photodynamic therapy

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)

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

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

• 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.

• 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

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 µs

Radius affected < 0.02 µm

Introduction:Reaction Mechanisms

• 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.

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

INDIRECT CYTOTOXICITYANTI-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

• 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 upon-

1. Tumor cell l ine

2. Photosensit izer

DIRECT CYTOTOXICITY

• PHOTOSENSITIZERS• LIGHT• OXYGEN

COMPONENTS OF PDT

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 e6

(Npe6)

lutetium texaphyrin (Lu-Tex)

HPPH

Pthalocyanine-4

LS11

• 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.

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.

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

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)

Photosensit izer Excitat ion 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 nm635 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

• 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.

LIGHT APPLICATION

• Experiments on oxic and hypoxic cells and tissues show that pretreatment tumor hypoxia signif icantly decreases the eff icacy of PDT.

• Limited studies of PDT and tumor hypoxia in clinical samples confirm this relationship between hypoxia and decreased PDT efficacy

OXYGEN EFFECTS

• 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

CLINICAL APPLICATION

• 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.

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


• 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.

• 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



• 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)



• 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).


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


• 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.

• 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.

• 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.

• 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


• 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


• 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

Conclusions:Clinical Approval of Photosensitizers

Nature 2003, 3, 380.

• 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.

• 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.

• 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.

Thank you

photodynamic therapy

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