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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

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

Angela Dann

Monday, October 9, 2006

slide2
History
  • Introduction
    • Process of Photodynamic therapy (PDT)
    • PDT to treat cancer
  • Photosensitizing Agents
    • Requirements
    • Advancements
  • Trials using PDT on tumor cells
  • Conclusions
  • Future applications
history
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.

history4
History

Nature2003, 3, 380.

history5
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.

history6
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.

history7
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.

history8
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.

introduction process of photodynamic therapy
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.

introduction reaction mechanisms
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.

introduction reaction mechanisms11
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.

slide13

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.

slide14

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.

slide15

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.

slide16

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.

photosensitizing agents requirements
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.

photosensitizing agents classes
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.

photosensitizing agents examples
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)
photosensitizing agents photofrin
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.

photosensitizing agents photofrin21
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.

photosensitizing agents photofrin22
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.

photosensitizing agents advancements
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
photosensitizing agents foscan
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.

photosensitizing agents 5 aminolevulinic acid 5 ala
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.

photosensitizing agents mono l aspartyl chlorin e6 npe6
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.

photosensitizing agents phthalocyanines
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.

photosensitizing agents phthalocyanines28
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.

photosensitizing agents meta tetra hydroxyphenyl porphyrins mthpp
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.

photosensitizing agents texaphyrins
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.

photosensitizing agents tin ethyl etiopurpurin
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.

pdt trials on tumor cells breast cancer
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.

pdt trials on tumor cells breast cancer33
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.

pdt trials on tumor cells breast cancer34
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.

pdt trials on tumor cells skin cancer
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.

pdt trials on tumor cells skin cancer36
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.

pdt trials on tumor cells skin cancer37
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.

slide38

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.

slide39

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.

pdt trials on tumor cells skin cancer40
PDT Trials on Tumor Cells:Skin Cancer

Pharmaceutical Research2000, 17, 1447.

pdt trials on tumor cells skin cancer41
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.

pdt trials on tumor cells skin cancer42
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.

pdt trials on tumor cells skin cancer43
PDT Trials on Tumor Cells:Skin Cancer

Photodermatol Photoimmunol Photomed 2005, 21, 72.

pdt trials on tumor cells skin cancer44
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.

conclusions
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
conclusions46
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
future applications treatment of other diseases
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.

future applications tumor detection using fluorescence
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.

future applications tumor detection using fluorescence50
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.

future applications photosensitizing drugs
Future Applications:Photosensitizing Drugs
  • 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
    • Creating a preferred treatment of cancer

Nature2003, 3, 380.