Photodynamic Therapy of Cancer: The Design and Characterization of Photosensitizing Agents .


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HistoryIntroductionProcess of Photodynamic treatment (PDT)PDT to treat cancerPhotosensitizing AgentsRequirementsAdvancementsTrials utilizing PDT on tumor cellsConclusionsFuture applications. History. Light utilized as restorative operators for 3000 yearsEgyptian, Indian, and Chinese civilizationsPsoriasis, rickets, vitiligo, skin cancerPhotodynamic Therapy (PDT) created inside of the most recent century.
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Photodynamic Therapy of Cancer: The Design and Characterization of Photosensitizing Agents Angela Dann Monday, October 9, 2006

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History Introduction Process of Photodynamic treatment (PDT) PDT to treat malignancy Photosensitizing Agents Requirements Advancements Trials utilizing PDT on tumor cells Conclusions Future applications

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History Light utilized as helpful specialist for a long time Egyptian, Indian, and Chinese human advancements Psoriasis, rickets, vitiligo, skin growth Photodynamic Therapy (PDT) created inside the most recent century Nature 2003 , 3 , 380.

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History Nature 2003 , 3 , 380.

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History Niels Finsen (late 19 th century) Red light to forestall development and release of little pox postules UV light from the sun to treat cutaneous tuberculosis Nobel Prize 1903 Oscar Rabb (100+ years back) Acridine in blend with specific wavelengths of light Lethal to infusoria Nature 2003 , 3 , 380.

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History Herman Von Tappeiner, A. Jesionek Defined photodynamic activity Topically connected eosin and white light W. Hausmann 1 st thinks about with haematoporphyrin and light Killed paramecium and red platelets Friedrich Meyer-Betz (1913) 1 st to treat people with porphyrins Haematoporphyrin connected to skin, bringing on swelling/torment with light introduction Nature 2003 , 3 , 380.

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History Samuel Schwartz (1960\'s) Developed haematoporphyrin subordinate (HpD) Haematoporphyrin treated with acidic and sulfuric acids, killed with sodium acetic acid derivation Lipson, E.J. Baldes HpD confinement in tumor cells, fluorescence I. Jewel (1972) Use PDT to treat tumor Nature 2003 , 3 , 380.

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History Thomas Dougherty (1975) HpD and red light Eradicated mammary tumor development in mice J.F. Kelly (1976) 1 st human trials utilizing HpD Bladder growth Canada (1999) 1 st PDT sedate affirmed Nature 2003 , 3 , 380.

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Introduction: Process of Photodynamic treatment Two independently non-lethal parts united to bring about unsafe impacts on cells and tissues Photosensitizing agent Light of particular wavelength Nature 2003 , 3 , 380.

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Introduction: Reaction Mechanisms Type 1: Direct response with substrate (cell film or particle) Transfer of H molecule to shape Radicals respond with O 2 to frame oxygenated items Type 2: Transfer of vitality to O 2 to frame 1 O 2 Nature 2003 , 3 , 380.

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Introduction: Reaction Mechanisms Ratio of Type 1/Type 2 relies on upon: Photosensitizing specialist, convergence of substrate and O 2 , restricting fondness of photosensitizing operator to substrate Reactive oxygenated species (ROS) Free radicals or 1 O 2 Half-existence of 1 O 2 < 0.04 m s Radius influenced < 0.02 m Nature 2003 , 3 , 380.

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Introduction: Type 1 and 2 Reactions Nature 2003 , 3 , 380.

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Introduction: Treatment of malignancy PDT most appropriate for: Early stage tumors Inoperable for different reasons Limited accomplishment because of absence of specificity and intensity of photosensitizing specialists Three instruments of tumor harm Nature 2003 , 3 , 380.

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Introduction: Mechanism 1 Direct Photodamage to Tumors by ROS Problems: Non-homogenous conveyance of photosensitizing specialist inside tumor Availability of O 2 inside tumor cells Reduction of O 2 nearness amid PDT Overcoming O 2 consumption: Lower light fluence rate Pulse light conveyance – permit re-oxygenation Nature 2003 , 3 , 380. J. of Nuclear Medicine 2006 , 47 , 1119.

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Introduction: Mechanism 2 Vascular Damage Blood vessels supply supplements to tumor cells Effects: Microvascular fall Tissue hypoxia and anoxia Thrombus arrangement Associated with stopping tumor development Angiogenic components upregulated Nature 2003 , 3 , 380. J. of Nuclear Medicine 2006 , 47 , 1119.

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Introduction: Mechanism 3 Immune Response Movement of lymphocytes, leukocytes, macrophages into treated tissue Difference in responses toward ordinary and tumor tissues Upregulation of interleukin, not tumor rot consider a Neutrophil – eases back tumor development Required to cleanse remaining cells Nature 2003 , 3 , 380.

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Photosensitizing Agents: Requirements Selectivity to tumor cells Photostability Biological security Photochemical proficiency No cytotoxicity without light Strong retention – 600-800 nm Good tissue entrance Long triplet energized state lifetime J. of Photochemistry and Photobiology A: Chemistry 2002 , 153 , 245. Photochemistry and Photobiology 2001 , 74 , 656.

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Photosensitizing Agents: Classes Porphyrin subordinates Most generally utilized Chlorins Reduced porphyrins Derivatives from chlorophyll or porphyrins Phthalocyanines 2 nd era Contain diamagnetic metal particle Porphycenes Synthetic porphyrins Pharmaceutical Research 2000 , 17 , 1447.

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Photosensitizing Agents: Examples Photofrin Foscan 5-Aminolevulinic corrosive (5-ALA) Mono-L-aspartyl chlorin e6 (NPe6) Phthalocyanines Meso-tetra(hydroxyphenyl)porphyrins (mTHPP) Texaphyrins Tin ethyl etiopurpurin (SnET2, Purlytin)

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Photosensitizing Agents: Photofrin 1 st clinical endorsement (1999) in Canada Bladder tumor treatment Most usually utilized photosensitizer Destroys mitochondria Dihematoporphyrin ether (DHE) bis-1-[3(1-hydroxy-ethyl)deuteroporphyrin-8-yl] ethyl ether Active segment of HpD Photochemistry and Photobiology 2001 , 74 , 656.

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Photosensitizing Agents: Photofrin Partially purged haematoporphyrin subordinate (HpD) Mixture of mono-, di-, and oligomers Twice as phototoxic as rough haematoporphyrin (Hp) Crude Hp comprises of scope of porphyrins Convert to HpD by acetylation and decrease utilizing acidic and sulfuric acids, sifting, and killing with sodium acetic acid derivation Photochemistry and Photobiology 2001 , 74 , 656. Nature 2003 , 3 , 380.

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Photosensitizing Agents: Photofrin Limitations: Contains 60 mixes Difficult to repeat sythesis At 630 nm, molar ingestion coefficient is low (1,170 M - 1 cm - 1 ) Main retention at 400 nm High groupings of medication and light required Not extremely specific toward tumor cells Absorption by skin cells causes dependable photosensitivity (½ life = 452 hr) Nature 2003 , 3 , 380. J. of Photochemistry and Photobiology A: Chemistry 2002 , 153 , 245.

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Photosensitizing Agents: Advancements Need to beat constraints of Photofrin New photosensitizers created by circumstances Increase specificity to tumor cells Increase intensity Decrease time of affectability to daylight after treatment

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Photosensitizing Agents: Foscan Chlorin photosensitizing specialist Approved for treatment of head and neck malignancy Low medication dosage (0.1 mg/kg body weight) Low light measurements (10 J/cm 2 ) Complications because of power Nature 2003 , 3 , 380.

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Photosensitizing Agents: 5-Aminolevulinic corrosive (5-ALA) Hydrophilic zwitterion at physiological pH Approved for treatment of actinic keratosis and BCC of skin Topical application most every now and again utilized Endogenous photosensitizing operator 5-ALA not straightforwardly photosensitizing Creates porphyria-like disorder Precursor to protoporphyrin IX (PpIX) Nature 2003 , 3 , 380. Photochemistry and Photobiology 2001 , 74 , 656. Pharmaceutical Res. 2000 , 17 , 1447.

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Photosensitizing Agents: Mono-L-aspartyl chlorin e6 (NPe6) 2 nd era hydrophilic chlorin Derived from chlorophyll a Chemically immaculate Absorption at 664 nm Localizes in lysosomes (rather than mitochondria) Reduced confinements contrasted with Photofrin Decreased affectability to daylight (1 week) ½ life = 105.9 hr Photodermatol Photoimmunol Photomed 2005 , 21 , 72.

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Photosensitizing Agents: Phthalocyanines 2 nd era Ring of 4 isoindole units connected by N-iotas Stable chelates with metal cations Sulfonate bunches increment water dissolvability Examples (AlPcS 4 , ZnPcS 2 ) Aluminum chlorophthalocyanine sulfonate More delayed photosensitization than HpD Less skin affectability in daylight Photochemistry and Photobiology 2001 , 74 , 656. J. of Nuclear Medicine , 2006 , 47 , 1119.

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Photosensitizing Agents: Phthalocyanines Tetrasulfonated AlPcS 4 Hydrophilic Deposited in vascular stroma Affects vascular framework – roundabout cell demise Disulfonated ZnPcS 2 Amphophilic Transported by lipoproteins Direct cell passing Photochemistry and Photobiology 2001 , 74 , 656. J. of Nuclear Medicine , 2006 , 47 , 1119.

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Photosensitizing Agents: Meta-tetra(hydroxyphenyl)porphyrins (mTHPP) Commercially accessible as meta-tetra(hydroxyphenyl)chlorin – (mTHPC) 2 nd era Improved red light assimilation 25-30 times more intense than HpD More particular toward tumor cells Most dynamic photosensitizer with low medication and light measurements Not conceded endorsement Photochemistry and Photobiology 2001 , 74 , 656. Int. J. Growth 2001 , 93 , 720.

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Photosensitizing Agents: Texaphyrins Synthetic – porphycene Water solvent Related to porphyrins Absorption between 720-760 nm (far red) Sufficiently enters tissue Photochemistry and Photobiology 2001 , 74 , 656.

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Photosensitizing Agents: Tin ethyl etiopurpurin SnET2, Purlytin Chlorin Treatment of cutaneous metastatic malignancies Results of stage III review (934 patients) not yet discharged Photochemistry and Photobiology 2001 , 74 , 656.

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PDT Trials on Tumor Cells: Breast Cancer Chest divider repeats – issue with mastectomy treatment (5-19%) Study: 7 patients, 57.6 years of age (12.6) 89 metastatic hubs treated 11 PDT sessions Photosensitizing specialist: (m-THPC) meta-tetra(hydroxyphenyl)chlorin 2 nd era photosensitizing operator Int. J. Growth 2001 , 93 , 720.

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PDT Trials on Tumor Cells: Breast Cancer Dosage: Diode laser used to create l = 652 nm 3 patients 0.10 mg/kg add up to body weight 48 hr under 5 J/cm 2 4 patients 0.15 mg/kg add up to body weight 96 hr under 10 J/cm 2 Int. J. Malignancy 2001 , 93 , 720.

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