaking down biofilms may inhibit plasmid
exchange involved in the transfer of antibiotic
resistance, and disrupt colonization.
An example is Periowave, a photodynamic
disinfection system developed by Ondine Biopharma
Corporation that utilizes low intensity lasers and
wavelength-specific, light-activated compounds to
specifically target and destroy microbial pathogens
and reduce the symptoms of disease. The

Veerendra Nath Reddy, et, al.

photosensitive compounds are topically applied in

the gingival sulcus and the laser is used to activate
the compounds and complete the disinfection. 11
Activity of PACT against oral biofilms include in
vitro studies by,12-15 and few in vivo studies (in animal
model) are available.16-19 All these studies found PDT
to be effective in reducing bacterial load in the
biofilm. Studies done by Braun et al., 2008 in patients
with chronic periodontitis showed better clinical
outcomes when PDT was used along with
conventional therapy. 20 However, Oliveira et al., 2009
could not find any statistical differences between PDT
and scaling and root planning in patients with
aggressive periodontitis. 21
PERSPECTIVE AND FUTURE DIRECTIONS
In general, however, PDT remains on the
periphery of the treatment options for head and neck
cancer. Thus far, the lack of accurate dosimetry and
appropriate illumination devices, coupled with
poorly defined treatment parameters, has diminished
the success of PDT. The development of new, more
tumor-specific photosensitizers and light delivery
systems, and well-designed, randomized, and
standardized controlled trials should improve the
efficacy of PDT and accelerate the FDAs approval of
its use for the treatment of head and neck cancers. A
moderate enhancement of photosensitizer
accumulation in tumor tissues provides a first level
of selectivity, while further selectivity may be
provided by the homogenous illumination of the
target area with a custom-size fiber optic. Developing
such devices would be a much-needed future
direction for PDT. The LED devices that can be shaped
into numerous forms and sizes, and are cost-effective,
may replace laser light sources and their fiber optics.
Recent concept include (i) a metronomic PDT that
uses a continuous delivery of photosensitizer and
light at low rates for extended periods of time, (ii)
implantable light sources, and (iii) the attachment of
bioluminescent material to photosensitizers.
PACT will not replace antimicrobial
chemotherapy, but the photodynamic approach may
improve the treatment of oral infections, accelerating
and lowering the cost of the treatment. Development
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49

Photodynamic Therapy

of new photosensitizers, more efficient light delivery

systems, and further animal studies are required to
establish the optimum treatment parameters before
investigators can proceed to clinical trials and
eventual clinical use.
Major controversies in PDT includes: (i) the
difficulty in establishing the optimum conditions for
a treatment that has several components, (ii) clinician
and hospital resistance to a new approach, (iii) the
cost of setting up a PDT center, (iv) the previous lack
of inexpensive and convenient light sources, and (v)
difficulty in obtaining FDA approval.2
CONCLUSION:
Thus to summarize PDT may have a significant
potential for the treatment of oral cancer and oral
dysplastic lesions, as well as PACT for the treatment
of oral infections, but its future depends on
interactions between clinical applications and
technological innovations.

Veerendra Nath Reddy, et, al.

10.

Wainwright M, Crossley KB. Photosensitizing agents

circumventing resistance and breaking down biofilms: a
review. Int Biodeterior Biodegrad 2004;53:119-126.

11.

Thomas B., Saatian S. et al. Photodynamic theory-is it more

effective than the current standard of care? An evidence
based study of literature 2006.

12.

Amir Azarpazhooh, Prakash S. Shah et al., The effects of

photodynamic therapy for periodontitis: a systematic
review and meta-analysis. Journal of Periodontology
2009;July: 1-9.

13.

Williams JA, Pearson GJ, Colles MJ. Antibacterial action of

photoactivated disinfection {PAD} used on endodontic
bacteria in planktonic suspension and in artificial and
human root canals. J Dent 2006;34:363-371

14.

Donnelly RF, McCarron PA, Tunney MM, Woolfson A.

Potential of photodynamic therapy in treatment of fungal
infections of the mouth. Design and characterisation of a
mucoadhesive patch containing toluidine blue O. J
Photochem Photobiol 2007;86:59-69.

15.

Garcez AS, Ribeiro MS, Tegos GP, Nunez SC, Jorge AO,
Hamblin MR. Antimicrobial photodynamic therapy
combined with conventional endodontic treatment to
eliminate root canal biofilm infection. Lasers Surg
Med2007;39:59-66.

16.

Kmerik N, Nakanishi H, MacRobert AJ, Henderson B,

Speight P, Wilson M. In vivo killing of Porphyromonas
gingivalis by toluidine bluemediated photosensitization in
an animal model. Antimicrob Agents Chemother 2003;
47:932-940.

17.

Hayek RR, Arajo NS, Gioso MA, Ferreira J, Baptista-Sobrinho

CA, Yamada AM, et al. Comparative study between the
effects of photodynamic therapy and conventional therapy
on microbial reduction in ligature-induced peri-implantitis
in dogs. J Periodontol 2005;76:1275-1281.

18.

Sigusch BW, Pfitzner A, Albrecht V, Glockmann E. Efficacy

of photodynamic therapy on inflammatory signs and two
selected periodontopathogenic species in a beagle dog
model. J Periodontol 2005;76:1100-1105.

19.

Shibli JA, Martins MC, Ribeiro FS, Garcia VG, Nociti FH,
Marcantonio Em. Lethal photosensitization and guided
bone regeneration in treatment of peri-implantitis: an
experimental study in dogs. Clin Oral Implants Res
2006;17:273-281.

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R. R. de Oliveria et al., Antimicrobial photodynamic therapy

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