Download Photodynamic therapy is based on the concept

Photodynamic Therapy in Cancer:
DR SUHAS K R
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
History
• Samuel Schwartz (1960’s)
• Thomas Dougherty (1975)
Developed haematoporphyrin
– HpD and red light
derivative (HpD)
– Eradicated mammary tumor
Haematoporphyrin treated with
acetic and sulfuric acids,
neutralized with sodium acetate
growth in mice
• J.F. Kelly (1976)
– 1st human trials using HpD
• I. Diamond (1972) Use PDT to
treat cancer
– Bladder cancer
• Canada (1999)
– 1st PDT drug approved
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
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
Nature 2003, 3, 380.
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
and O2,
substrate
Ratio of Type 1/Type 2 depends on:
Photosensitizing agent, concentration of substrate
binding affinity of photosensitizing agent to
Reactive oxygenated species (ROS)
Free radicals or 1O2
Half-life of 1O2 < 0.04 ms
Radius affected < 0.02 mm
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 Photobiology 2001, 74, 656.
MECHANISMS OF PDT
CYTOTOXICITY
• INDIRECT–
• DIRECT-
changes in tumor
direct tumor cell killing due to
microenvironment
macromolecule damage
- anti-vascular effects
- apoptosis
- anti-tumor immune response
- necrosis/ by-stander effect
INDIRECT CYTOTOXICITY
ANTI-TUMOR IMMUNE
RESPONSE
- release of pro-inflammatory
cytokines
- fixation of complement
- release of tumor associated
antigens
ANTI-VASCULAR EFFECTS
- vessel leakage
- vasocontriction
- thrombosis
strongly dependent on—
photosensitizer used & time interval
between the administration of
photosensitizer & light
DIRECT CYTOTOXICITY
• 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
• 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 upon1. Tumor cell line
2. Photosensitizer
COMPONENTS OF PDT
• PHOTOSENSITIZERS
• LIGHT
• OXYGEN
PHOTOSENSITIZERS
 FIRST GENERATION
-Hematoporphyrin
-HPD
-Porfimer sodium (most widely
used)
 SECOND GENERATION
-ALA
-BPD
-mTHCP
• NEWER
PHOTOSENSITIZERS tin ethyl etiopurpurin (SnET2)
 mono-L-aspartyl
chlorin
(Npe6)
 lutetium texaphyrin (Lu-Tex)
 HPPH
 Pthalocyanine-4
 LS11
e6
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)
Nature 2003, 3, 380. J. of Photochemistry and Photobiology A: Chemistry 2002, 153,
245.
Photosensitizing Agents:
Foscan
5-Aminolevulinic acid (5-ALA)
• Chlorin photosensitizing agent
• Approved for treatment of head
and neck cancer
• Low drug dose (0.1 mg/kg body
weight)
• 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.
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
Photosensitizing Agents:
Meta-tetra(hydroxyphenyl)porphyrins (mTHPP)
• 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 Photobiology 2001, 74, 656. Int. J. Cancer 2001, 93, 720.
PHOTOSENSITIZERS
Photosensitizer
Porfimer sodium
(Photofrin)
Excitation
Wavelength
630 nm
Clinical Uses
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)
BPD (Visudyne)
400-450 nm
635 nm
690 nm
AK*+, BCC+, Bowen's disease, bladder cancer, vulvar
cancer
Macular degeneration+*, BCC
mTHCP (Foscan)
652 nm
HPPH
(Photochlor)
Silicon
pthalocyanine-4
(Pc-4)
665 nm
Head and neck+, pancreatic cancer, cancer, pleural
cancers, brain
BCC, pleural cancers
672 nm
Cutaneous and subcutaneous metastases malignancies
LIGHT APPLICATION
• Conventional, broad-spectrum light
sources, ARC LAMPS-
cheap and easy to use
LIGHT APPLICATION
 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
• 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
• 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
• LIGHT EMITTING DIODES (LEDs) are less
expensive than other light sources, are small, and
can provide a power output up to 150 mW/cm2
at wavelengths in the range of 350–1,100 nm
LIGHT APPLICATION
• OPTICAL FIBER TECHNOLOGY
meet the demands of illumination at
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
• OPTICAL FIBER TECHNOLOGY

In hollow organs ---- endobronchial, esophagus, and bladder,
illumination is often performed with cylindrical diffusers
combined with inflated balloons for uniform light distribution.

Black coating of one side of the balloon is sometimes used to
shield adjacent normal tissue areas for protection.
LIGHT APPLICATION
 OPTICAL FIBER TECHNOLOGY

In hollow organs ---- endobronchial, esophagus, and bladder, illumination is
often performed with cylindrical diffusers combined with inflated balloons for
uniform light distribution.
 Black coating of one side of the balloon is sometimes used to shield adjacent
normal tissue areas for protection.
OXYGEN EFFECTS
• 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
CLINICAL APPLICATION
• 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 without scarring
 can be repeated
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 Research 2000, 17, 1447.
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 followup
• Minimal side effects
Pharmaceutical Research 2000, 17, 1447.
PDT Trials on Tumor Cells:
Skin Cancer
Pharmaceutical Research 2000, 17, 1447.
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 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 Cancer
Photodermatol Photoimmunol Photomed 2005, 21, 72.
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.
PDT for Early Stage Cancers
• 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
• 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
 HEAD AND NECK CANCER patients used HpD or porfimer sodium but
nowadays mTHPC is more often used in combination with 10–20 J/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 of 96% for lip carcinoma
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. Cancer 2001, 93, 720.
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. Cancer 2001, 93, 720.
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. Cancer 2001, 93, 720.
ADVANCED & PALLIATIVE
SETTINGS
• 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
• 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
• 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
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
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
Conclusions:
Clinical Approval of Photosensitizers
Nature 2003, 3, 380.
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
Nature 2003, 3, 380.
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
Nature 2003, 3, 380.
Future Applications:
Photosensitizing Drugs
• Improved Specificity and Potency
– Better photosensitizers developed and under investigation in
clinical trials
– Use of carriers – conjugated antibodies directed to tumorassociated 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
Nature 2003, 3, 380.
Thank you