Clinically relevant technology in
photodynamic therapy and photodynamic diagnosis

Michael Unger, M.D., F..X.C.P., F.C.C.P.
Director Pulmonarv Endoscopv
Director, Laser Research
and Development
Clinical Associate Professor of Medicine

I.Jniversitv of Pennsylvania, Pennsvlvania Hospital
301 South Sth Street Suite 2B
Philadelphia, PA 19106

This presentation will not attempt to review the vast field of technoloov adapted for photodvnamic therapv 
(PDT). The boat which will be rather more modest altfiouoh not less ambitious, is to try to highlight different 
aspects of clinically relevant technological applications. We hope in this attempt to bridge the cap separating 
basic scientists. engineers, various hibll tech manufacturers, and clinicians, and thus bring the benefits of 
Photodynamic therapy closer to the patients.

Arbituily then, we will concentrate on three major aspects.

1. Energy sources and appropriate therapeutic wavelengths

applicators.

2. Delivery devices which will include superficial, intercavitaly, and intravaRnIllnr

3. Dosimetrv and more specifically the dosimetrv of enerov delivered, absorbed and distributed in the tissues: 
the dosimetrv of the photosensitizers in vivo as well as the relationship between the dosimetry of the delivered 
stimulating energy and the rate of photobleachin~. We will also briefly discus the diagnostic fluorescence.

1. ENERGY SOURCES FOR THERAPEUTIC EFFECTS

The major relevant energy sources for therapeutic effects can be classified into noncoherent sources, lasers, 
and energy emitting diodes.

1,1 Non-cohel ent sources

The simplest sources of such enerov am e various ty pes of overhead pro jectors anal stu-:ical headlamps. 
There have been several previotls reports in the literature and others will be presented at this conference. of the 
use of such devices. mostlv for superficial and dennatolo ical applications. Of particular interest. however. •vill 
be a saldv from the LTK. usino n .mlino]evulillic acid PDT, which concluded that the use of white li oht, 
presumablv at full spectmlll. •vas adequate to obtain results equivalent to those obtained with a pulsed laser 
source. but hlfeliol to the effects of a broad spectrum red lioht. In another study the use of a 1200 watt metal 
halooen lamp venerating wavelengths between 580 and 740 lml with appropriate filters, •vas clinically 
effective for Skill PDT.

The noncoherent sources of stimtllatintX enero+rt present obvious aclvalltaMes in their silllplicitv of 
constltlction and maintenance. which shoillcl result in a notch towel cost. the disadvantages, however. include 
obviously the lack of coherence and luliformitz of ctistlibution, a

decreased output of energy and fluence rate as well as possible difficulties in couplino these sources north 
other devices. There rniaht be also an additional component of more dificulty in controlling the thermal 
effects. These tvpes of devices seem to be most appropriate for PDT of superficial derrnatological lesions We 
have to remembers however. that many types of lesions are not flat and thus present the additional problem of 
appropriate dosimetry.

1.2. Lasers

For some time alreadv, an ongoing debate has ensued concemulg possible advantaoes and disadvantages of 
continuous versus pulse mode lasers. Several studies suggest the possible superiority of one svstem over the 
other in a specific experimental design, others vielded similar results. NIost frequentlv reported experiments 
used KTP pulsed dve lasers Copper vapor, Gold vapor and esimer lasers for a pulsed type energy sources (axe) 
From a clinical standpoint however no firm conclusions can be drawn in part, due to the nonuniformity in 
design of the research protocols.

Technological advances permit more readily achievable various tunable lasers.
Another interesting new development, as reported by Japanese researchers seems to be the introduction of 
optical parametric osci11atorssvith a t Gable beam betweenA10 and 2;O0 nm. These devices are pumped by 
third harmonics of the Q switch Nd: Y.AC laser.

The advantages of laser based devices are obviouslv the hiash potential energv output more precise tunability 
of the wavelength and the possibilitv of coupling to various accessories. C)n the other hand, the same 
equipment becomes prohibitively expensive and thus less accessible.

1.3 Light Emitting Diodes

Technolooical advances are now reaching a level where sufficient ponver OtltpUt can be expected from newer 
LED devices. Several presentations at this meeting will deal With I F.lds which can be tamed to wavelengths 
between 650 and 700 nm. thus assuring deeper tissue penetration. These types of devices also permit the 
development of many other wavelengths.

Light in all its various forms and wavelengths is onlv one part of the electromagnetic spectrum. It is not 
surprising then that we are witnessino a burgeoning interest in the exploration of other potential fields of 
stimulation and responses by appropriate sensitizers. It is interesting to note the preliminary report fi om 
Lithuania of the effectiveness of sonodvnamic therapv using energy of 1.8 W/Clll 2 for five minutes, 
Venerated at the frequency of 880 KHz.

The plethora of possible achievable svavelen~ths, frequencies. and amounts of energy delivered suooests that 
probable at the present time, the major difficulty in clinical applications of PDT resides in the development of 
appropriate specific old nontoxic photosensitizing agents.

A 1)ELIN F,R\' OEX'T(~I£S

Several research oroups dealino With PDT stressed and documented the neecl for proper placement of lioht 
enerov diffusers if the ooal is to achieve both the best reproducible effects and uniform tissue distribution. .R 
relativelv small misplacement of the lioht source in relation to the target area can result in several orders of 
magnitude of ch.ml_e of the light dose delivered to the tissue. For this reason. there has been rapid progress in 
developing various laser balloon catheters filled With air. normal saline solutions, or diffuser media in the 
form of intralipid.

The length of the diffusers can now be more readily tailored to the length of the lesions

treated. Appropriate feedback from the clinicians. pointing to the fact that most of intracavitarv or 
intravascular lesions are excentric and not circumferential and also to the observation of potential 
complications due to irradiation of non targeted struchlres or tissues. prompted the development of more 
precise and more effective directed deliverv systems with optical windows and target illumination. (Dur 
technology advanced at the same time, pennittin2 the use of diffusers or balloon delively systems for 
intracavitary or intravascular capabilitv with on line monitoring of
dOSilnetry.(3) (4) (5)

Bener measurement of feedback dosimetrv and target tissue necrosis as well as better energy sources 
stimulated the introduction of multiple diffuser svstems With the simultaneous delivery of light and 
measurement by several fibers introduced into the zones of treatment.(6)

3. DOSINIETR Y

Clinical considerations are predicated upon an understanding of the biology of the • alious lesions treated such 
as tumors. atheromas and other vascular abnormalities. Advances in hlmor pharmacoliinetics and molecular 
bioloov of neoplastic and non neoplastic tissues permit improved taroetin2 and selectivitv of pllotosensitizers 
bv use of liposomes or monoclonal antiboclies. The combination of photosensitizers uld 
immunophotodetection utilizing monoclonal antibodies mioht open a new venue in clinical applications.(7) 
After studies of the interaction of photosensitizers with these lesions in vitro, we need sophisticated technoloov 
for in vivo measturements and assessments. At the same time we are handicapped by the lack of precise 
knowledge of the appropriate physical parameters to be studied in order to predict consistently reproducible 
biological responses.

The most complex aspect of the teclmolooy of PDT involves dosimetrv. The clinicallv relevant dosimetlv has 
to deal with the amount and rate of energv delivered and its clistlibutioll in the tissues at the time of 
therapv.t8) The dosimetrv is also expected to provide us information regarding the concentration of the 
photosensitizers in the tissues and their rate of photoblbaching. Another aspect of the dosimetrv is the 
provision of technolo Micas data of tissue destruction in vivo by Photodynamic therapy.

3.1. Dosimetrv of the energy cleli~tered to the tissues

Several studies have souoht to determine the amount of enerov delivered to the tissues. Some results were 
obtained bv the implantation of photodetectors in the treated areas and the determination of the interstitial 
dose of lioht. Standardization and predictabilitv of results are hampered by the • ariabilih of distribution of 
tight in various tissues. There are measurable interpatient variations expressing biolooical differences of the 
ttunors and specific personal responses. as was shown in the studies of interstitial prostatic carcinomas front 
the I5.K.e(,> Although a priory these biological differences nti~^ht not appear statistically sirnif'ic;ult. they 
could be _mportant therapeutically.

The same consiclelatioll should also applv to other modalities •vhicll attempt to (letem_ine the dosimetry by 
on line monitoring by isotropic probes. These probes can. for instance. be placed on the balloon delivery 
svstems. The aim. once more. is to obtain a real time measurement of either the delivered light tncl its 
uniformity or the bacli scattered light.

.Amoll:, other still tsresolvecl questions is the determination of the ideals clinic.lllx relevant time interval 
betxveell the introduction of the calls ulcl the light delivela!.ls)

3.2. Dosimetrv of photosensitizers and photobleaching

Several techniques are potentially available for dosimetry of photosensitizers and photobleachino. Among the 
most notable are absorption spectroscope time resolved photoacoustic spectroscope and fluorescence 
spectrophotometlic detection capabilities. These systems can be based upon a sinole emission wavelength, 
while newer approaches utilize a dtual emission wavelenoth with single wavelength excitation. The deoree of 
photobleaching can also be velified by the use of ultrashort laser pulses and time correlated sinale photon 
counting

Dosimetrv determination svstems are obviously complex and require sophisticated maintenance. Some of 
them. combine high definition CCD cameras 1 0 1

The capabilitv of differentiation of normal from abnormal tissue bv means of fluorescence has been introduced 
for detection of early lesions which otherwise would not have been detectable bv presentlv available 
diaonostic means.ell)(l2)(l3) One of the most clinically relevant developments in this field was the 
introduction of the ltulg imaoino fluorescence endoscopv (L_ek) system which delived its origin from an 
attempt to diagnose endobronchial carcinomas while usino HPD. Ns a result of teclmolooical refinements. we 
now have an instillment reaching the potential of the verv earlv detection of neoplasms on the basis of the 
variabilitv of tissue autofluorescence and without the use of a specific photosensitizer for detection or 
localization. The discovers of premaligllantlesions or minimallv invasive ltmg carcinoma, which inciclentallx 
in its more advanced staoe is the number one killer in both men and women, mioht permit treatment of this 
disease in its earlv stares. It has. thus, the potential for eradication of the honor with PDT as was shown bv 
researchers from Japan and the .Mavo Clinic. It is hoped that this will contribute greatly to the improvement of 
what has been until now dismal mortality data for this specific type of cancer.

1 Other types of dosimetric equipment utilize v,alious fiberoptic systems. .X11 of them
owever. are hiohlv dependent upon the determination of deliven! and the collection of information efficieilcs 
of the optical fibers. LTnderstandablx, thes are also highly dependent on the lioht source and the responsivitv 
of the detector svstem. It seems that. at the present time of our lcnowledae. tissue concentration of a 
photosensitizes is of limited use in pr'edicting the optimal clinical effect of light activation 1 1 )

Considelino that these parameters chanoe sionificantlv when Usill  one specific photosensitizes in the 
different oroans or tissue. it is apparent how complex these measurements become when there is a need to use 
different excitation wavelenotlls for • ;uious photosensitizes The difficulties in specificity! and accuracv of 
measurements are potentiated bv autofluorescence.
Which has to be accounted for in all calculations. Standardization thus. becomes almost impossible, and 
reproducibility of results is very tedious With possibly questionable relev.ulce.

For these svstems to become really useful clinically thev should provide us with information regardin ^ the 
photodnnamics of the dlllg, in real time.

It remains however unrealistic to expect that all this dosirlletlic information can be translated into either a 
quantification of tissue clestlllction or an expected change as a result of PDT. Attempts are being made to 
reach this ooal using once more. othel parameters of the electromagnetic spectrum. notably ultrasotmcl and 
ma_netic resonance. The ultrasound imagine and Doppler ultrasollographn have not. as of vet. vieldetl 
sufficiently specific infonnation. similarly NE ima_ino cannot distinguish between non specific ilfllanlmatorv 
reaction and tissue clestmctiol1. As of now there is still no _ood correlation between this tvpe of' information 
and a final and definitive pathological analysis. On the other hand NIR spectroscopy!. although more

sensitive gives us only average readings, which again. can't be fullv conoborated by the pathologist.

In summary. it seems that at the present time our advances have reached the staoe of "techilolooy in search of 
applications." On the other hand. we still don't Blow what physical paran1eters should be measured or 
controlled to obtain predictable clinical results. We can however expect in the future an increasina.role for 
gene taroeting accents and their appropriate activation. Further rapid progress will be possible only if •ve 
achieve much closer cooperation and understanding of mutually important problem resolution amono basic 
scientists. clinicians, and bioenoineers. Open 'cross pollination of ideas" and their translation into clinically 
relevant projects resulting in improved well being of potential patients are the primarv coals of this meetin ,.. 
curd hopefully lvill be successfully achieved.

.\CENON\tLEDGMENTS

This work was supported in part bv the Pulmonarv Laser Foundation and the Betz Rese.uch Fund. The author 
wishes to thank K Treinor, Y Diehl and C Johnson for their technical assistance.

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