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

Photodynamic Therapy of Cancer: The Design and Characterization of Photosensitizing Agents. Angela Dann Monday, October 9, 2006. History Introduction Process of Photodynamic therapy (PDT) PDT to treat cancer Photosensitizing Agents Requirements Advancements

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

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

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

  3. History • 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 Nature2003, 3, 380.

  4. History Nature2003, 3, 380.

  5. History • Niels Finsen (late 19th 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) • Acridine in combination with certain wavelengths of light • Lethal to infusoria Nature2003, 3, 380.

  6. History • Herman Von Tappeiner, A. Jesionek • Defined photodynamic action • Topically applied eosin and white light • W. Hausmann • 1st studies with haematoporphyrin and light • Killed paramecium and red blood cells • Friedrich Meyer-Betz (1913) • 1st to treat humans with porphyrins • Haematoporphyrin applied to skin, causing swelling/pain with light exposure Nature2003, 3, 380.

  7. History • Samuel Schwartz (1960’s) • Developed haematoporphyrin derivative (HpD) • Haematoporphyrin treated with acetic and sulfuric acids, neutralized with sodium acetate • Lipson, E.J. Baldes • HpD localization in tumor cells, fluorescence • I. Diamond (1972) • Use PDT to treat cancer Nature2003, 3, 380.

  8. History • Thomas Dougherty (1975) • HpD and red light • Eradicated mammary tumor growth in mice • J.F. Kelly (1976) • 1st human trials using HpD • Bladder cancer • Canada (1999) • 1st PDT drug approved Nature2003, 3, 380.

  9. Introduction:Process of Photodynamic therapy • Two individually non-toxic components brought together to cause harmful effects on cells and tissues • Photosensitizing agent • Light of specific wavelength Nature2003, 3, 380.

  10. Introduction:Reaction Mechanisms • Type 1: • Direct reaction with substrate (cell membrane or molecule) • Transfer of H atom to form radicals • Radicals react with O2 to form oxygenated products • Type 2: • Transfer of energy to O2 to form 1O2 Nature2003, 3, 380.

  11. Introduction:Reaction Mechanisms • Ratio of Type 1/Type 2 depends on: • Photosensitizing agent, concentration of substrate and O2, binding affinity of photosensitizing agent to substrate • Reactive oxygenated species (ROS) • Free radicals or 1O2 • Half-life of 1O2 < 0.04 ms • Radius affected < 0.02 mm Nature2003, 3, 380.

  12. Introduction:Type 1 and 2 Reactions Nature2003, 3, 380.

  13. Introduction:Treatment of cancer • PDT best suited for: • Early stage tumors • Inoperable for various reasons • Limited success due to lack of specificity and potency of photosensitizing agents • Three mechanisms of tumor damage Nature2003, 3, 380.

  14. Introduction:Mechanism 1 • Direct Photodamage to Tumors by ROS • Problems: • Non-homogenous distribution of photosensitizing agent within tumor • Availability of O2 within tumor cells • Reduction of O2 presence during PDT • Overcoming O2 depletion: • Lower light fluence rate • Pulse light delivery – allow re-oxygenation Nature2003, 3, 380. J. of Nuclear Medicine2006, 47, 1119.

  15. Introduction:Mechanism 2 • Vascular Damage • Blood vessels supply nutrients to tumor cells • Effects: • Microvascular collapse • Tissue hypoxia and anoxia • Thrombus formation • Associated with halting tumor growth • Angiogenic factors upregulated Nature2003, 3, 380. J. of Nuclear Medicine2006, 47, 1119.

  16. Introduction:Mechanism 3 • 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-a • Neutrophil – slows tumor growth • Required to purge remaining cells Nature2003, 3, 380.

  17. Photosensitizing Agents:Requirements • Selectivity to tumor cells • Photostability • Biological stability • Photochemical efficiency • No cytotoxicity in absence of light • Strong absorption – 600-800 nm • Good tissue penetration • Long triplet excited state lifetime J. of Photochemistry and Photobiology A: Chemistry 2002, 153, 245. Photochemistry and Photobiology2001, 74, 656.

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

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

  20. Photosensitizing Agents:Photofrin • 1st clinical approval (1999) in Canada • Bladder cancer treatment • Most commonly used photosensitizer • Destroys mitochondria • Dihematoporphyrin ether (DHE) • bis-1-[3(1-hydroxy-ethyl)deuteroporphyrin-8-yl] ethyl ether • Active component of HpD Photochemistry and Photobiology2001, 74, 656.

  21. Photosensitizing Agents:Photofrin • 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 Photochemistry and Photobiology2001, 74, 656. Nature2003, 3, 380.

  22. Photosensitizing Agents:Photofrin • 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) Nature2003, 3, 380. J. of Photochemistry and Photobiology A: Chemistry2002, 153, 245.

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

  24. Photosensitizing Agents:Foscan • Chlorin photosensitizing agent • Approved for treatment of head and neck cancer • Low drug dose (0.1 mg/kg body weight) • Low light dose (10 J/cm2) • Complications due to potency Nature2003, 3, 380.

  25. Photosensitizing Agents:5-Aminolevulinic acid (5-ALA) • Hydrophilic zwitterion at physiological pH • Approved for treatment of actinic keratosis and BCC of skin • Topical application most frequently used • Endogenous photosensitizing agent • 5-ALA not directly photosensitizing • Creates porphyria-like syndrome • Precursor to protoporphyrin IX (PpIX) Nature2003, 3, 380. Photochemistry and Photobiology2001, 74, 656. Pharmaceutical Res.2000, 17, 1447.

  26. Photosensitizing Agents:Mono-L-aspartyl chlorin e6 (NPe6) • 2nd generation hydrophilic chlorin • Derived from chlorophyll a • Chemically pure • Absorption at 664 nm • Localizes in lysosomes (instead of mitochondria) • Reduced limitations compared to Photofrin • Decreased sensitivity to sunlight (1 week) • ½ life = 105.9 hr Photodermatol Photoimmunol Photomed2005, 21, 72.

  27. Photosensitizing Agents:Phthalocyanines • 2nd generation • Ring of 4 isoindole units linked by N-atoms • Stable chelates with metal cations • Sulfonate groups increase water solubility • Examples (AlPcS4, ZnPcS2) • Aluminum chlorophthalocyanine sulfonate • More prolonged photosensitization than HpD • Less skin sensitivity in sunlight Photochemistry and Photobiology2001, 74, 656. J. of Nuclear Medicine, 2006, 47, 1119.

  28. Photosensitizing Agents:Phthalocyanines • Tetrasulfonated AlPcS4 • Hydrophilic • Deposited in vascular stroma • Affects vascular system – indirect cell death • Disulfonated ZnPcS2 • Amphophilic • Transported by lipoproteins • Direct cell death Photochemistry and Photobiology2001, 74, 656. J. of Nuclear Medicine, 2006, 47, 1119.

  29. Photosensitizing Agents:Meta-tetra(hydroxyphenyl)porphyrins (mTHPP) • Commercially available as meta-tetra(hydroxyphenyl)chlorin – (mTHPC) • 2nd generation • Improved red light absorption • 25-30 times more potent than HpD • More selective toward tumor cells • Most active photosensitizer with low drug and light doses • Not granted approval Photochemistry and Photobiology2001, 74, 656. Int. J. Cancer2001, 93, 720.

  30. Photosensitizing Agents:Texaphyrins • Synthetic – porphycene • Water soluble • Related to porphyrins • Absorption between 720-760 nm (far red) • Sufficiently penetrates tissue Photochemistry and Photobiology2001, 74, 656.

  31. Photosensitizing Agents:Tin ethyl etiopurpurin • SnET2, Purlytin • Chlorin • Treatment of cutaneous metastatic malignancies • Results of phase III study (934 patients) not yet released Photochemistry and Photobiology2001, 74, 656.

  32. PDT Trials on Tumor Cells:Breast Cancer • Chest wall recurrences – problem with mastectomy treatment (5-19%) • Study: • 7 patients, 57.6 years old (12.6) • 89 metastatic nodes treated • 11 PDT sessions • Photosensitizing agent: (m-THPC) meta-tetra(hydroxyphenyl)chlorin • 2nd generation photosensitizing agent Int. J. Cancer2001, 93, 720.

  33. PDT Trials on Tumor Cells:Breast Cancer • Dosage: • Diode laser used to generate l = 652 nm • 3 patients • 0.10 mg/kg total body weight • 48 hr under 5 J/cm2 • 4 patients • 0.15 mg/kg total body weight • 96 hr under 10 J/cm2 Int. J. Cancer2001, 93, 720.

  34. PDT Trials on Tumor Cells:Breast Cancer • 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. Cancer2001, 93, 720.

  35. PDT Trials on Tumor Cells:Skin Cancer • Traditional Treatments: • Surgery, electrodesiccation, cryosurgery, topical application of podophyllin or 5-fluorouracil, radiation • Problems: • High cost, scarring, pigmentation changes, pain, inflammation, irritation Pharmaceutical Research2000, 17, 1447.

  36. PDT Trials on Tumor Cells:Skin Cancer • Most promising treatment using PDT • Skin highly accessible to light exposure • 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 Pharmaceutical Research2000, 17, 1447.

  37. PDT Trials on Tumor Cells:Skin Cancer • 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 Pharmaceutical Research2000, 17, 1447.

  38. PDT Trials on Tumor Cells:Skin Cancer • Mechanism (continued): • PpIX accumulates with minimized amount of ferrochelatase • Tissues with increased concentration of PpIX undergo phototoxic damage upon light exposure • 3PpIX is formed, energy transferred to create 1O2 • PpIX nearly completely cleared within 24 hr Pharmaceutical Research2000, 17, 1447.

  39. PDT Trials on Tumor Cells:Skin Cancer • 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 • Minimal side effects Pharmaceutical Research2000, 17, 1447.

  40. PDT Trials on Tumor Cells:Skin Cancer Pharmaceutical Research2000, 17, 1447.

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

  42. PDT Trials on Tumor Cells:Skin Cancer • 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/cm2 • Argon-pumped tunable dye laser set at 664 nm • Dose dependent on tumor size/shape Photodermatol Photoimmunol Photomed 2005, 21, 72.

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

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

  45. Conclusions • PDT of cancer regulated by: • Type of photosensitizing agent • Type of administration • Dose of photosensitizer • Light dose • Fluence rate • O2 availability • Time between administration of photosensitizer and light

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

  47. Conclusions:Clinical Approval of Photosensitizers Nature2003, 3, 380.

  48. Future Applications:Treatment of Other Diseases • Dermatology • Psoriasis, scleroderma, vitiligo • Rheumatology • Arthritis • Cardiovascular diseases • Artherosclerotic plaque resolution, post-stent implantation • Age-related eye diseases • Macular degeneration • Immunotherapy Nature2003, 3, 380. Photochemistry and Photobiology 2001, 74, 656.

  49. Future Applications:Tumor Detection Using Fluorescence • Mechanism by which HpD selectively accumulates in tumor cells – not well understood • High vascular permeability of 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 Nature2003, 3, 380.

  50. Future Applications:Tumor Detection Using Fluorescence • a: Green vascular endothelial cells of a tumor • b: Red photosensitizing agent localizes to vascular endothelial cells after intravenous injection Nature2003, 3, 380.

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