photodynamic therapy of cancer: the design and characterization of photosensitizing agents

Photodynamic Therapy Photodynamic Therapy of Cancer: of Cancer: The Design The Design and Characterization of and Characterization of Photosensitizing AgentsPhotosensitizing Agents

Angela DannAngela Dann

Monday, October 9, 2006Monday, October 9, 2006

HistoryHistory IntroductionIntroduction

– Process of Photodynamic therapy Process of Photodynamic therapy (PDT)(PDT)

– PDT to treat cancerPDT to treat cancer Photosensitizing AgentsPhotosensitizing Agents

– RequirementsRequirements– AdvancementsAdvancements

Trials using PDT on tumor cellsTrials using PDT on tumor cells ConclusionsConclusions Future applicationsFuture applications

HistoryHistory

Light used as therapeutic agent for Light used as therapeutic agent for 3000+ years3000+ years– Egyptian, Indian, and Chinese Egyptian, Indian, and Chinese

civilizationscivilizations– Psoriasis, rickets, vitiligo, skin cancerPsoriasis, rickets, vitiligo, skin cancer

Photodynamic Therapy (PDT) Photodynamic Therapy (PDT) developed within the last centurydeveloped within the last century

Nature 2003, 3, 380.

HistoryHistory

Nature 2003, 3, 380.

Niels Finsen (late 19Niels Finsen (late 19thth century) century)– Red light to prevent formation and Red light to prevent formation and

discharge of small pox postulesdischarge of small pox postules– UV light from the sun to treat cutaneous UV light from the sun to treat cutaneous

tuberculosistuberculosis– Nobel Prize 1903Nobel Prize 1903

Oscar Rabb (100+ years ago)Oscar Rabb (100+ years ago)– Acridine in combination with certain Acridine in combination with certain

wavelengths of lightwavelengths of light– Lethal to infusoriaLethal to infusoria

HistoryHistory

Nature 2003, 3, 380.

Herman Von Tappeiner, A. JesionekHerman Von Tappeiner, A. Jesionek– Defined photodynamic actionDefined photodynamic action– Topically applied eosin and white lightTopically applied eosin and white light

W. HausmannW. Hausmann– 11stst studies with haematoporphyrin and studies with haematoporphyrin and

lightlight– Killed paramecium and red blood cellsKilled paramecium and red blood cells

Friedrich Meyer-Betz (1913)Friedrich Meyer-Betz (1913)– 11stst to treat humans with porphyrins to treat humans with porphyrins– Haematoporphyrin applied to skin, Haematoporphyrin applied to skin,

causing swelling/pain with light exposurecausing swelling/pain with light exposureNature 2003, 3, 380.

HistoryHistory

Samuel Schwartz (1960’s)Samuel Schwartz (1960’s)– Developed haematoporphyrin derivative Developed haematoporphyrin derivative

(HpD)(HpD) Haematoporphyrin treated with acetic and Haematoporphyrin treated with acetic and

sulfuric acids, neutralized with sodium acetatesulfuric acids, neutralized with sodium acetate

Lipson, E.J. BaldesLipson, E.J. Baldes– HpD localization in tumor cells, HpD localization in tumor cells,

fluorescencefluorescence I. Diamond (1972)I. Diamond (1972)

– Use PDT to treat cancerUse PDT to treat cancer

HistoryHistory

Nature 2003, 3, 380.

Thomas Dougherty (1975)Thomas Dougherty (1975)– HpD and red lightHpD and red light– Eradicated mammary tumor growth in Eradicated mammary tumor growth in

micemice J.F. Kelly (1976)J.F. Kelly (1976)

– 11stst human trials using HpD human trials using HpD– Bladder cancerBladder cancer

Canada (1999)Canada (1999)– 11stst PDT drug approved PDT drug approved

Nature 2003, 3, 380.

HistoryHistory

Two individually non-toxic Two individually non-toxic components brought together to components brought together to cause harmful effects on cells and cause harmful effects on cells and tissuestissues– Photosensitizing Photosensitizing

agentagent– Light of specific Light of specific

wavelengthwavelength

Nature 2003, 3, 380.

Introduction:Introduction:Process of Photodynamic therapyProcess of Photodynamic therapy

Type 1:Type 1:– Direct reaction with substrate (cell Direct reaction with substrate (cell

membrane or molecule)membrane or molecule)– Transfer of H atom to form radicalsTransfer of H atom to form radicals– Radicals react with ORadicals react with O22 to form to form

oxygenated productsoxygenated products Type 2:Type 2:

– Transfer of energy to OTransfer of energy to O22 to form to form 11OO22

Introduction:Introduction:Reaction MechanismsReaction Mechanisms

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Ratio of Type 1/Type 2 depends on:Ratio of Type 1/Type 2 depends on:– Photosensitizing agent, concentration Photosensitizing agent, concentration

of substrate and Oof substrate and O22, binding affinity of , binding affinity of photosensitizing agent to substratephotosensitizing agent to substrate

Reactive oxygenated species (ROS)Reactive oxygenated species (ROS)– Free radicals or Free radicals or 11OO22

Half-life of Half-life of 11OO22 < 0.04 < 0.04 ss– Radius affected < 0.02 Radius affected < 0.02 mm

Introduction:Introduction:Reaction MechanismsReaction Mechanisms

Nature 2003, 3, 380.

Introduction:Introduction:Type 1 and 2 ReactionsType 1 and 2 Reactions

Nature 2003, 3, 380.

Introduction:Introduction:Treatment of cancerTreatment of cancer

PDT best suited for:PDT best suited for:– Early stage tumorsEarly stage tumors– Inoperable for various reasonsInoperable for various reasons

Limited success due to lack of Limited success due to lack of specificity and potency of specificity and potency of photosensitizing agentsphotosensitizing agents

Three mechanisms of tumor damageThree mechanisms of tumor damageNature 2003, 3, 380.

Direct Photodamage to Tumors by Direct Photodamage to Tumors by ROSROS

Problems: Problems: – Non-homogenous distribution of Non-homogenous distribution of

photosensitizing agent within tumorphotosensitizing agent within tumor– Availability of OAvailability of O22 within tumor cells within tumor cells

Reduction of OReduction of O22 presence during PDT presence during PDT

Overcoming OOvercoming O22 depletion: depletion:– Lower light fluence rateLower light fluence rate– Pulse light delivery – allow re-oxygenationPulse light delivery – allow re-oxygenation

Introduction:Introduction:Mechanism 1Mechanism 1

Nature 2003, 3, 380. J. of Nuclear Medicine 2006, 47, 1119.

Vascular DamageVascular Damage– Blood vessels supply nutrients to tumor Blood vessels supply nutrients to tumor

cellscells Effects:Effects:

– Microvascular collapseMicrovascular collapse– Tissue hypoxia and anoxiaTissue hypoxia and anoxia– Thrombus formationThrombus formation

Associated with halting tumor growthAssociated with halting tumor growth

Angiogenic factors upregulatedAngiogenic factors upregulated


Nature 2003, 3, 380. J. of Nuclear Medicine 2006, 47, 1119.

Immune ResponseImmune Response– Movement of lymphocytes, leukocytes, Movement of lymphocytes, leukocytes,

macrophages into treated tissuemacrophages into treated tissue– Difference in reactions toward normal Difference in reactions toward normal

and tumor tissuesand tumor tissues– Upregulation of interleukin, not tumor Upregulation of interleukin, not tumor

necrosis factor-necrosis factor-– Neutrophil – slows tumor growthNeutrophil – slows tumor growth

Required to purge remaining cellsRequired to purge remaining cells


Nature 2003, 3, 380.

Selectivity to tumor cellsSelectivity to tumor cells PhotostabilityPhotostability Biological stabilityBiological stability Photochemical efficiencyPhotochemical efficiency No cytotoxicity in absence of lightNo cytotoxicity in absence of light Strong absorption – 600-800 nmStrong absorption – 600-800 nm

– Good tissue penetrationGood tissue penetration Long triplet excited state lifetimeLong triplet excited state lifetime

Photosensitizing Agents:Photosensitizing Agents:RequirementsRequirements

J. of Photochemistry and Photobiology A: Chemistry 2002, 153, 245. Photochemistry and Photobiology 2001, 74, 656.

Photosensitizing Agents:Photosensitizing Agents:ClassesClasses

Porphyrin derivativesPorphyrin derivatives– Most widely usedMost widely used

ChlorinsChlorins– Reduced porphyrinsReduced porphyrins– Derivatives from chlorophyll or Derivatives from chlorophyll or

porphyrinsporphyrins PhthalocyaninesPhthalocyanines

– 22ndnd generation generation– Contain diamagnetic metal ionContain diamagnetic metal ion

PorphycenesPorphycenes– Synthetic porphyrinsSynthetic porphyrinsPharmaceutical Research 2000, 17, 1447.

N

NH N

HN

Photosensitizing Agents:Photosensitizing Agents:ExamplesExamples

PhotofrinPhotofrin FoscanFoscan 5-Aminolevulinic acid (5-ALA)5-Aminolevulinic acid (5-ALA) Mono-L-aspartyl chlorin e6 (NPe6)Mono-L-aspartyl chlorin e6 (NPe6) PhthalocyaninesPhthalocyanines Meso-tetra(hydroxyphenyl)porphyrins Meso-tetra(hydroxyphenyl)porphyrins

(mTHPP)(mTHPP) TexaphyrinsTexaphyrins Tin ethyl etiopurpurin (SnET2, Purlytin)Tin ethyl etiopurpurin (SnET2, Purlytin)

11stst clinical approval (1999) in Canada clinical approval (1999) in Canada Bladder cancer treatmentBladder cancer treatment Most commonly used photosensitizerMost commonly used photosensitizer Destroys mitochondriaDestroys mitochondria Dihematoporphyrin ether (DHE) Dihematoporphyrin ether (DHE)

– bis-1-[3(1-hydroxy-bis-1-[3(1-hydroxy-ethyl)deuteroporphyrin-8-yl] ethyl etherethyl)deuteroporphyrin-8-yl] ethyl ether

– Active component of HpDActive component of HpD

Photosensitizing Agents:Photosensitizing Agents:PhotofrinPhotofrin

Photochemistry and Photobiology 2001, 74, 656.

Partially purified haematoporphyrin Partially purified haematoporphyrin derivative (HpD)derivative (HpD)– Mixture of mono-, di-, and oligomersMixture of mono-, di-, and oligomers– Twice as phototoxic as crude Twice as phototoxic as crude

haematoporphyrin (Hp)haematoporphyrin (Hp)– Crude Hp consists of range of porphyrinsCrude Hp consists of range of porphyrins– Convert to HpD by acetylation and Convert to HpD by acetylation and

reduction using acetic and sulfuric acids, reduction using acetic and sulfuric acids, filtering, and neutralizing with sodium filtering, and neutralizing with sodium acetateacetate


Photochemistry and Photobiology 2001, 74, 656. Nature 2003, 3, 380.

Limitations:Limitations:– Contains 60 compoundsContains 60 compounds– Difficult to reproduce compositionDifficult to reproduce composition– At 630 nm, molar absorption coefficient is At 630 nm, molar absorption coefficient is

low (1,170 Mlow (1,170 M-1-1 cm cm-1-1))– Main absorption at 400 nmMain absorption at 400 nm– High concentrations of drug and light High concentrations of drug and light

neededneeded– Not very selective toward tumor cellsNot very selective toward tumor cells– Absorption by skin cells causes long-Absorption by skin cells causes long-

lasting photosensitivity (½ life = 452 hr)lasting photosensitivity (½ life = 452 hr)


Nature 2003, 3, 380. J. of Photochemistry and Photobiology A: Chemistry 2002, 153, 245.

Need to overcome limitations of Need to overcome limitations of PhotofrinPhotofrin

New photosensitizers developed New photosensitizers developed according to ideal situationsaccording to ideal situations– Increase specificity to tumor cellsIncrease specificity to tumor cells– Increase potencyIncrease potency– Decrease time of sensitivity to sunlight Decrease time of sensitivity to sunlight

after treatmentafter treatment

Photosensitizing Agents:Photosensitizing Agents:AdvancementsAdvancements

Chlorin photosensitizing agentChlorin photosensitizing agent Approved for treatment of head and Approved for treatment of head and

neck cancerneck cancer Low drug dose (0.1 mg/kg body Low drug dose (0.1 mg/kg body

weight)weight) Low light dose (10 J/cmLow light dose (10 J/cm22)) Complications due to potencyComplications due to potency

Photosensitizing Agents:Photosensitizing Agents:FoscanFoscan

Nature 2003, 3, 380.

Hydrophilic zwitterion at physiological pHHydrophilic zwitterion at physiological pH Approved for treatment of actinic Approved for treatment of actinic

keratosis and BCC of skinkeratosis and BCC of skin Topical application most frequently usedTopical application most frequently used Endogenous photosensitizing agentEndogenous photosensitizing agent

– 5-ALA not directly photosensitizing5-ALA not directly photosensitizing– Creates porphyria-like syndromeCreates porphyria-like syndrome– Precursor to protoporphyrin IX (PpIX)Precursor to protoporphyrin IX (PpIX)

Nature 2003, 3, 380. Photochemistry and Photobiology 2001, 74, 656. Pharmaceutical Res. 2000, 17, 1447.

Photosensitizing Agents:Photosensitizing Agents:5-Aminolevulinic acid (5-ALA)5-Aminolevulinic acid (5-ALA)

22ndnd generation hydrophilic chlorin generation hydrophilic chlorin Derived from chlorophyll aDerived from chlorophyll a Chemically pureChemically pure Absorption at 664 nmAbsorption at 664 nm Localizes in lysosomes (instead of Localizes in lysosomes (instead of

mitochondria)mitochondria) Reduced limitations compared to PhotofrinReduced limitations compared to Photofrin Decreased sensitivity to sunlight (1 week)Decreased sensitivity to sunlight (1 week)

– ½ life = 105.9 hr½ life = 105.9 hr

Photodermatol Photoimmunol Photomed 2005, 21, 72.

Photosensitizing Agents:Photosensitizing Agents:Mono-L-aspartyl chlorin e6 (NPe6)Mono-L-aspartyl chlorin e6 (NPe6)

22ndnd generation generation Ring of 4 isoindole units linked by N-Ring of 4 isoindole units linked by N-

atomsatoms Stable chelates with metal cations Stable chelates with metal cations Sulfonate groups increase water solubilitySulfonate groups increase water solubility Examples (AlPcSExamples (AlPcS44, ZnPcS, ZnPcS22))

– Aluminum chlorophthalocyanine sulfonateAluminum chlorophthalocyanine sulfonate More prolonged photosensitization than HpDMore prolonged photosensitization than HpD Less skin sensitivity in sunlightLess skin sensitivity in sunlight

Photochemistry and Photobiology 2001, 74, 656. J. of Nuclear Medicine, 2006, 47, 1119.

Photosensitizing Agents:Photosensitizing Agents:PhthalocyaninesPhthalocyanines

Tetrasulfonated AlPcSTetrasulfonated AlPcS44

– HydrophilicHydrophilic– Deposited in vascular stromaDeposited in vascular stroma– Affects vascular system – indirect cell Affects vascular system – indirect cell

deathdeath Disulfonated ZnPcSDisulfonated ZnPcS22

– AmphophilicAmphophilic– Transported by lipoproteins Transported by lipoproteins – Direct cell deathDirect cell death

Photochemistry and Photobiology 2001, 74, 656. J. of Nuclear Medicine, 2006, 47, 1119.

Photosensitizing Agents:Photosensitizing Agents:PhthalocyaninesPhthalocyanines

Photochemistry and Photobiology 2001, 74, 656. Int. J. Cancer 2001, 93, 720.

Photosensitizing Agents:Photosensitizing Agents:Meta-tetra(hydroxyphenyl)porphyrins Meta-tetra(hydroxyphenyl)porphyrins

(mTHPP)(mTHPP) Commercially available as meta-Commercially available as meta-

tetra(hydroxyphenyl)chlorin – (mTHPC)tetra(hydroxyphenyl)chlorin – (mTHPC) 22ndnd generation generation Improved red light absorptionImproved red light absorption 25-30 times more potent than HpD25-30 times more potent than HpD More selective toward tumor cellsMore selective toward tumor cells Most active photosensitizer with low drug Most active photosensitizer with low drug

and light dosesand light doses Not granted approvalNot granted approval

Synthetic – porphyceneSynthetic – porphycene Water solubleWater soluble Related to porphyrinsRelated to porphyrins Absorption between 720-760 nm (far Absorption between 720-760 nm (far

red)red)– Sufficiently penetrates tissueSufficiently penetrates tissue


Photosensitizing Agents:Photosensitizing Agents:TexaphyrinsTexaphyrins

SnET2, PurlytinSnET2, Purlytin ChlorinChlorin Treatment of cutaneous metastatic Treatment of cutaneous metastatic

malignanciesmalignancies Results of phase III study (934 Results of phase III study (934

patients) not yet releasedpatients) not yet released

Photosensitizing Agents:Photosensitizing Agents:Tin ethyl etiopurpurinTin ethyl etiopurpurin


Chest wall recurrences – problem Chest wall recurrences – problem with mastectomy treatment (5-19%)with mastectomy treatment (5-19%)

Study:Study:– 7 patients, 57.6 years old (12.6)7 patients, 57.6 years old (12.6)– 89 metastatic nodes treated89 metastatic nodes treated– 11 PDT sessions11 PDT sessions– Photosensitizing agent: (m-THPC)Photosensitizing agent: (m-THPC)

meta-tetra(hydroxyphenyl)chlorinmeta-tetra(hydroxyphenyl)chlorin 22ndnd generation photosensitizing agent generation photosensitizing agent

PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Breast CancerBreast Cancer

Int. J. Cancer 2001, 93, 720.

Dosage:Dosage:– Diode laser used to generate Diode laser used to generate = 652 = 652

nmnm 3 patients3 patients

– 0.10 mg/kg total body weight0.10 mg/kg total body weight– 48 hr under 5 J/cm48 hr under 5 J/cm22

4 patients4 patients– 0.15 mg/kg total body weight0.15 mg/kg total body weight– 96 hr under 10 J/cm96 hr under 10 J/cm22

Int. J. Cancer 2001, 93, 720.


Results:Results:– Complete response in all 7 patientsComplete response in all 7 patients– Pain – 10 days, Healing – 8-10 weeksPain – 10 days, Healing – 8-10 weeks– Patients advised to use sun block or Patients advised to use sun block or

clothing to protect skin from light for 2 clothing to protect skin from light for 2 weeksweeks 4 days after treatment – 1 patient with skin 4 days after treatment – 1 patient with skin

erythema and edema from reading lighterythema and edema from reading light

– 6 of 7 patients given medication for pain6 of 7 patients given medication for pain Mostly based on size, not lightdoseMostly based on size, not lightdose

– Recurrences in 2 patients (2 months)Recurrences in 2 patients (2 months)Int. J. Cancer 2001, 93, 720.


Traditional Treatments:Traditional Treatments:– Surgery, electrodesiccation, Surgery, electrodesiccation,

cryosurgery, topical application of cryosurgery, topical application of podophyllin or 5-fluorouracil, radiationpodophyllin or 5-fluorouracil, radiation

Problems:Problems:– High cost, scarring, pigmentation High cost, scarring, pigmentation

changes, pain, inflammation, irritationchanges, pain, inflammation, irritation

PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer

Pharmaceutical Research 2000, 17, 1447.

Most promising treatment using PDTMost promising treatment using PDT– Skin highly accessible to light exposureSkin highly accessible to light exposure

Most common methodMost common method– Topical administration of 5-ALA Topical administration of 5-ALA – Non-invasive, short photosensitization Non-invasive, short photosensitization

period, treat multiple lesions, good period, treat multiple lesions, good cosmetic results, well accepted by cosmetic results, well accepted by patients, no side effectspatients, no side effects



Mechanism of 5-ALA use:Mechanism of 5-ALA use:– 5-ALA formed 5-ALA formed in vivoin vivo in mitochondria by in mitochondria by

condensation of glycine and succinyl CoA condensation of glycine and succinyl CoA (catalyzed by ALA-syntase)(catalyzed by ALA-syntase)

– Subsequent reactions produce Subsequent reactions produce protoporphyrin IX (PpIX)protoporphyrin IX (PpIX) Converted to heme using ferrochelatase and FeConverted to heme using ferrochelatase and Fe Heme inhibits synthesis of 5-ALAHeme inhibits synthesis of 5-ALA

– Excess administered 5-ALA passes through Excess administered 5-ALA passes through abnormal epidermis and converts to PpIXabnormal epidermis and converts to PpIX




Mechanism (continued):Mechanism (continued):– PpIX accumulates with minimized amount of PpIX accumulates with minimized amount of

ferrochelataseferrochelatase– Tissues with increased concentration of Tissues with increased concentration of

PpIX undergo phototoxic damage upon light PpIX undergo phototoxic damage upon light exposureexposure 33PpIX is formed, energy transferred to create PpIX is formed, energy transferred to create 11OO22

– PpIX nearly completely cleared within 24 hrPpIX nearly completely cleared within 24 hr



Clinical Studies performed on Clinical Studies performed on superficial skin cancer types:superficial skin cancer types:– Actinic keratosis (AK)Actinic keratosis (AK)– Basal cell carcinoma (BCC)Basal cell carcinoma (BCC)– Squamous cell carcinoma (SCC)Squamous cell carcinoma (SCC)– Bowen’s disease (BD)Bowen’s disease (BD)

Complete response (CR) – no clinical Complete response (CR) – no clinical or histopathologic signs after follow-upor histopathologic signs after follow-up

Minimal side effectsMinimal side effects


Clinical trials with mono-L-aspartyl Clinical trials with mono-L-aspartyl chlorin e6 (NPe6)chlorin e6 (NPe6)

14 patients – 9 male, 5 female14 patients – 9 male, 5 female– 46-82 years old (64 yrs average)46-82 years old (64 yrs average)– BCC – 22 lesions, SCC – 13 lesions, BCC – 22 lesions, SCC – 13 lesions,

papillary carcinoma – 14 lesionspapillary carcinoma – 14 lesions



Clinical trials (continued)Clinical trials (continued)– 5 different intravenous doses of NPe6 5 different intravenous doses of NPe6

over 30 minutes (0.5 mg/kg – 3.5 mg/kg)over 30 minutes (0.5 mg/kg – 3.5 mg/kg) 4-8 hr prior to light administration (due to 4-8 hr prior to light administration (due to

number of lesions)number of lesions)

– Light dose – 25-200 J/cmLight dose – 25-200 J/cm22

Argon-pumped tunable dye laser set at 664 Argon-pumped tunable dye laser set at 664 nmnm

Dose dependent on tumor size/shapeDose dependent on tumor size/shape



Results:Results:– 4 weeks later: 20 of 22 BCC – CR, 18 of 27 4 weeks later: 20 of 22 BCC – CR, 18 of 27

other – CRother – CR CR – no evidence of tumor in treatment fieldCR – no evidence of tumor in treatment field PR – >50% reduction in tumor sizePR – >50% reduction in tumor size

– Photosensitivity gone within 1 week (12 of Photosensitivity gone within 1 week (12 of 14)14) 3 patients – mild to moderate pruritis, facial 3 patients – mild to moderate pruritis, facial

edema or blistering, erythema, tinglingedema or blistering, erythema, tingling 1 patient – severe intermittent burning pain1 patient – severe intermittent burning pain 1 patient – erythema, edema, moderate pain 1 patient – erythema, edema, moderate pain

(gone within 2 weeks)(gone within 2 weeks)



ConclusionsConclusions PDT of cancer regulated by:PDT of cancer regulated by:

– Type of photosensitizing Type of photosensitizing agentagent

– Type of administrationType of administration– Dose of photosensitizerDose of photosensitizer– Light doseLight dose– Fluence rateFluence rate– OO22 availability availability

– Time between administration Time between administration of photosensitizer and lightof photosensitizer and light

ConclusionsConclusions

Tumor cells show some selectivity for Tumor cells show some selectivity for photosensitizing agent uptakephotosensitizing agent uptake

Limited damage to surrounding Limited damage to surrounding tissuestissues

Less invasive approach Less invasive approach Outpatient procedureOutpatient procedure Various application typesVarious application types Well accepted cosmetic resultsWell accepted cosmetic results

Conclusions:Conclusions:Clinical Approval of Clinical Approval of

PhotosensitizersPhotosensitizers

Nature 2003, 3, 380.

DermatologyDermatology– Psoriasis, scleroderma, vitiligoPsoriasis, scleroderma, vitiligo

RheumatologyRheumatology– ArthritisArthritis

Cardiovascular diseasesCardiovascular diseases– Artherosclerotic plaque resolution, post-Artherosclerotic plaque resolution, post-

stent implantationstent implantation Age-related eye diseasesAge-related eye diseases

– Macular degenerationMacular degeneration ImmunotherapyImmunotherapy

Future Applications:Future Applications:Treatment of Other DiseasesTreatment of Other Diseases

Nature 2003, 3, 380. Photochemistry and Photobiology 2001, 74, 656.

Mechanism by which HpD selectively Mechanism by which HpD selectively accumulates in tumor cells – not well accumulates in tumor cells – not well understoodunderstood– High vascular permeability of agents?High vascular permeability of agents?

Testing photosensitizing agents:Testing photosensitizing agents:– Porphyrins, haematoporphyrins, HpD, ALA-DPorphyrins, haematoporphyrins, HpD, ALA-D– Administer photosensitizer and monitor fluorescence Administer photosensitizer and monitor fluorescence

with endoscopewith endoscope– SCC shows increased fluorescenceSCC shows increased fluorescence– More invasive tumors show even greater More invasive tumors show even greater

fluorescencefluorescence

Future Applications:Future Applications:Tumor Detection Using Tumor Detection Using

FluorescenceFluorescence

Nature 2003, 3, 380.

Future Applications:Future Applications:Tumor Detection Using Tumor Detection Using

FluorescenceFluorescence

Nature 2003, 3, 380.

a: Green vascular endothelial cells of a a: Green vascular endothelial cells of a tumortumor

b: Red photosensitizing agent localizes to b: Red photosensitizing agent localizes to vascular endothelial cells after intravenous vascular endothelial cells after intravenous injectioninjection

Improved Specificity and PotencyImproved Specificity and Potency– Better photosensitizers developed and Better photosensitizers developed and

under investigation in clinical trialsunder investigation in clinical trials– Use of carriers – conjugated antibodies Use of carriers – conjugated antibodies

directed to tumor-associated antigensdirected to tumor-associated antigens– New compounds that absorb light of longer New compounds that absorb light of longer

wavelength – better tissue penetrationwavelength – better tissue penetration– New compounds with less skin New compounds with less skin

photosensitivityphotosensitivity Improved EfficacyImproved Efficacy

– Creating a preferred treatment of cancerCreating a preferred treatment of cancer

Future Applications:Future Applications:Photosensitizing DrugsPhotosensitizing Drugs

Nature 2003, 3, 380.

Thank youThank you

photodynamic therapy of cancer: the design and characterization of photosensitizing agents

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