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Photodynamic Therapy of Cancer: The Design and Characterization of Photosensitizing Agents Angela Dann Monday, October 9, 2006.

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Presentation on theme: "Photodynamic Therapy of Cancer: The Design and Characterization of Photosensitizing Agents Angela Dann Monday, October 9, 2006."— Presentation transcript:

1 Photodynamic Therapy of Cancer: The Design and Characterization of Photosensitizing Agents Angela Dann Monday, October 9, 2006

2 History History Introduction Introduction –Process of Photodynamic therapy (PDT) –PDT to treat cancer Photosensitizing Agents Photosensitizing Agents –Requirements –Advancements Trials using PDT on tumor cells Trials using PDT on tumor cells Conclusions Conclusions Future applications Future applications

3 History Light used as therapeutic agent for 3000+ years Light used as therapeutic agent for 3000+ years –Egyptian, Indian, and Chinese civilizations –Psoriasis, rickets, vitiligo, skin cancer Photodynamic Therapy (PDT) developed within the last century Photodynamic Therapy (PDT) developed within the last century Nature 2003, 3, 380.

4 History

5 Niels Finsen (late 19 th century) Niels Finsen (late 19 th century) –Red light to prevent formation and discharge of small pox postules –UV light from the sun to treat cutaneous tuberculosis –Nobel Prize 1903 Oscar Rabb (100+ years ago) Oscar Rabb (100+ years ago) –Acridine in combination with certain wavelengths of light –Lethal to infusoria History Nature 2003, 3, 380.

6 Herman Von Tappeiner, A. Jesionek Herman Von Tappeiner, A. Jesionek –Defined photodynamic action –Topically applied eosin and white light W. Hausmann W. Hausmann –1 st studies with haematoporphyrin and light –Killed paramecium and red blood cells Friedrich Meyer-Betz (1913) Friedrich Meyer-Betz (1913) –1 st to treat humans with porphyrins –Haematoporphyrin applied to skin, causing swelling/pain with light exposure Nature 2003, 3, 380. History

7 Samuel Schwartz (1960’s) Samuel Schwartz (1960’s) –Developed haematoporphyrin derivative (HpD)  Haematoporphyrin treated with acetic and sulfuric acids, neutralized with sodium acetate Lipson, E.J. Baldes Lipson, E.J. Baldes –HpD localization in tumor cells, fluorescence I. Diamond (1972) I. Diamond (1972) –Use PDT to treat cancer History Nature 2003, 3, 380.

8 Thomas Dougherty (1975) Thomas Dougherty (1975) –HpD and red light –Eradicated mammary tumor growth in mice J.F. Kelly (1976) J.F. Kelly (1976) –1 st human trials using HpD –Bladder cancer Canada (1999) Canada (1999) –1 st PDT drug approved Nature 2003, 3, 380. History

9 Two individually non-toxic components brought together to cause harmful effects on cells and tissues Two individually non-toxic components brought together to cause harmful effects on cells and tissues –Photosensitizing agent –Light of specific wavelength Nature 2003, 3, 380. Introduction: Process of Photodynamic therapy

10 Type 1: Type 1: –Direct reaction with substrate (cell membrane or molecule) –Transfer of H atom to form radicals –Radicals react with O 2 to form oxygenated products Type 2: Type 2: –Transfer of energy to O 2 to form 1 O 2 Introduction: Reaction Mechanisms Nature 2003, 3, 380.

11 Ratio of Type 1/Type 2 depends on: Ratio of Type 1/Type 2 depends on: –Photosensitizing agent, concentration of substrate and O 2, binding affinity of photosensitizing agent to substrate Reactive oxygenated species (ROS) Reactive oxygenated species (ROS) –Free radicals or 1 O 2 Half-life of 1 O 2 < 0.04  s Half-life of 1 O 2 < 0.04  s –Radius affected < 0.02  m Introduction: Reaction Mechanisms Nature 2003, 3, 380.

12 Introduction: Type 1 and 2 Reactions Nature 2003, 3, 380.

13 Introduction: Treatment of cancer PDT best suited for: PDT best suited for: –Early stage tumors –Inoperable for various reasons Limited success due to lack of specificity and potency of photosensitizing agents Limited success due to lack of specificity and potency of photosensitizing agents Three mechanisms of tumor damage Three mechanisms of tumor damage Nature 2003, 3, 380.

14 Direct Photodamage to Tumors by ROS Direct Photodamage to Tumors by ROS Problems: Problems: –Non-homogenous distribution of photosensitizing agent within tumor –Availability of O 2 within tumor cells  Reduction of O 2 presence during PDT Overcoming O 2 depletion: Overcoming O 2 depletion: –Lower light fluence rate –Pulse light delivery – allow re-oxygenation Introduction: Mechanism 1 Nature 2003, 3, 380. J. of Nuclear Medicine 2006, 47, 1119.

15 Vascular Damage Vascular Damage –Blood vessels supply nutrients to tumor cells Effects: Effects: –Microvascular collapse –Tissue hypoxia and anoxia –Thrombus formation  Associated with halting tumor growth Angiogenic factors upregulated Angiogenic factors upregulated Introduction: Mechanism 2 Nature 2003, 3, 380. J. of Nuclear Medicine 2006, 47, 1119.

16 Immune Response Immune Response –Movement of lymphocytes, leukocytes, macrophages into treated tissue –Difference in reactions toward normal and tumor tissues –Upregulation of interleukin, not tumor necrosis factor-  –Neutrophil – slows tumor growth Required to purge remaining cells Required to purge remaining cells Introduction: Mechanism 3 Nature 2003, 3, 380.

17 Selectivity to tumor cells Selectivity to tumor cells Photostability Photostability Biological stability Biological stability Photochemical efficiency Photochemical efficiency No cytotoxicity in absence of light No cytotoxicity in absence of light Strong absorption – 600-800 nm Strong absorption – 600-800 nm –Good tissue penetration Long triplet excited state lifetime Long triplet excited state lifetime Photosensitizing Agents: Requirements J. of Photochemistry and Photobiology A: Chemistry 2002, 153, 245. Photochemistry and Photobiology 2001, 74, 656.

18 Photosensitizing Agents: Classes Porphyrin derivatives Porphyrin derivatives –Most widely used Chlorins Chlorins –Reduced porphyrins –Derivatives from chlorophyll or porphyrins Phthalocyanines Phthalocyanines –2 nd generation –Contain diamagnetic metal ion Porphycenes Porphycenes –Synthetic porphyrins Pharmaceutical Research 2000, 17, 1447.

19 Photosensitizing Agents: Examples Photofrin Photofrin Foscan Foscan 5-Aminolevulinic acid (5-ALA) 5-Aminolevulinic acid (5-ALA) Mono-L-aspartyl chlorin e6 (NPe6) Mono-L-aspartyl chlorin e6 (NPe6) Phthalocyanines Phthalocyanines Meso-tetra(hydroxyphenyl)porphyrins (mTHPP) Meso-tetra(hydroxyphenyl)porphyrins (mTHPP) Texaphyrins Texaphyrins Tin ethyl etiopurpurin (SnET2, Purlytin) Tin ethyl etiopurpurin (SnET2, Purlytin)

20 1 st clinical approval (1999) in Canada 1 st clinical approval (1999) in Canada Bladder cancer treatment Bladder cancer treatment Most commonly used photosensitizer Most commonly used photosensitizer Destroys mitochondria Destroys mitochondria Dihematoporphyrin ether (DHE) Dihematoporphyrin ether (DHE) –bis-1-[3(1-hydroxy-ethyl)deuteroporphyrin-8- yl] ethyl ether –Active component of HpD Photosensitizing Agents: Photofrin Photochemistry and Photobiology 2001, 74, 656.

21 Partially purified haematoporphyrin derivative (HpD) Partially purified haematoporphyrin derivative (HpD) –Mixture of mono-, di-, and oligomers –Twice as phototoxic as crude haematoporphyrin (Hp) –Crude Hp consists of range of porphyrins –Convert to HpD by acetylation and reduction using acetic and sulfuric acids, filtering, and neutralizing with sodium acetate Photosensitizing Agents: Photofrin Photochemistry and Photobiology 2001, 74, 656. Nature 2003, 3, 380.

22 Limitations: Limitations: –Contains 60 compounds –Difficult to reproduce composition –At 630 nm, molar absorption coefficient is low (1,170 M -1 cm -1 ) –Main absorption at 400 nm –High concentrations of drug and light needed –Not very selective toward tumor cells –Absorption by skin cells causes long-lasting photosensitivity (½ life = 452 hr) Photosensitizing Agents: Photofrin Nature 2003, 3, 380. J. of Photochemistry and Photobiology A: Chemistry 2002, 153, 245.

23 Need to overcome limitations of Photofrin Need to overcome limitations of Photofrin New photosensitizers developed according to ideal situations New photosensitizers developed according to ideal situations –Increase specificity to tumor cells –Increase potency –Decrease time of sensitivity to sunlight after treatment Photosensitizing Agents: Advancements

24 Chlorin photosensitizing agent Chlorin photosensitizing agent Approved for treatment of head and neck cancer Approved for treatment of head and neck cancer Low drug dose (0.1 mg/kg body weight) Low drug dose (0.1 mg/kg body weight) Low light dose (10 J/cm 2 ) Low light dose (10 J/cm 2 ) Complications due to potency Complications due to potency Photosensitizing Agents: Foscan Nature 2003, 3, 380.

25 Hydrophilic zwitterion at physiological pH Hydrophilic zwitterion at physiological pH Approved for treatment of actinic keratosis and BCC of skin Approved for treatment of actinic keratosis and BCC of skin Topical application most frequently used Topical application most frequently used Endogenous photosensitizing agent Endogenous photosensitizing agent –5-ALA not directly photosensitizing –Creates porphyria-like syndrome –Precursor to protoporphyrin IX (PpIX) Nature 2003, 3, 380. Photochemistry and Photobiology 2001, 74, 656. Pharmaceutical Res. 2000, 17, 1447. Photosensitizing Agents: 5-Aminolevulinic acid (5-ALA)

26 2 nd generation hydrophilic chlorin 2 nd generation hydrophilic chlorin Derived from chlorophyll a Derived from chlorophyll a Chemically pure Chemically pure Absorption at 664 nm Absorption at 664 nm Localizes in lysosomes (instead of mitochondria) Localizes in lysosomes (instead of mitochondria) Reduced limitations compared to Photofrin Reduced limitations compared to Photofrin Decreased sensitivity to sunlight (1 week) Decreased sensitivity to sunlight (1 week) –½ life = 105.9 hr Photodermatol Photoimmunol Photomed 2005, 21, 72. Photosensitizing Agents: Mono-L-aspartyl chlorin e6 (NPe6)

27 2 nd generation 2 nd generation Ring of 4 isoindole units linked by N-atoms Ring of 4 isoindole units linked by N-atoms Stable chelates with metal cations Stable chelates with metal cations Sulfonate groups increase water solubility Sulfonate groups increase water solubility Examples (AlPcS 4, ZnPcS 2 ) Examples (AlPcS 4, ZnPcS 2 ) –Aluminum chlorophthalocyanine sulfonate  More prolonged photosensitization than HpD  Less skin sensitivity in sunlight Photochemistry and Photobiology 2001, 74, 656. J. of Nuclear Medicine, 2006, 47, 1119. Photosensitizing Agents: Phthalocyanines

28 Tetrasulfonated AlPcS 4 Tetrasulfonated AlPcS 4 –Hydrophilic –Deposited in vascular stroma –Affects vascular system – indirect cell death Disulfonated ZnPcS 2 Disulfonated ZnPcS 2 –Amphophilic –Transported by lipoproteins –Direct cell death Photochemistry and Photobiology 2001, 74, 656. J. of Nuclear Medicine, 2006, 47, 1119. Photosensitizing Agents: Phthalocyanines

29 Photochemistry and Photobiology 2001, 74, 656. Int. J. Cancer 2001, 93, 720. Photosensitizing Agents: Meta-tetra(hydroxyphenyl)porphyrins (mTHPP) Commercially available as meta- tetra(hydroxyphenyl)chlorin – (mTHPC) Commercially available as meta- tetra(hydroxyphenyl)chlorin – (mTHPC) 2 nd generation 2 nd generation Improved red light absorption Improved red light absorption 25-30 times more potent than HpD 25-30 times more potent than HpD More selective toward tumor cells More selective toward tumor cells Most active photosensitizer with low drug and light doses Most active photosensitizer with low drug and light doses Not granted approval Not granted approval

30 Synthetic – porphycene Synthetic – porphycene Water soluble Water soluble Related to porphyrins Related to porphyrins Absorption between 720-760 nm (far red) Absorption between 720-760 nm (far red) –Sufficiently penetrates tissue Photochemistry and Photobiology 2001, 74, 656. Photosensitizing Agents: Texaphyrins

31 SnET2, Purlytin SnET2, Purlytin Chlorin Chlorin Treatment of cutaneous metastatic malignancies Treatment of cutaneous metastatic malignancies Results of phase III study (934 patients) not yet released Results of phase III study (934 patients) not yet released Photosensitizing Agents: Tin ethyl etiopurpurin Photochemistry and Photobiology 2001, 74, 656.

32 Chest wall recurrences – problem with mastectomy treatment (5-19%) Chest wall recurrences – problem with mastectomy treatment (5-19%) Study: Study: –7 patients, 57.6 years old (12.6) –89 metastatic nodes treated –11 PDT sessions –Photosensitizing agent: (m-THPC) meta-tetra(hydroxyphenyl)chlorin  2 nd generation photosensitizing agent PDT Trials on Tumor Cells: Breast Cancer Int. J. Cancer 2001, 93, 720.

33 Dosage: Dosage: –Diode laser used to generate  = 652 nm 3 patients 3 patients –0.10 mg/kg total body weight –48 hr under 5 J/cm 2 4 patients 4 patients –0.15 mg/kg total body weight –96 hr under 10 J/cm 2 Int. J. Cancer 2001, 93, 720. PDT Trials on Tumor Cells: Breast Cancer

34 Results: Results: –Complete response in all 7 patients –Pain – 10 days, Healing – 8-10 weeks –Patients advised to use sun block or clothing to protect skin from light for 2 weeks  4 days after treatment – 1 patient with skin erythema and edema from reading light –6 of 7 patients given medication for pain  Mostly based on size, not lightdose –Recurrences in 2 patients (2 months) Int. J. Cancer 2001, 93, 720. PDT Trials on Tumor Cells: Breast Cancer

35 Traditional Treatments: Traditional Treatments: –Surgery, electrodesiccation, cryosurgery, topical application of podophyllin or 5- fluorouracil, radiation Problems: Problems: –High cost, scarring, pigmentation changes, pain, inflammation, irritation PDT Trials on Tumor Cells: Skin Cancer Pharmaceutical Research 2000, 17, 1447.

36 Most promising treatment using PDT Most promising treatment using PDT –Skin highly accessible to light exposure Most common method Most common method –Topical administration of 5-ALA –Non-invasive, short photosensitization period, treat multiple lesions, good cosmetic results, well accepted by patients, no side effects PDT Trials on Tumor Cells: Skin Cancer Pharmaceutical Research 2000, 17, 1447.

37 Mechanism of 5-ALA use: Mechanism of 5-ALA use: –5-ALA formed in vivo in mitochondria by condensation of glycine and succinyl CoA (catalyzed by ALA-syntase) –Subsequent reactions produce protoporphyrin IX (PpIX)  Converted to heme using ferrochelatase and Fe  Heme inhibits synthesis of 5-ALA –Excess administered 5-ALA passes through abnormal epidermis and converts to PpIX PDT Trials on Tumor Cells: Skin Cancer Pharmaceutical Research 2000, 17, 1447.

38 PDT Trials on Tumor Cells: Skin Cancer Mechanism (continued): Mechanism (continued): –PpIX accumulates with minimized amount of ferrochelatase –Tissues with increased concentration of PpIX undergo phototoxic damage upon light exposure  3 PpIX is formed, energy transferred to create 1 O 2 –PpIX nearly completely cleared within 24 hr Pharmaceutical Research 2000, 17, 1447.

39 PDT Trials on Tumor Cells: Skin Cancer Clinical Studies performed on superficial skin cancer types: Clinical Studies performed on superficial skin cancer types: –Actinic keratosis (AK) –Basal cell carcinoma (BCC) –Squamous cell carcinoma (SCC) –Bowen’s disease (BD) Complete response (CR) – no clinical or histopathologic signs after follow-up Complete response (CR) – no clinical or histopathologic signs after follow-up Minimal side effects Minimal side effects Pharmaceutical Research 2000, 17, 1447.

40 PDT Trials on Tumor Cells: Skin Cancer Pharmaceutical Research 2000, 17, 1447.

41 Clinical trials with mono-L-aspartyl chlorin e6 (NPe6) Clinical trials with mono-L-aspartyl chlorin e6 (NPe6) 14 patients – 9 male, 5 female 14 patients – 9 male, 5 female –46-82 years old (64 yrs average) –BCC – 22 lesions, SCC – 13 lesions, papillary carcinoma – 14 lesions PDT Trials on Tumor Cells: Skin Cancer Photodermatol Photoimmunol Photomed 2005, 21, 72.

42 Clinical trials (continued) Clinical trials (continued) –5 different intravenous doses of NPe6 over 30 minutes (0.5 mg/kg – 3.5 mg/kg)  4-8 hr prior to light administration (due to number of lesions) –Light dose – 25-200 J/cm 2  Argon-pumped tunable dye laser set at 664 nm  Dose dependent on tumor size/shape PDT Trials on Tumor Cells: Skin Cancer Photodermatol Photoimmunol Photomed 2005, 21, 72.

43 PDT Trials on Tumor Cells: Skin Cancer Photodermatol Photoimmunol Photomed 2005, 21, 72.

44 Results: Results: –4 weeks later: 20 of 22 BCC – CR, 18 of 27 other – CR  CR – no evidence of tumor in treatment field  PR – >50% reduction in tumor size –Photosensitivity gone within 1 week (12 of 14)  3 patients – mild to moderate pruritis, facial edema or blistering, erythema, tingling  1 patient – severe intermittent burning pain  1 patient – erythema, edema, moderate pain (gone within 2 weeks) PDT Trials on Tumor Cells: Skin Cancer Photodermatol Photoimmunol Photomed 2005, 21, 72.

45 Conclusions PDT of cancer regulated by: PDT of cancer regulated by: –Type of photosensitizing agent –Type of administration –Dose of photosensitizer –Light dose –Fluence rate –O 2 availability –Time between administration of photosensitizer and light

46 Conclusions Tumor cells show some selectivity for photosensitizing agent uptake Tumor cells show some selectivity for photosensitizing agent uptake Limited damage to surrounding tissues Limited damage to surrounding tissues Less invasive approach Less invasive approach Outpatient procedure Outpatient procedure Various application types Various application types Well accepted cosmetic results Well accepted cosmetic results

47 Conclusions: Clinical Approval of Photosensitizers Nature 2003, 3, 380.

48 Dermatology Dermatology –Psoriasis, scleroderma, vitiligo Rheumatology Rheumatology –Arthritis Cardiovascular diseases Cardiovascular diseases –Artherosclerotic plaque resolution, post-stent implantation Age-related eye diseases Age-related eye diseases –Macular degeneration Immunotherapy Immunotherapy Future Applications: Treatment of Other Diseases Nature 2003, 3, 380. Photochemistry and Photobiology 2001, 74, 656.

49 Mechanism by which HpD selectively accumulates in tumor cells – not well understood Mechanism by which HpD selectively accumulates in tumor cells – not well understood –High vascular permeability of agents? Testing photosensitizing agents: Testing photosensitizing agents: –Porphyrins, haematoporphyrins, HpD, ALA-D –Administer photosensitizer and monitor fluorescence with endoscope –SCC shows increased fluorescence –More invasive tumors show even greater fluorescence Future Applications: Tumor Detection Using Fluorescence Nature 2003, 3, 380.

50 Future Applications: Tumor Detection Using Fluorescence Nature 2003, 3, 380. a: Green vascular endothelial cells of a tumor a: Green vascular endothelial cells of a tumor b: Red photosensitizing agent localizes to vascular endothelial cells after intravenous injection b: Red photosensitizing agent localizes to vascular endothelial cells after intravenous injection

51 Improved Specificity and Potency Improved Specificity and Potency –Better photosensitizers developed and under investigation in clinical trials –Use of carriers – conjugated antibodies directed to tumor-associated antigens –New compounds that absorb light of longer wavelength – better tissue penetration –New compounds with less skin photosensitivity Improved Efficacy Improved Efficacy –Creating a preferred treatment of cancer Future Applications: Photosensitizing Drugs Nature 2003, 3, 380.

52 Thank you


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