The role of photodynamic therapy „PDT… physicsTimothy C. Zhua� and Jarod C. FinlayDepartment of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

�Received 14 April 2008; revised 7 May 2008; accepted for publication 8 May 2008;published 16 June 2008�

Photodynamic therapy �PDT� is an emerging treatment modality that employs the photochemicalinteraction of three components: light, photosensitizer, and oxygen. Tremendous progress has beenmade in the last 2 decades in new technical development of all components as well as understand-ing of the biophysical mechanism of PDT. The authors will review the current state of art in PDTresearch, with an emphasis in PDT physics. They foresee a merge of current separate areas ofresearch in light production and delivery, PDT dosimetry, multimodality imaging, new photosensi-tizer development, and PDT biology into interdisciplinary combination of two to three areas. Ulti-mately, they strongly believe that all these categories of research will be linked to develop anintegrated model for real-time dosimetry and treatment planning based on biologicalresponse. © 2008 American Association of Physicists in Medicine. �DOI: 10.1118/1.2937440�

Key words: PDT, spectroscopy, implicit dosimetry, explicit dosimetry, dynamic process

I. INTRODUCTION

Photodynamic therapy �PDT� is an emerging cancer treat-ment modality based on the interaction of light, a photosen-sitizing drug, and oxygen.1 PDT has been approved by theU.S. Food and Drug Administration for the treatment of mi-croinvasive lung cancer, obstructing lung cancer, and ob-structing esophageal cancer, as well as for premalignant ac-tinic keratosis and age-related macular degeneration. Studieshave shown some efficacy in the treatment of a variety ofmalignant and premalignant conditions including head andneck cancer,2,3 lung cancer,4–6 mesothelioma,7 Barrett’sesophagus,8,9 prostate,10–12 and brain tumors.9,13–15 Unlike ra-diation therapy, PDT uses nonionizing radiation and can beadministered repeatedly without cumulative long-term com-plications since it does not appear to target DNA.

There has been tremendous progress made in the last 2decades in new technologies and in understanding of thebasic biophysical mechanisms of PDT. The most importantquestion to be answered is: “What determines PDT efficacyfor a particular patient, photosensitizer, and treatment proto-col?” Answering this question will require a unified under-standing of the interactions of the three basic components:light, photosensitizer, and tissue oxygenation. We have cat-egorized the current basic research in PDT into five areas: �1�light sources, light transport, and light delivery in tissue; �2�PDT dosimetry; �3� optical and anatomic imaging; �4� newphotosensitizers; and �5� PDT biology. Among these, the de-velopment of new photosensitizers and PDT biology is tra-ditionally considered outside of the realm of PDT physicsand will only be briefly described for completeness. All fiveareas are linked by a quantitative understanding of the dy-namic processes involved in the photochemical interactionthat drives PDT. In the next section, we will describe these

areas separately.

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II. THE PROBLEMS IN CLINICAL PDT

II.A. Modeling the dynamic process of PDT

Photodynamic therapy is inherently a dynamic process.There are three principal components: photosensitizer, light,and oxygen, all of which interact on time scales relevant to asingle treatment. The distribution of light is determined bythe light source characteristics and the tissue optical proper-ties. The tissue optical properties, in turn, are influenced bythe concentration of photosensitizer and the concentrationand oxygenation of the blood. The distribution of oxygen isaltered by the photodynamic process, which consumes oxy-gen. Finally, the distribution of photosensitizer may changeas a result of photobleaching, the photodynamic destructionof the photosensitizer itself. To account for these interac-tions, a dynamic model of the photodynamic process is re-quired.

At the most fundamental level, the photodynamic processdepends on the photosensitizer molecule itself. Figure 1shows the energy level, or Jablonski, diagram for a typicaltype-II photosensitizer. The photochemical reaction is initi-ated by the absorption of a photon of light by a photosensi-tizer molecule in its ground state �S0�, promoting it to anexcited state �S1�. Both this state and the ground state arespectroscopic singlet states. One essential property of a goodphotosensitizer is a high intersystem crossing �ISC� yield,i.e., a high probability of transition from S1 to an excitedtriplet state �T1�. In the T1 state, the photosensitizer cantransfer energy to molecular oxygen �3O2�, exciting it to itshighly reactive singlet state �1O2�. The details of this energytransfer process are beyond the scope of this article but havebeen an area of active study.16

Two approaches have been used to study PDT dynamics.First, a microscopic model takes into account diffusion ofoxygen and photosensitizer from blood vessels and can de-termine the singlet oxygen concentration in cells microscopi-

cally. Foster et al. were the first to propose such a quantita-

3127127/10/$23.00 © 2008 Am. Assoc. Phys. Med.

3128 T. C. Zhu and J. C. Finlay: PDT physics 3128

tive model and to verify its results in multicell tumorspheroid models.17,18 These models demonstrate that thedominant effect of the fluence rate in photodynamic therapyarises because the photochemical process itself consumesoxygen. If the rate of photochemical oxygen consumption isgreater than the rate at which oxygen can be resupplied bythe vasculature or ambient medium, an induction of transienthypoxia by PDT can result. This effect has been modeledtheoretically and has been demonstrated in cell spheroids,17

animals,19 and human tissues,20 and continues to be an areaof active research.21 A second, macroscopic model has alsobeen developed.22,23 This is an empirical model that does nottake into account the actual oxygen and photosensitizer dif-fusion processes microscopically but instead approximatesthem with simpler functions. It does, however, explicitly ac-count for the larger-scale spatial variation in fluence ratebased on the diffusion approximation. This model provides aquantity �reacted singlet oxygen� that can be used directly forclinical PDT dosimetry, and that relates directly to the three-dimensional distribution of photosensitizers, light fluencerate, and a mean tissue oxygenation distribution.22,23

II.B. Current areas of basic PDT research

II.B.1. Light source, transport, and delivery

PDT became popular after the invention of the laser,which allowed the production of monochromatic light thatcould be easily coupled into optical fibers. The wavelengthof light used for PDT is typically in the wavelength rangebetween 600–800 nm, the so called “therapeutic window.”24

In this wavelength range, the energy of each photon �h�� ishigh enough ��1.5 eV� to excite the photosensitizer and yetis low enough so that the light has sufficient penetration intothe tissue. Early lasers were based on either argon gas lasers�488 and 514.5 nm� or frequency doubled Nd:yttrium-aluminun-garnet solid state lasers �532 nm�, which werethen used to pump a dye laser to produce light in the desiredwavelength range. With the development of the diode laser,

S1

S0

T11O2

3O2Sensitizer

Photonabsorption

Energytransfer tooxygen

ISC

Oxygen

FIG. 1. Energy level diagram for a typical type II photosensitizer and oxy-gen. The sensitizer in its ground state �S0� absorbs a photon of light and isexcited to its first singlet state �S1�. It spontaneously decays to its excitedtriplet state �T1� via ISC. From T1, energy is transferred to ground statemolecular oxygen �3O2�, creating reactive singlet oxygen �1O2�.

the laser source has become portable and a turn-key opera-

Medical Physics, Vol. 35, No. 7, July 2008

tion. Development of more powerful and cheaper lasersources, e.g., fiber lasers, which couple more efficiently intooptical fiber, is an active area of research.

The invention of optical fiber allowed light to be directedeasily to deliver irradiation to desired regions without therequirement of a straight light path and is another enabler ofPDT. Currently, most PDT procedures are performed withoptical fibers. By attaching diffuse scattering tips of variousgeometrical shapes at the exit end of the fiber, point, linear,and planar light sources can be produced.25 Further develop-ment in light delivery devices that produce a light field withvarious geometrical shapes and in power distribution modu-lation that covers a larger area and has higher power is stillan active area of research.

Light distributions can be modeled using the diffusionapproximation to radiative transport.26 The finite-elementmethod is commonly used to solve the diffusion equation27

in an optically heterogeneous medium with arbitrary geom-etry. Various boundary conditions are used to describe vari-ous tissue-tissue, tissue-air, and tissue-water interfaces.26,28

However, the solution is often inaccurate in regions withouta sufficient number of multiple scattering �near the lightsource or nonscattering medium�. In these regions MonteCarlo simulation provides more accurate results but is muchslower.29 Active research is on going to solve the Boltzmannequation of light transport directly to provide accurate resultwhile improve the speed of calculation.26,30

II.B.2. PDT dosimetry

Three general strategies have been developed for dosim-etry based on the cumulative dose of singlet oxygen, whichis presumed to be predictive of tissue damage. Explicit do-simetry refers to the prediction of singlet oxygen dose on thebasis of measurable quantities that contribute to the photo-dynamic effect.31 The quantities of interest are typically thedistributions of light, photosensitizer, and oxygen. The dis-tributions of photosensitizer and oxygenation can be mea-sured via optical spectroscopy, as described above. In currentclinical practice, however, the quantity most straightforwardto measure is the light dose. Flat photodiode detectors havebeen used to measure the incident irradiance at the tissuesurface in intraoperative PDT.32 These measurements, how-ever, may not accurately reflect the fluence rate in the tissueitself because they neglect contribution of backscatteredlight. Detectors based on optical fibers overcome this prob-lem by collecting light isotropically.33 The effect on the mea-sured fluence rate is significant.34 Because these probes col-lect light via multiple scattering, the interface between thescattering tip and the surrounding medium can change thesensitivity of the detector by as much as a factor of 2, requir-ing careful calibration.35

Because complete explicit dosimetry requires measure-ment of three different parameters, it is inherently challeng-ing. Two alternatives have been suggested that require mea-surement of only a single parameter. Direct dosimetry relieson the detection of singlet oxygen itself, either through its

own phosphorescence emission or via singlet-oxygen-

3129 T. C. Zhu and J. C. Finlay: PDT physics 3129

sensitive chromophores. Implicit dosimetry31 uses a quan-tity such as fluorescence photobleaching of the photosensi-tizer, which is indirectly predictive of the production ofsinglet oxygen. Strategies for direct and implicit dosimetryare under development and will be discussed in later sec-tions.

II.B.3. Anatomic and optical imaging

The most commonly used medical imaging modalities in-clude ultrasound, computer tomography �CT�, magneticresonance, magnetic resonance spectroscopy, single photonemission computer tomography, and positron emission to-mography �PET�. The first three modalities produce excellentanatomical images, while the latter three provide functionalinformation �e.g., oxygen perfusion or tissue metabolism� atthe expense of image resolution. Diffuse optical tomography�DOT� is a viable new biomedical imaging modality.36 Thistechnique images the absorption and scattering properties ofbiological tissues and has been explored as a diagnosis toolin breast,37–42 brain,43,44 and bones and joints.45 Some pre-liminary attempts have been made to perform DOT forprostate.46–49 DOT at the treatment wavelength can be usedas input to calculate light fluence rate distribution for PDT.In addition, it provides access to a variety of physiologicalparameters that cannot otherwise be measured easily. An-other modality, optical coherence tomography �OCT� usescoherent light to obtain high resolution images. However,OCT is rarely used in PDT because of the limitation of pen-etration depth ��1 mm�.50

Most image reconstruction of DOT is based on solvingthe inverse problem for the diffusion equation.27 This is anill-posed problem because of the strong scattering in the tur-bid medium. As a result, the image resolution of DOT islimited when compared with other imaging modalities, suchas magnetic resonance imaging �MRI� or CT. The use ofspectroscopic information and/or a priori anatomic informa-tion is common to provide additional constraint to producereliable DOT reconstruction. Interested readers can find moreinformation from some excellent review articles.51,52

The concept of absorption and fluorescence spectroscopyas a modality for the diagnosis of disease dates back severaldecades.53 In recent years, the potential for spectroscopy todiagnose cancer54 and to monitor the progress of cancertreatment55 has been increasingly appreciated. In addition toits role in diagnosis, spectroscopy is particularly applicableto PDT in determining the local drug and oxygenconcentrations.56

Photodynamic therapy can cause changes in the concen-tration and oxygenation of blood in tissue both directly,through photochemical oxygen consumption, and indirectly,through effects on the vasculature and general physiologicalresponses. The monitoring of these responses may, therefore,be predictive of treatment outcome. For oxygen monitoring,the difference in absorption spectra between oxy- and deoxy-hemoglobin is used to determine the hemoglobin oxygensaturation, i.e., the fraction of total hemoglobin that is in its

oxygenated state. This quantity can be related to the oxygen

Medical Physics, Vol. 35, No. 7, July 2008

concentration in the blood using the Hill curve.57 This mea-surement does not directly measure the concentration of oxy-gen in the tissue itself, however, it is possible to model therelationship between the vascular and tissue oxygenation.This concept has been investigated in animal models inwhich the blood flow and/or oxygenation were monitoredand changes correlated with outcome.58,59

II.B.4. New photosensitizers

Various photosensitizing drugs have been developed. Thefirst-generation photosensitizer, hematoporphyrin derivative,is a mixture of porphyrin monomers and oligomers that ispartially purified to produce the commercially availableproduct, porfimer sodium, marketed under the tradenamePhotofrin®. Photofrin® was approved for treatment of earlystage lung cancer in 1998 and for Barrett’s esophagus in2003. The clinical applicability of Photofrin® has been lim-ited by two factors. First, its absorption peak occurs at tooshort a wavelength �630 nm� to allow deep penetration intissue. Second, administration of Photofrin® results in cuta-neous photosensitivity lasting up to 6 weeks. These limita-tions have inspired the development of a second generationof photosensitizers with longer-wavelength absorption peaksand more rapid clearance from skin. Among these was ben-zoporphyrin derivative monoacid A �BPD-MA�, or vertepor-fin. In preclinical trials, it was observed that verteporfin pref-erentially targeted neovasculature. This selectivity has beenexploited for the treatment of choroidal neovascularization�CNV�, an abnormal growth of vessels in the retina associ-ated with age-related macular degeneration �AMD�, the lead-ing cause of blindness in the developed world. Verteporfinwas approved in the U.S. under the tradename Visudyne forCNV treatment in 2000. Tetra �m-hydroxyphenyl� chlorin�mTHPC, Foscan®� is another second generation photosen-sitizer, a pure synthetic chlorin compound, which is activatedby 652 nm light.60 The major advantages of mTHPC are ashort duration of skin photosensitivity �15 days�, a highquantum yield for singlet oxygen, and depth of tumor necro-sis of up to 10 mm in preclinical models.61 mTHPC has beenused for treatment of pleural mesothelioma,7 head-and-neckcancers,62,63 esophagus,64,65 prostate,10,66 pancreas,67 arthriticjoints,68 and skin cancers69 and was approved in Europe forPDT of head-and-neck and varieties of other tumors in 2001.

Another development of note is the prodrug�-aminolevulinic acid �ALA�. Unlike other PDT drugs, ALAitself is not a photosensitizer. When taken up by cells, how-ever, it is converted by a naturally occurring biosyntheticprocess into the photosensitizer protoporphyrin IX �PpIX�.ALA can be applied topically, and was approved by the FDAin 1999 for the treatment of actinic keratosis �AK�. Table Isummaries several of the more widely used photosensitizerscurrently available.

II.B.5. PDT biology

From the point of view of biological response, PDT isfundamentally different from other cancer therapies. Unlike

ionizing radiation, PDT achieves its cytotoxic effects prima-

3130 T. C. Zhu and J. C. Finlay: PDT physics 3130

rily though damage to targets other than DNA. The specificsubcellular targets damaged by PDT depend on the photosen-sitizer’s localization within the cell, which varies amongphotosensitizers and cell lines. Different types of damage canlead to different mechanisms of cell death. Damage to mito-chondria in particular can lead to apoptosis even at relativelylow light doses.70 Recently, the role of autophagic cell deathin PDT has been increasingly recognized.71 In addition to thevariation among photosensitizers in their subcellular targets,there is considerable variability in the macroscopic targetingof photosensitizers. Photosensitizers that are retained in thevasculature can destroy tumors via vascular damage ratherthan direct cell killing. Some photosensitizers may act asvascular agents at short times after injection and at high flu-ence rates, where only the vasculature is sufficiently oxygen-ated, and produce direct cell kill at low fluence rates and

TABLE I. An incomplete list of photosensitizers currently undergoing human

Photosensitizer Trade name Approval

Porfimer sodium Photofrin 1998, 2003 �FDA�ALA-PpIX Levulan Keratastick 1999 �FDA�Methyl aminolevulate-PpIX Metvix 2004 �FDA�Hexyl aminolevulate-PpIX Hexvix 2005 �EU�BPD-MA Verteporfin, Visudyne 2000 �FDA�mTHPC Foscan Phase I trials, 2001 �

Motexafin Lutetium MLu, Lutex, Lutrin Phase I trialsPd-bacteriopheophorbide Tookad Phase I trialsTaloporfin sodium�mono-L-aspartyl chlorin e6�

LS11 Phase I and II trials

Silicon pthalocyanine 4 PC-4 Phase I trials

Real-timand treatmbased o

res

Light Dosimetrywith Feedback

Explicit and,Implicit

Dosimetry,SOLD

ComplexDosimetry withFeedback,

Real-time TPS

PMBresim

Light Delivery Dosimetry Im

FIG. 2. Diagram illustrating the progress of PDT development from a set ofbiologists, chemists, physicists, and engineers. The second row illustrates th

The third row illustrates the future research direction and the fourth row is the ult

Medical Physics, Vol. 35, No. 7, July 2008

long times after injection.72 An additional level of complex-ity arises from the fact that the response to PDT is not con-fined to the cells where the singlet oxygen is deposited butcan involve physiological73 and immunological74,75 re-sponses as well.

III. CURRENT DEVELOPMENTS

Much of the research in the early decades of PDT and itsrelated fields proceeded in five almost independent areas, asillustrated in the top row of Fig. 2. The problems associatedwith light source and light delivery system development, do-simetry, and optical imaging were treated as physics prob-lems, while photosensitizer development and PDT biologywere treated as problems of chemistry and biology, respec-tively. In recent years, however, the most promising ad-

ical trials.

Excitation�nm�

Drug-lightinterval

Clearancetime Sites

630 48–150 h 4–6 weeks Lung, Barrett’s esophagus405, 635 14–18 h �2 days AK405, 635 3 h �2 days AK

405 1–3 h �2 days Detection of bladder tumors689 15 min 5 days CNV652 48–110 h 15 days Head and neck, prostate, pancreas,

esophagus, mesothelioma732 3 h Prostate, atherosclerosis762 �30 min �2 h Prostate664 1 h CNV, liver and colorectal metastasis

672 24–36 h Skin

simetryplanninglogicale

BiomarkersMolecularBeacons

TargetedPhotosensitizer,

Photo-immunotherapy

se-iveg

BiologicalResponseImaging

g PDTBiology

PhotosensitizerDevelopment

arate fields �top row� to a collaborative effort unifying the contributions ofent state of art of research and represents integration of two separate fields.

clin

EU�

e doentn biopons

, doponsagin

agin

dispe curr

imate integration of all disparate fields. See text for a complete description.

3131 T. C. Zhu and J. C. Finlay: PDT physics 3131

vances have come out of interdisciplinary collaborationsamong these areas. The systems and strategies currently inpreclinical and clinical trials are examples of suchcollaborations.

III.A. Light dosimetry with real-time feedback

It is very difficult to assess the efficacy and toxicity of anytreatment in a clinical trial without a rigorous quantitativemeasurement of the treatment given. One reason that radio-therapy has become an accepted locoregional therapy is thatthe dose to tissues has been quantified accurately and cura-tive doses can be delivered safely. In our current clinicaltrials, we deliver a dose of light to the treatment sites basedupon measurements made from implanted isotropic lightdetectors.34,76 These detectors allow us to prescribe the lightdose based upon actual measurements in the prostate ratherthan the output of the laser. This dosimetric approach alsoensures that the same amount of light energy �as measuredby the isotropic detectors� is deposited uniformly in the pros-tate within each cohort of patients as a specific dose level.

The measurement of light fluence in vivo is necessary butnot sufficient to optimize the light fluence distribution. Opti-mization of the light fluence depends upon accurate calcula-tion of the light fluence rate in the entire prostate volume,which in turn requires accurate characterization of the in vivoprostate optical properties as input. Many studies have beenconducted to determine the in vivo optical properties of hu-man prostate.77–79 These light fluence measurements showthat the optical properties of the prostate vary substantiallywithin a prostate gland as well as among separate prostateglands. The optical properties of prostate tissue may alsovary over time during a PDT procedure.

The state of the art for prostate PDT uses only in vivolight fluence rate monitoring to determine the light fluenceusing equal weight of linear light sources. This is not suffi-cient since light fluence at only selected points are known.Integrating ultrasound imaging and the PDT dose calculationengine into the PDT delivery system, with input of tissueoptical properties and drug uptake, will allow the clinician tooptimize the weight of each light-delivery fiber, and thusimprove the light fluence distribution in the prostate gland.Adequate treatment planning often uses various optimizationengines to optimize the distribution of light sourceintensities.

III.B. Implicit dosimetry and dosimetric imaging

The most commonly cited example of implicit dosimetryis fluorescence photobleaching. Wilson31 suggested that thephotobleaching of the photosensitizer, if moderated by thesame mechanism as the photodynamic effect, could indicatethe extent of damage. The theoretical basis for quantitativeimplicit dosimetry using fluorescence photobleaching wasformalized by Georgakoudi et al.18 for the case of multicelltumor spheroids. Fluorescence photobleaching has been usedin animal models to investigate the fluence-rate dependenceof photodynamic therapy80–82 and has been shown to corre-

83

late with visible skin damage. A device for skin PDT do-

Medical Physics, Vol. 35, No. 7, July 2008

simetry using photobleaching has been developed for use inclinical trials84 and work to extend the spheroid models torealistic tissues is ongoing.85

Fluorescence photobleaching is relatively inexpensive andstraightforward to implement, however, its quantitative inter-pretation involves several challenges. First, fluorescencemeasurement in vivo must always account for the confound-ing effects of light scattering and absorption. Second, thevalidity of the relationship between fluorescence pho-tobleaching and reacted singlet oxygen dose assumes that thephotobleaching is mediated primarily by singlet oxygen re-action with the photosensitizer. There is experimental evi-dence to suggest that other bleaching mechanisms may beimportant for the commonly used photosensitizersPhotofrin®82 and ALA-induced PpIX,86 and the in vivo pho-tobleaching of mTHPC exhibits features that are not readilyinterpretable.81 Care should therefore be exercised in usingphotobleaching as a dose metric.

Two methods have been developed for the detection ofsinglet oxygen itself. Qin et al. have demonstrated achemoluminescent compound that emits light in the presenceof singlet oxygen.87 The translation of this technology intopatients will require the development of a nontoxic, singlet-oxygen-specific chemoluminescent probe that distributesuniformly in tissue.

Direct measurement of singlet oxygen can be accom-plished via detection of its 1270 nm phosphorescence emis-sion, a technique known as singlet oxygen luminescence do-simetry �SOLD�.88 Detection of this signal presentssignificant technical challenges due to the long wavelengthof the emission and the weak signal. Jarvi et al.88 have de-veloped a system based on a photomultiplier tube capable ofdetecting the long-wavelength emission of singlet oxygen.The emission is stimulated by a pulsed laser at the treatmentwavelength, and a time-resolved measurement of the emittedsignal allows determination of the singlet oxygen lifetime inthe system being measured. An additional challenge is theinterpretation of the singlet oxygen phosphorescence signal.The phosphorescence emission arises from a transition ofoxygen from its singlet state to its ground state. This processtherefore competes with the reaction of singlet oxygen withcellular and extracellular substrates. This leads to an increasein phosphorescence emission in conditions where substratesfor singlet oxygen are not plentiful. To differentiate betweenthe cellular signal corresponding to PDT effect and the ex-tracellular signal, the time-resolved emission signal can be fitas a sum of signals with different lifetimes.

III.C. Biomarkers and molecular beacons

Because the goal of PDT is ultimately to deliver the op-timal treatment to the tumor, the idea of using noninvasivedetection and imaging to determine the status of tumor cellsat the molecular level is very attractive. This concept hasdriven the development of molecular beacons, molecules thattarget specific molecular pathways that can be imaged using,for instance, near-infrared fluorescence. Steflova et al. have

developed a series of molecular beacons whose fluorescence

3132 T. C. Zhu and J. C. Finlay: PDT physics 3132

is quenched in their latent state and restored under the actionof specific cellular processes of interest.89 Because these bea-cons target specific molecules, it is likely that they will betumor-type specific, however, the variety of cellular pro-cesses that can potentially be imaged using this approachmakes it very promising. Molecular beacons are a subset ofthe general category of cancer biomarkers, molecules whichallow imaging of specific biological processes via variousmodalities including MRI, PET,90 and optical imaging.

III.D. Enhancement and targeting of photosensitizers

Several researchers have developed methods for enhanc-ing the ability of a photosensitizer to target tumors. Onestrategy to accomplish this is to optimize the timing the ad-ministration of light to coincide with the desired distributionof the photosensitizer.72 This approach has been used to tar-get vasculature by applying light while the photosensitizer isin circulation, for the treatment of AMD using Vertepofin andthe prostate using Tookad.12 In cases where the rate of pro-duction of singlet oxygen is limited by the vascular resupplyof oxygen, changes in the light fluence rate can change thedistribution of deposited singlet oxygen, with higher fluencerates leading to preferential targeting of vascular-adjacent tis-sue. Thus, the combination of drug-light interval and fluencerate can be adjusted to enhance the treatment of the desiredtissue type.

A more direct approach to photosensitizer targeting is theconjugation of the photosensitizer to a tumor-selective mol-ecule or particle.91 The last 2 decades have seen tremendousprogress in the development of tumor-targeted therapeuticand imaging agents for cancer in general.92,93 These innova-tions will continue to inform the development of new photo-sensitizers targeted to specific tumor types.

Recent research has shown PDT induced increases ofVEGF, MMPs, and/or COX-2 in tumor microenvironmentthat cause resistance to standard treatment. As a result, com-bination of therapy that suppresses these growth factors hasbeen proposed to enhance the therapeutic efficacy of PDT.C225, a monoclonal antibody that inhibits the receptor ty-rosine kinase activity of EGFR, has been shown to enhancethe PDT treatment in ovarian cancer.94,95 Other combinedmodalities seek to target treatment-induced angiogenesisand/or inflammation to enhance the effectiveness of PDT.96

IV. FUTURE DEVELOPMENTS ANDPREDICTIONS

We predict that future developments in PDT will continuethe trend toward interdisciplinary work and the inclusion ofmore technologies and subfields, such as imaging, noveldrug design, and biological modeling into the treatment plan-ning and dosimetry processes. Below are a few predictions offuture PDT physics research directions:

IV.A. Light sources: Faster, cheaper, larger, smaller

A significant driver in the development of new light

sources has been the advent of inexpensive, reliable diode

Medical Physics, Vol. 35, No. 7, July 2008

lasers and light-emitting diodes. Diode light sources havealready been made small enough to be implantable.97 Wepredict that this trend will continue, with future light sourcesbecoming ever smaller, cheaper, and more efficient. On theother hand, the increases in efficiency of these light sourceswill also lead to lasers with greater total power output, al-lowing the treatment of larger volumes of tissue using asingle source.

Simple increases in power are not the only advances wecan expect from future light sources. New delivery systemswill incorporate mechanisms to deliver a light distributioncustomizable to each patient’s treatment plan. In our group,we have developed a computer-controlled attenuator systemfor prostate PDT designed to adjust the intensities of up to 16implanted interstitial diffusing fibers independently and inreal time.98 Lilge et al. have investigated optical diffusingfibers whose emission profiles along the fiber axis can becustomized to deliver much more complex light distributionsthan conventional diffusers.99,100 We expect further develop-ments in this direction to allow more and more precise con-trol of the in vivo light distribution during PDT.

IV.B. Real-time oxygen monitoring

While it has long been recognized that oxygenation of thetarget tissue is essential to PDT, measurements of oxygen-ation are now starting to be implemented in preclinical andclinical trials. We anticipate that future clinical protocols in-volving real-time dosimetry will also include real-time oxy-gen monitoring, both to prevent PDT-induced hypoxia and totake advantage of the predictive value of PDT-inducedchanges in blood flow and hemoglobin oxygen saturation.58

The monitoring of hemoglobin saturation and blood flow hasbeen demonstrated in clinical trials.101 The translation ofmeasurements of hemoglobin oxygenation into a determina-tion of the cellular oxygen concentration requires a model ofoxygen diffusion and consumption. The development of suchmodels is ongoing and will inform future dosimetrydevelopments.85

An alternative to hemoglobin monitoring is the use oftime-resolved SOLD measurements. A sufficiently sophisti-cated analysis of the time dependence of the SOLD signalallows determination of the photosensitizer triplet lifetime,which is related to the local oxygen concentration. Hence,SOLD has the potential to provide both a measure of reactedsinglet oxygen dose and a measure of the molecular oxygenconcentration at the point of singlet oxygen generation.88

This approach has the additional advantage from the point ofview of explicit dosimetry of providing an intermediate veri-fication of the triplet lifetime predicted by the dosimetricmodel.

IV.C. Multifunctional, multimodality photosensitizers

Another area of active research in photodynamic therapyis the development of photosensitizers and photosensitizerdelivery systems that enhance the functionality of thephotosensitizer.102 For instance, a photosensitizer may be

linked to a fluorescent molecule to enhance its delectability

3133 T. C. Zhu and J. C. Finlay: PDT physics 3133

under fluorescence imaging.103 Pandey et al.104 have pro-posed combining photosensitizers with contrast agents foroptical, MRI and PET imaging, allowing image-guided PDTtreatment. Zheng et al. have combined the “molecular bea-con” concept with a photosensitizer to produce photody-namic molecular beacons.105 These molecules exhibitquenching that suppresses their production of 1O2 in theirlatent state. They can be activated by interaction with atumor-specific molecular marker, in this case the matrix met-alloproteinase MMP-7. The clinical implementation of strat-egies such as these has the potential to dramatically improvethe targeting of the photosensitizer to the tumor. An essentialcomponent of any targeting strategy will be the ability toverify the targeting of the drug to the desired target. Thedistribution of the photosensitizer can be determined opti-cally using fluorescence or absorption imaging. In addition,detailed models of the distributions and kinetics of light,photosensitizer, and oxygen will provide a quantitative rela-tionship between the microscopic distribution and photo-chemical properties of the drug and the macroscopically ob-served treatment response.106 In cases where the drug isactivated by an endogenous agent, the results will be predict-able only using such sophisticated models.

IV.D. Treatment planning integrated with dosimetry,imaging, and light delivery devices to allowadaptive treatment

The integration of dosimetry systems with multimodalityimaging �anatomic and DOT� and light delivery devices intoan integrated system has drawn great interest recently. Sev-eral groups are developing integrated systems to control lightdelivery, real-time light monitoring, and volumetric light flu-ence calculation. The group in Lund, Sweden is developing amultiple channel system of point sources that can be used aseither light sources or detectors.107 A personal computer con-trols the position and duration of the point sources to opti-mize light fluence distribution. Another group in Toronto,Canada has commercialized a four-channel light source withcomputerized power control in each channel. Our group hasdeveloped an integrated system that incorporates PDT do-simetry that include light fluence rate at multiple points,108 athree-dimensional map of optical properties,46 drug concen-tration distribution,56 and tissue oxygenation.98 A kernel-based algorithm was developed to calculate light fluence ratedistribution in the optically heterogeneous prostate gland,109

which, coupled with an optimization engine allows optimi-zation of light source powers to achieve a uniform light flu-ence distribution.110,98 This area of research will evolve intoa totally computerized delivery, monitoring, and dosimetrysystem for real-time feedback control.

IV.E. New dosimetry quantities based on modeling ofthe dynamic system

The current state of art in PDT dosimetry is to explicitlydetermine the quantity PDT dose, defined as the number ofphotons absorbed by photosensitizing drug per gram of

111

tissue. While this quantity takes into account the consump-

Medical Physics, Vol. 35, No. 7, July 2008

tion of photosensitizer, it does not consider the effect of tis-sue oxygenation on the quantum yield of oxidative radicals.Thus, it is only applicable in cases where ample oxygen sup-plies exist. It is anticipated that new dosimetry quantitiesbased on reacted singlet oxygen �1O2�rx, e.g., a product ofsinglet oxygen quantum yield and PDT dose, can be used toaccount for kinetics of the oxygen consumption during PDTprocess.23 Foster et al. have determined most of fundamentalparameters necessary for microscopic model of the oxygenconsumption during PDT.18,82,106,112 However, when apply-ing models developed in the microscopic scale to a macro-scopic environment, the values of many parameters maychange, and many parameters may be observable only in thevolume average, so extensive study will be required to deter-mine the values for each specific photosensitizer.

IV.F. Physiological effects of PDT will be exploited todevelop systemic therapy

The ability of PDT to elicit an immune response has beenrecognized for some time.75 The past decade has seen dra-matic progress in our understanding of the mechanisms ofPDT-induced immune response.74,113 In addition it has beendemonstrated that PDT can be used to generate vaccinesagainst specific tumor types.114,115 This strategy is particu-larly attractive for the treatment of cancer, where it is likelythat PDT will be used in combination with radiation andchemotherapy, both of which can have immunosuppressiveeffects.

As the details of the mechanisms of the immune responseare better understood, it is likely that new photosensitizersand delivery mechanisms will be developed for the expresspurpose of enhancing the immunological response and/ormoderate treatment induced angiogenesis and inflammation.Furthermore, the parameters which optimize immune re-sponse to PDT will be different from those that maximizesinglet oxygen dose or direct cell killing.116 Therefore, therewill be an increasing need for the incorporation of these ef-fects into PDT treatment planning and dosimetry. We predictthat PDT vaccines will find a use as an adjuvant therapy,even in cases where the tumor location or geometry pre-cludes conventional PDT as a primary treatment. In thesecases, it may be possible to perform PDT on ex vivo tissue orcell cultures, in which case the problems of light propagationand tumor physiology are greatly simplified, allowing a levelof treatment optimization not feasible in vivo.

V. CONCLUSIONS

We have predicted that PDT research will increasinglyrely on combinations of widely varied fields, leading to moreand more sophisticated treatment protocols. It is tempting toassume that such therapies will become so complex that theycan only be modeled empirically, and that the role of physicswill diminish. However, the history of PDT research demon-strates that many advances in the field are made not byavoiding the complexity of the problem but by embracing it.As we exploit our growing knowledge of the underlying pho-

tochemistry, biology, and physiology of PDT to develop new

3134 T. C. Zhu and J. C. Finlay: PDT physics 3134

and better treatments, it will be more important than ever tounderstand and optimize those treatment parameters overwhich we have direct control. In the future, as in the past, itwill be the understanding of the physics of PDT that willallow us to take advantage of our scientific understandingand translate it into improved clinical treatments.

ACKNOWLEDGMENTS

This work is supported by the National Institute of Health�NIH� Grant Nos. P01 CA87971 and R01 CA109456.

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