This document discusses photodynamic therapy (PDT) as an effective and promising method for cancer treatment. PDT involves using photosensitizing drugs along with light to kill cancer cells. It has several advantages over other cancer therapies, including fewer side effects, the ability to precisely target tumors, and the potential for repeated treatments. The document outlines the key components and mechanisms of PDT, including photosensitizers, light sources, oxygen, and the cell death pathways involved. It also reviews the history and clinical applications of PDT and discusses ongoing research to improve its effectiveness, such as through the use of oxygen-generating nanoparticles.

1. PHOTODYNAMIC THERAPY IS EFFECTIVE &
PROMISSING METHOD FOR CANCER TREATMENT
PREPARED BY:
SHAHID ANSARI
ROLL NO :2 UNDER THE GUIDENCE OF:
M.Pharm (1st Year) Dr. G.J.KHAN
(M.Pharm, Ph.D)
Principal
ALI - ALLANA COLLEGE OF PHARMACY
AKKALKUWA DIST: NANDURBAR, M.H.(425415)

2. Contents
• Introduction
– History
– Recent Update
•Method (How PDT is used to treat cancer)
• Advantages
•PDT over other oncotherapies
•Limitation
•Basic Components
•Cell Death Pathway
•Improvement
•Clinical PDT
•Conclusion
•Bibliography

3. SYNONYMS:
Photoradiation therapy.
Phototherapy.
Photochemotherapy.
DEFINATION: PDT is the treatment that uses special drugs called photosensitizer or
photosensitizing agents along with light to kill cancer cells the drugs only work after they have
been activated or turned on by certain kind of light.
• PDT is considered to be one of the most effective methods for treatment of early cancer &
palliation of advanced cancer.
• PDT has the potential to meet many currently unmet medical needs. Although still emerging
it is already a successful & clinically approved therapeutic modality used for the
management of neoplastic & non-malignant diseases.
• PDT was the first drug device combination approved by the USFDA almost 2 decades ago.

4. PDT consist of 3 essential components :
• Photosensitizer
• Light
• Oxygen
-None of these is individually toxic, but together they initiate a photochemical reaction that
culminates in the generation of highly reactive product termed singlet oxygen. The latter can
rapidly cause significant toxicity leading to cell death via apoptosis or necrosis.
Antitumor effect of PDT derive from 3 inter-related mechanism:
-Direct cytotoxic effect on cell
-Damage to tumor vasculature
-Induction of a robust inflammatory reaction
The relative contribution of these mechanism depends to a large extent on:
• The type & dose of PS used.
• Time gap between PS administration & light exposure.
• Total light dose ,oxygen concentration.

5. • PDT is the 2 stage procedure when the photosensitizers are exposed to a specific
wavelength of light, photoactivation causes the formation of singlet oxygen, which
produces peroxidative reaction that causes the cell damage and death.
• Each photosensitizer is activated by light of a specific wavelength, this wavelength
determines how far light can travel into the body.

6. • The history of photodynamic therapy (PDT) in medicine can be traced to the beginning
of the twentieth century. The first attempts to use photosensitizing drugs dates back to
ancient Egypt, India, and Greece, where Psoralen-containing plant extracts and light
were applied to treat psoriasis and vitiligo (Daniell and Hill, 1991).
• Raab first reported, in 1900, that paramecia cells (Paramecium caudatum) were not
affected when exposed to either acridine orange or a light source, but that they died
within 2 h if exposed to both acridine orange and the light at the same time.
• The German physician Friedrich Meyer-Betz performed the first study with what was
first called Photoradiation therapy(PTR) with porphyrins in humans in 1913.
Hematoporphyrin applied to skin, causing swelling, pain with light exposure.

7. • In 1924 Policard revealed the diagnostic capabilities of hematoporphyrin fluorescence
when he observed that ultraviolet radiation excited red fluorescence in the sarcomas of
laboratory rats. Policard hypothesized that the fluorescence was associated with
endogenous hematoporphyrin accumulation.
• PDT received even greater interest as result of Thomas Dougherty helping expand clinical
trials and forming the international Photodynamic Association, in 1986. By Eradicating
mammary tumor growth in mice.
• Herman Von Tappeiner defined photodynamic action and topically applied eosin and
white light.

8. • Photoimmunotherapy is an oncological treatment for various cancers that combines
photodynamic therapy of tumor with immunotherapy treatment. Combining
photodynamic therapy with immunotherapy enhances the immunostimulating response
and has synergistic effects for metastatic cancer treatment.
• Combinations of PDT and Various Therapeutic Modalities in Cancer Treatment:
DRUG OR TREATMENT MODALITY OUTCOME/RESULTS
Anthracyclines
Doxorubicin improves PDT-mediated tumor growth
control
Microtubule inhibitors
Vincristine administered prior to or immediately after
PDT improves its antitumor
COX-2 inhibitors
Potentiate antitumor effects of PDT, possibly through
indirect antiangiogenic effects
Combinations of 2 different
Photosensitizers 5-ALA and low-dose porfimer
sodium
Enhanced antitumor efficacy in vitro and in vivo with
no risk of prolonged skin photosensitivity

9. • In the first step of PDT for cancer treatment a PS is injected into bloodstream. The agent
is absorbed by the cell all over the body but stays in cancer cell longer than it does in
normal cells.
• Approximately 24 to 72 hours after the injection,
when most of agents has left normal cells but remains
in cancer cell, the tumor is exposed to light.
• Photosensitizer in tumor absorbs the light
and produce an active form of oxygen that destroys
nearby cancer cell.

10. MECHANISM OF PDT-MEDIATED CYTOTOXICITY-
• The lifetime of O2 is very short(10-320 nanoseconds), limiting its diffusion to only
approximately 10 nm to 55 nm in cells. Thus photodynamic damage will occurs very close to
the intracellular location of PS. Porfimer sodium is a complex mixture of porphyrin ethers
with variable localization pattern mostly associated with lipid membranes.
• Other PS agents in current use, the mono-L-aspartyl chlorin targets lysosomes, the
benzoporphyrin derivative targets mitochondria, m-tertahydroxyphenylchlorin has been
reported to target mitochondria, ER they may be multiple target .
• Specific pattern of localization may vary also among different cell types.

11. Modified Jabloski Diagram
• Light exposure takes a PS molecule from the ground singlet state to an excited singlet
state. The molecule in S1 may undergo intersystem crossing to an excited triplet state T1
& then either from radicals via a Type I reaction or more likely transfer its energy to
molecular oxygen and form singlet oxygen which is the major cytotoxic agent involved in
PDT.
Light
exposure
Electron transfer
singlet
Triplet

12. Steps in systemically infused PS
First the PS is administered intravenously into the cancer patient.
It travel through the bloodstream & is absorbed by every cell in the
body(both the normal & the cancerous cell)
The normal cells get rid of it in a couple of days but a lot of the drugs
stays in the cancer & normal skin cell.
PS is activated or turned on by light after 2-3 days of administering it into
the body.
This gives normal cells to get rid of the drug.

13. Direct a laser light at the area of cancer cells through a thin fiber optic glass
strand.
Laser used is a low power light so it does not burn. It gives minimal or no pain.
Depending on the size of the tumor, the light is given for 5-40 minutes.
Any dead tissue left in the treated area is removed after 4-5 days.
Therapy can be repeated.

14. ADVANTAGES
• It has no long term side effect when used properly.
• It is less invasive than surgery.
• It usually takes only a short time & is most often done as an outpatient.
• It can be targeted very precisely.
• Unlike radiation, PDT can be repeated many times at the site if needed.
• There’s little or no scarring after the site heals.
• It often costs less than other cancer treatments.
• PDT is currently used in a number of medical fields, including Oncology, dermatology &
cosmetic surgery.

15. PDT over other oncotherapies-
• The absence of systemic toxicity of drug alone.
• The ability to irradiate only tumor.
• The possibility of treating multiple lesions simultaneously.
• Ability to retreat a tumor in order to improve the response.

16. LIMITATIONS-
• The light needed to activate most photosensitizers cannot pass through more than
about one third of an inch of tissue.
• PDT is usually used to treat tumors on or just under the skin or on the lining of
internal organs or cavities.
• PDT is also less effective in treating other tumors, because the light cannot pass far
into these tumors.
• PDT is a local treatment & generally cannot used to treat cancer that has been
metastasized.

17. COMPLICATIONS OR SIDE EFFECTS-
• Drugs makes the skin and eyes sensitive to light for approximately 6 weeks after
treatment thus patients are advised to avoid direct sunlight & bright indoor light for at
least 6 weeks.
• Photosensitizers tend to build up in tumors & the activating light is focused on the
tumor.
• PDT can cause burns, swelling, pain & scarring in nearby healthy tissue.
• Other side effects includes:
-Coughing, painful breathing
-Trouble swallowing
-Stomach pain
-Shortness of breath

18. PHOTOSENSITIZERS
-This are the drugs that are pharmacologically inactive but when exposed to UV-radiation or
sun light converted to their active metabolite to produce a beneficial reaction affecting the
diseased tissue.
-Most of the PS used in cancer therapy are based on a tetrapyrrole structure, similar to that
of the protoporphyrin contained in haemoglobin.
The physicochemical properties of the PS are very important for
the photosensitization.
• Chemically pure & of known composition.
• Capability to localize neoplastic tissue.
• Rapid clearance from normal tissues.
• Activation at wavelength with optimal tissue penetration.
• Have the absorption peak between 600-800nm (red to deep red) as absorption of photon
with wavelength longer than 800nm does not provide enough energy to excite oxygen to
its singlet state.
Basic Components of PDT

19. Clinically applied PS
PS
WAVELENGTH
(nm)
APPROVED TRIAL CANCER TYPE
Porfimer sodium
(Photofrin, HPD)
630 Worldwide United kingdom
Lung, oesophagus,
bile duct
ALA(aminolevulinic
acid)
635 Worldwide United kingdom Skin, bladder, brain
ALA esters 635 Europe United states Skin, bladder
Temoporfin 652 Europe United states Lung, brain, skin
Verteporfin 690 Worldwide United kingdom
Ophthalmic,
pancreatic
Talaporfin 660 Worldwide United kingdom Liver, colon, brain

20. LIGHT SOURCES
• The light used for PDT includes laser.
• Laser light can be directed through fiber optic fiber (thin fibers that transmit light) to deliver light to
areas inside the body.
• Other light sources includes intense pulsed light, light emitting diodes
(LEDs), blue light, red light & many other visible lights.
• Blue light penetrates least efficiently through tissue,
whearas red & infrared radiation penetrates more
deeply. The region between 600 & 1200nm is often
called the optical window of tissue.
Fig. Light Permeation

21. • However light up to only approximately 800nm can generate O2, because longer
wavelength have insufficient energy to initiate a photodynamic reaction.
-The choice of light source based on:
• PS absorption (fluorescence excitation & action spectra)
• Disease (Location, size of lesions, accessibility & tissue characteristics)
• Cost.
• Size.
-The clinical efficiency of PDT is dependent on complex dosimetry:
• Total light dose.
• Light exposure time.
• Light delivery mode(single vs fractioned or even metronomic)
• Fluence rate either interstitially or on the surface of the tissue being treated.

22. • Both laser & incandescent light sources have been used for PDT & shows similar efficacies.
Unlike the large & inefficient pumped dye lasers, diode laser are small & cost effective, are
simple to install & have automated dosimetry & calibration features & longer operational
life.
• Pulsed laser, such as the gold vapour laser (GVL) & Copper vapour laser-pumped dye laser
(GVDL) produces brief light pulses of millisecond to nanosecond duration. The comparison
of continuous wave & pulsed laser in practice has shown no difference.
• Light emitting diodes(LRDs) are alternative light sources with relatively narrow spectral
bandwidths & high fluence rates. laser can be coupled into fibers with diffusing tips to treat
tumors in the urinary bladder & the digestive tract.
• The choice of optimal combination of PSs, light sources & treatment parameters is crucible
for successful PDT.

23. OXYGEN
• The efficacy of photosensitization is directly related to the yield of O2 in the tumor
environment & the yield of O2 depends on the concentration of oxygen in the tissue.
Hypoxic cell are very resistant to photosensitization & the photodynamic reaction
mechanism it self may consume oxygen at a rate sufficient to inhibit further
photosensitization effects. It is suggested that hyperbaric oxygen might enhances the
Photosensitization effect.
• Hypoxic cell- Tumor cells have been deprived of oxygen. As a tumor grows it rapidly
outgrows its blood supply, leaving portions of the tumor with regions where the oxygen
concentration is significantly lower than in healthy tissues.
• Hyperbaric oxygen- HBOT which enhances the body’s natural healing process by
inhalation of 100% oxygen in the body chamber .

24. PHOTOSENSITIZATION DOSE -
• As the therapy is the combined effect of PS, light & oxygen measurement of each
component is required for an ideal photosensitization dose evaluation. In order to
optimize photosensitization it is important to know the photosensitizer pharmacokinetics
& concentration in normal and tumor tissue.
• The most reliable method available to determine the PS concentration requires
continuous sampling of blood serum and tissue biopsies. The obvious limitation in taking
multiple blood & tissue biopsies from patients has stimulated researches to develop non-
invasive system capable of measuring photosensitizer concentration using its
fluorescence properties.
• The successful eradication of target tissue requires a sufficient concentration of PS within
it & the presence of photo activating light in the malignant cells.

25. • PDT can evoke the 3 main cell death pathways: Apoptotic, Necrotic & autophagy
associated cell death.

26. IMPROVEMENT
• Oxygen generating nanoparticles -As oxygen is a key requirement for the generation of ROS in
PDT, CaO2 nanoparticle (NP) formulation coated with a pH-sensitive polymer to enable the
controlled generation of molecular oxygen as a function of pH. The polymer coat was designed to
protect the particles from decomposition while in circulation but enable their activation at lower pH
values in hypoxic regions of solid tumors.
• Increasing the efficiency of PDT improved light delivery and oxygen supply using an
anticoagulant in a solid- Tumor-Vascular closure during PDT reduces oxygen supply to the
targeted tissue. On the other hand, with the changes in blood perfusion, the tissue optical properties
change, and result in variation in irradiation light transmission. For these reasons, it becomes very
important to avoid blood coagulation and vascular closure during PDT. The efficiency of PDT
combined with the anticoagulant heparin was studied in a BALB/c mouse model with subcutaneous
EMT6 mammary carcinomas. Mice were randomized into three groups: control, PDT-only, and PDT
with heparin. The results clearly demonstrated that PDT combined with pre-administered heparin
can significantly reduce thrombosis during light irradiation.

27. STUDY DESIGN AND METHOD: The efficiency of PDT combined with the
anticoagulant heparin was studied in mouse model with subcutaneous mammary
carcinomas. Mice were randomized into three groups: control, PDT-only, and PDT with
heparin. The photosensitizer Photofrin was used in our experiments. Light transmission,
blood perfusion, and local production of reactive oxygen species (ROS) were monitored
during the treatment. The corresponding histological examinations were performed to
determine the thrombosis immediately after irradiation and to evaluate tumor necrosis 48
hours after the treatment.
RESULTS: The results clearly demonstrated that PDT combined with pre-administered
heparin can significantly reduce thrombosis during light irradiation. The blood perfusion,
oxygen supply, and light delivery are all improved. Improved tumor responses in the
combined therapy, as shown with the histological examination and tumor growth assay, are
clearly demonstrated and related to an increased local ROS production.
CONCLUSION: Transitory anticoagulation treatment significantly enhances the antitumor
effect of PDT. It is mainly due to the improvement of the light delivery and oxygen supply
in tumor, and ultimately the amount of ROS produced during PDT.

28. Clinical PDT
• The clinical use of PDT for cancer dates to the late 1970s, when there was a study published on PS
in 5 patients with bladder cancer. PDT produces mostly superficial effects. Due to a limited light
penetration through tissues, the depth of tumor destruction ranges from a few millimetres to up to
1cm.
• This apparent disadvantage can be favourably exploited in the treatment of superficial diseases,
such as premalignant conditions, carcinoma in situ or superficial tumors.
• Moreover PDT can be used supplemental to surgery, to irradiate the tumor bed a7 to increase the
probability of long term local disease control.
Skin tumors-
• PDT is currently approved in united state, Canada & European Union for the treatment of actinic
keratosis. It has demonstrated efficacy in treating squamous cell carcinoma(SCC)/Bowen disease
in extra mammary paget disease.

29. Head & Neck tumors-
• PDT has been successfully employed to treat early carcinomas of the oral cavity, pharynx
larynx, preserving normal tissue & vital functions of speech & swallowing.
Digestive system tumors-
• The application of PDT in the GIT has been divided into 2 groups: PDT of esophagus &
beyond various grades of dysplasia & early oesophageal cancer are the best studied PDT
application in the GI tract.
Intraperitoneal malignancies-
• The treatment of patient with peritoneal carcinomatosis or sarcomatosis is typically palliative
in nature. PDT has the potential to combine the selective destruction of cancerous tissue
compared with normal tissue with the ability to treat & conform to relatively large surface
areas.

30. • Moreover the intrinsic physical limitation in the depth of visible light penetration through tissue
limits PDT damage to deeper structures, thereby providing additional potential for tumor cell
selectivity.
Prostate cancer-
• Patient with prostate cancer who elect to undergo definitive radiotherapy have limited option for
option salvage therapy for isolated local failure. Prostate cancer with either surgery or ionizing
radiotherapy has significant associated morbidities due to the proximity of normal structure such as
nerves, bladder & rectum.
• The intrinsic limitation in the range of PDT mediated damage imposed by visible light has the
potential to selectively treat the prostate while sparing the surrounding normal tissue, light can be
delivered to the entire prostate gland using interstitial, cylindrically diffusing optical fibers.
• Unlike the chemotherapy or radiotherapy, the mechanism of cell killing by PDT is not dependent on
DNA damage or cell cycle effects.

31. Bladder cancer-
• Bladder cancer, which are often superficial & multifocal, can be assessed & debulked
endoscopically. In addition, the geometry of the bladder should allow for improved and
homogeneous delivery of light. These factors make superficial bladder cancer an attractive target
for PDT.
• In general early response rates to PDT have been observed in approximately 50% to 80% of the
patient, with longer term (1 year -2 years) durable responses noted in 20% to 60% of patients.
Non-small cell lung cancer –
• PDT for NSCLC was first used in 1982 by Hayata to achieve tumor necrosis & reopening of
airways. PDT for lung cancer is particularly useful for patients with advanced disease in whom
PDT is used as a palliation strategy & patients with early central lung cancer when patients are
unable to undergo surgery.

32. • A report described the result PDT procedures performed on 133 patient who presented with
NSCLC(89), metastatic airway lesions(31), small cell lung cancer(4), benign tumor (7) &
others unspecified lung conditions.
• The lesions were most commonly located in the main stem bronchi. PDT remains a very
promising therapeutic approach in the treatment of NSCLC.
Brain tumor-
• PDT is currently undergoing intensive clinical investigation ass an adjunctive treatment for
brain tumors.
• Malignant ependymomas
• Melanoma
• Lung cancer brain metastasis
• Recurrent pituitary adenomas

33. Conclusion-
PDT is still considered to be a new & promising antitumor strategy. The advantages of PDT
compared with surgery, chemotherapy Or radiotherapy are reduced long term morbidity & the
fact that PDT does not compromise future treatment option for patients with residual or
recurrent diseases.
PDT can be repeated without compromising its efficacy. These are significant limiting factors
for chemotherapy & radiotherapy. PDT induced immunogenic cell death associated with
induction of a potent local inflammatory reaction offers the possibility to flourish into a
therapeutic procedure with excellent local antitumor activity & the capability of boosting the
immune response for effective destruction of metastases.

34. Bibliography
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O.Gollnick, Stephen M. Hahn, Asta Juzeniene, David Kessel. Photodynamic Therapy of cancer: An
Update. Cacancerjournal 2011; 61: 250-75.
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• Yang L, Wei Y, Xing D, Chen Q. Increasing the efficiency of Photodynamic Therapy by improved light
delivery and oxygen supply using an anticoagulant in a solid tumor model: An update. Lesser surgmed
2010; 42(7): 671-9.
• Theodossiou, T.; Spiro, M.D.; Jacobson, J.; Hothersall, J.S.; Macrobert, A.J. Evidence for Intracellular
Aggregation of Hypericin and the Impact on its Photocytotoxicity in PAM 212 Murine Keratinocytes:
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therapy: Photochem Photobiol B.1994;23:3-8.
• Juzeniene A, Juzenas P, Ma LW, Iani V,Moan J. Effectiveness of different light sources for 5-
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