Photodynamic Therapy of Cancer: The Design and Characterization of Photosensitizing Agents
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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
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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
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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.
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HistoryHistory
Nature 2003, 3, 380.
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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.
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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
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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.
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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
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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
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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.
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Introduction:Introduction:Type 1 and 2 ReactionsType 1 and 2 Reactions
Nature 2003, 3, 380.
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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.
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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.
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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
Introduction:Introduction:Mechanism 2Mechanism 2
Nature 2003, 3, 380. J. of Nuclear Medicine 2006, 47, 1119.
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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
Introduction:Introduction:Mechanism 3Mechanism 3
Nature 2003, 3, 380.
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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.
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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
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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)
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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.
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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
Photosensitizing Agents:Photosensitizing Agents:PhotofrinPhotofrin
Photochemistry and Photobiology 2001, 74, 656. Nature 2003, 3, 380.
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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)
Photosensitizing Agents:Photosensitizing Agents:PhotofrinPhotofrin
Nature 2003, 3, 380. J. of Photochemistry and Photobiology A: Chemistry 2002, 153, 245.
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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
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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.
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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)
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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)
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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
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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
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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
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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
Photochemistry and Photobiology 2001, 74, 656.
Photosensitizing Agents:Photosensitizing Agents:TexaphyrinsTexaphyrins
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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
Photochemistry and Photobiology 2001, 74, 656.
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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.
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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.
PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Breast CancerBreast Cancer
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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.
PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Breast CancerBreast Cancer
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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.
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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
PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
Pharmaceutical Research 2000, 17, 1447.
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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
PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
Pharmaceutical Research 2000, 17, 1447.
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PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
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
Pharmaceutical Research 2000, 17, 1447.
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PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
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
Pharmaceutical Research 2000, 17, 1447.
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PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
Pharmaceutical Research 2000, 17, 1447.
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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
PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
Photodermatol Photoimmunol Photomed 2005, 21, 72.
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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
PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
Photodermatol Photoimmunol Photomed 2005, 21, 72.
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PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
Photodermatol Photoimmunol Photomed 2005, 21, 72.
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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)
PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:Skin CancerSkin Cancer
Photodermatol Photoimmunol Photomed 2005, 21, 72.
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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
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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
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Conclusions:Conclusions:Clinical Approval of Clinical Approval of
PhotosensitizersPhotosensitizers
Nature 2003, 3, 380.
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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.
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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.
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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
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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.
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Thank youThank you