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photodynamic therapy

photodynamic therapy in cancer

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photodynamic therapy

  1. 1. Photodynamic Therapy in Cancer: DR SUHAS K R
  2. 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. 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. 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. 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. 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. 7. • 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.
  8. 8. 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
  9. 9. 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
  10. 10. • 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
  11. 11. • 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
  12. 12. • PHOTOSENSITIZERS • LIGHT • OXYGEN COMPONENTS OF PDT
  13. 13. 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
  14. 14. • 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.
  15. 15. 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.
  16. 16. 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
  17. 17. 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)
  18. 18. 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
  19. 19. • Conventional, broad-spectrum light sources, ARC LAMPS- cheap and easy to use LIGHT APPLICATION
  20. 20.  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
  21. 21. • 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
  22. 22. • 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
  23. 23. • 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
  24. 24. • 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
  25. 25. • 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
  26. 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 coatingof one side of the balloon is sometimes used to shield adjacent normal tissue areas for protection. LIGHT APPLICATION
  27. 27. • 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
  28. 28. • 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
  29. 29. • 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.
  30. 30. 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.
  31. 31. PDT Trials on Tumor Cells: Skin Cancer Pharmaceutical Research 2000, 17, 1447.
  32. 32. • 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 PDT Trials on Tumor Cells: Skin Cancer Photodermatol Photoimmunol Photomed 2005, 21, 72.
  33. 33. • 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.
  34. 34. PDT Trials on Tumor Cells: Skin Cancer Photodermatol Photoimmunol Photomed 2005, 21, 72.
  35. 35. • 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.
  36. 36. • 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
  37. 37. • 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
  38. 38. 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
  39. 39. • 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.
  40. 40. • 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.
  41. 41. • 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.
  42. 42. • 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
  43. 43. • 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
  44. 44. • 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
  45. 45. • 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
  46. 46. • 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
  47. 47. Conclusions: Clinical Approval of Photosensitizers Nature 2003, 3, 380.
  48. 48. • 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.
  49. 49. • 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.
  50. 50. • 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.
  51. 51. Thank you

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