2. 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
• Herman Von Tappeiner,
– Defined photodynamic action
– Topically applied eosin and
white light
• Friedrich Meyer-Betz (1913)
– 1st
to treat humans with
porphyrins
– Haematoporphyrin applied to
skin, causing swelling/pain with
light exposure
3. History
• Samuel Schwartz (1960’s)
Developed haematoporphyrin
derivative (HpD)
Haematoporphyrin treated with
acetic and sulfuric acids,
neutralized with sodium acetate
• I. Diamond (1972) Use PDT to
treat cancer
• 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
4. Photodynamic therapy is based on the concept
(1) certain photosensitizers can be localized (somewhat preferentially) in
neoplastic tissue, and
(2) subsequently, these photosensitizers can be activated with the appropriate
wavelength (energy) of light to generate active molecular species, such as free
radicals and singlet oxygen (1O2) that are toxic to cells and tissues
5. • Two individually non-toxic components
brought together to cause harmful effects
on cells and tissues
– Photosensitizing
agent
– Light of specific
wavelength
Introduction:
Process of Photodynamic therapy
Nature 2003, 3, 380.
6. • 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 1
O2
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 1
O2
Half-life of 1
O2 < 0.04 µs
Radius affected < 0.02 µm
Introduction:
Reaction Mechanisms
7.
8. • 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
Photosensitizing Agents:
Requirements
J. of Photochemistry and Photobiology A: Chemistry 2002, 153, 245.
Photochemistry and Photobiology 2001, 74, 656.
9. MECHANISMS OF PDT
CYTOTOXICITY
• INDIRECT–
changes in tumor
microenvironment
- anti-vascular effects
- anti-tumor immune response
• DIRECT-
direct tumor cell killing due to
macromolecule damage
- apoptosis
- necrosis/ by-stander effect
10. INDIRECT CYTOTOXICITY
ANTI-VASCULAR
EFFECTS
- vessel leakage
- vasocontriction
- thrombosis
strongly dependent on—
photosensitizer used & time interval
between the administration of
photosensitizer & light
ANTI-TUMOR
IMMUNE RESPONSE
- release of pro-inflammatory
cytokines
- fixation of complement
- release of tumor associated
antigens
11. • The lifetime of singlet oxygen is 0.03 to 0.18 mcs, &
corresponds to a diffusion distance of less than 0.2
mcm, or about 1/50th of a cell diameter.
• Thus, the macromolecular damage inside the cell occurs very
close to the location of photosensitizer activation/singlet oxygen
production.
• Different photosensitizers are known to localize to - plasma
membrane, lysosome, mitochondria, Golgi apparatus,
endoplasmic reticulum, or nuclear membrane.
DIRECT CYTOTOXICITY
12. • Apoptotic cell death tends to predominate in the most PDT-sensitive
cell lines at lower light/photosensitizer doses
• necrotic/ nonapoptotic mechanisms tend to predominate at higher
light/photosensitizer doses.
The percentage apoptosis achieved, as well as the
mechanism of apoptosis (extrinsic vs. intrinsic) is
dependent upon-
1. Tumor cell line
2. Photosensitizer
DIRECT CYTOTOXICITY
15. • 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.
16. Photosensitizing Agents:
Foscan
•Chlorin photosensitizing agent
•Approved for treatment of head and
neck cancer
•Low drug dose (0.1 mg/kg body
weight)
5-Aminolevulinic acid (5-
ALA)
•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
Nature 2003, 3, 380.
17. Photosensitizing Agents:
Mono-L-aspartyl chlorin e6 (NPe6)
•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
Phthalocyanines
•Ring of 4 isoindole units linked by
N-atoms
•Stable chelates with metal cations
•Sulfonate groups increase water
solubility
•Examples (AlPcS4, ZnPcS2)
• More prolonged
photosensitization than
HpD
• Less skin sensitivity in
sunlight
18. Photochemistry and Photobiology 2001, 74, 656. Int. J. Cancer 2001, 93, 720.
• 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
Photosensitizing Agents:
Meta-tetra(hydroxyphenyl)porphyrins (mTHPP)
19. Photosensitizer
Excitation
Wavelength
Clinical Uses
Porfimer sodium
(Photofrin)
630 nm Barrett's esophagus+*
, endobroncheal cancer*+
,
esophageal+
, serosal cancers (pleural peritoneal), bladder
cancer, skin cancer Bowen's disease or AK), breast
cancer metastases, head and neck cancer, brain
ALA (Levulan),
mALA (Metvixv)
400-450 nm
635 nm
AK*+
, BCC+
, Bowen's disease, bladder cancer, vulvar
cancer
BPD (Visudyne) 690 nm Macular degeneration+*
, BCC
mTHCP (Foscan) 652 nm Head and neck+
, pancreatic cancer, cancer, pleural
cancers, brain
HPPH
(Photochlor)
665 nm BCC, pleural cancers
Silicon
pthalocyanine-4
(Pc-4)
672 nm Cutaneous and subcutaneous metastases malignancies
PHOTOSENSITIZERS
21. difficult to couple them to light delivery fibers
without reducing their optical power.
difficult to calculate the effective delivered light
dose
power output is limited to a maximum of 1 W.
Filters are also required to cut off UV radiation
and infrared emission
LIGHT APPLICATION
22. • LASERS -- emit light of precise wavelengths in
easily focused beams.
Early lasers were expensive, large, immobile
machines that required a level of technical
support.
LIGHT APPLICATION
23. • SEMICONDUCTOR DIODE TECHNOLOGY resulted in cheaper
systems, which are compact and portable while still retaining high power
output.
• However, diode lasers offer only a single output wavelength, limiting their
versatility.
LIGHT APPLICATION
24. • LIGHT EMITTING DIODES (LEDs) are less
expensive than otherlight sources, are small, and
can provide a power output up to 150 mW/cm2
at wavelengths in the rangeof 350–1,100 nm
LIGHT APPLICATION
25. • OPTICAL FIBER TECHNOLOGY
meet the demands of illuminationat
different localizations.
• For superficial illumination of, for example, oral
mucosa, optic fibers with a lens tip are used to
spread the light over the target area.
LIGHT APPLICATION
26. • OPTICAL FIBER TECHNOLOGY
In hollow organs ---- endobronchial, esophagus, and bladder,
illumination is often performed with cylindrical diffusers
combined withinflated balloons for uniform light distribution.
Black coating of one side of the balloon is sometimes used to
shield adjacentnormal tissue areas for protection.
LIGHT APPLICATION
27. OPTICAL FIBER TECHNOLOGY
In hollow organs ---- endobronchial, esophagus, and bladder, illumination is
often performed with cylindrical diffusers combined withinflated balloons for
uniform light distribution.
Black coatingof one side of the balloon is sometimes used to shield adjacent
normal tissue areas for protection.
LIGHT APPLICATION
28. • Experiments on oxic and hypoxic cells and
tissues show that pretreatment tumor hypoxia
significantly decreases the efficacy of
PDT.
• Limited studies of PDT and tumor hypoxia in
clinical samples confirm this relationship
between hypoxia and decreased PDT efficacy
OXYGEN EFFECTS
29. • ADVANTAGES OF PDT
single injection of drug followed after a certain time interval by single
illumination
local, rather than systemic, treatment
limited light penetration protects normal tissue from phototoxicity
functional recovery withoutscarring
can be repeated
CLINICAL APPLICATION
30. • 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
PDT Trials on Tumor Cells:
Skin Cancer
Pharmaceutical Research 2000, 17, 1447.
31. PDT Trials on Tumor Cells:PDT Trials on Tumor Cells:
Skin CancerSkin 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 Research 2000, 17, 1447.
32. PDT Trials on Tumor Cells:
Skin Cancer
Pharmaceutical Research 2000, 17, 1447.
34. • 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
PDT Trials on Tumor Cells:
Skin Cancer
Photodermatol Photoimmunol Photomed 2005, 21, 72.
35. PDT Trials on Tumor Cells:
Skin Cancer
Photodermatol Photoimmunol Photomed 2005, 21, 72.
36. • 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.
37. • EARLY STAGE, ENDOBRONCHIAL LUNG CANCER
In a phase II trial, porfimer sodium (2 mg/kg) was administered to 51 patients
with 61 total carcinoma lesions, and PDT was performed 48 hours later using
150 to 200 J/cm2
630 nm light.
complete response rate was 85% no grade 3 or 4 toxicities were reported.
PDT for Early Stage Cancers
38. • BARETT’S ESOPHAGUS
At 18 months of follow-up, 75% of patients treated with PDT-PPI showed
ablation of HGD versus 36% of patients treated with PPI alone (P <.0001).
BARETT’S ESOPHAGUS
52% of patients treated with PDT-PPI showed complete return to normal
squamous epithelium versus 7% of patients treated with PPI (P <.0001).
Finally, with an average follow-up of nearly a year, 13% of the patients in the
PDT-PPI arm showed progression to cancer versus 28% of patients on the
PPI arm (P <.006).
PDT for Early Stage Cancers
39. HEAD AND NECK CANCER patients used HpD or porfimer sodium but
nowadays mTHPC is more often used in combination with 10–20J/cm2
.
For early-stage primary tumors of the oral cavity or oropharynx, a CR rate of
85% at 1 year, decreasing to 77% at 2 years, is reported with an even higher
CR rate of96% for lip carcinoma
PDT for Early Stage Cancers
40. • Dosage:
– Diode laser used to generate λ = 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
PDT Trials on Tumor Cells:
Breast Cancer
Int. J. Cancer 2001, 93, 720.
41. • 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
PDT Trials on Tumor Cells:
Breast Cancer
Int. J. Cancer 2001, 93, 720.
42. • 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)
PDT Trials on Tumor Cells:
Breast Cancer
Int. J. Cancer 2001, 93, 720.
43. • INTRAPERITONEAL PHOTODYNAMIC THERAPY FOR
CARCINOMATOSIS OR SARCOMATOSIS
intraoperative PDT following maximal surgical debulking resulted in a 76%
complete cytologic response rate with tolerable toxicity
ADVANCED & PALLIATIVE
SETTINGS
44. • INTRAPERITONEAL PHOTODYNAMIC THERAPY FOR
CARCINOMATOSIS OR SARCOMATOSIS
associated with a postoperative capillary leak syndrome that necessitated
massive fluid resuscitation in the immediate postoperative period that was in
excess of the typical fluid needs of patients who receive surgery alone
ADVANCED & PALLIATIVE
SETTINGS
45. • Postoperative Photodynamic Therapy for Pleural-Based Spread of Non
Small-Cell Lung Cancer and Mesothelioma
• Palliation of Obstructing Lesions
• Prostate and Bladder Cancers
• Brain Tumors
ADVANCED & PALLIATIVE
SETTINGS
46. • 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
Conclusions
47. • 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
Conclusions
49. • 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
Future Applications:
Tumor Detection Using Fluorescence
Nature 2003, 3, 380.
50. • a: Green vascular endothelial cells of a tumor
• b: Red photosensitizing agent localizes to vascular
endothelial cells after intravenous injection
Future Applications:
Tumor Detection Using Fluorescence
Nature 2003, 3, 380.
51. • 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
Future Applications:
Photosensitizing Drugs
Nature 2003, 3, 380.
