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46-452: It is a photosensitiser for use in photodynamic therapy to treat skin conditions and superficial cancers. It has also been tested for use in photoangioplasty (photodynamic treatment of diseased arteries). It is photoactivated by 732 nm light which allows greater depth of penetration. Phase II clinical trials were in progress in 1999. A phase I trial for prostate cancer reported in 2009. This dermatologic drug article

92-460: A superoxide radical anion (O 2 • ), which can go on to produce the highly reactive hydroxyl radical (OH•), initiating a cascade of cytotoxic free radicals; this process is common in the oxidative damage of fatty acids and other lipids. The Type-I process (ii) involves the transfer of a hydrogen atom (reduction) to the excited state photosensitiser (Psen*). This generates free radicals capable of rapidly reacting with molecular oxygen and creating

138-454: A characteristic ultra-violet visible (UV-VIS) spectrum. The spectrum typically consists of an intense, narrow absorption band ( ε > 200000 L⋅mol−1 cm−1) at around 400 nm, known as the Soret band or B band, followed by four longer wavelength (450–700 nm), weaker absorptions ( ε > 20000 L⋅mol−1⋅cm−1 ( free-base porphyrins)) referred to as the Q bands. The Soret band arises from

184-438: A complex mixture of reactive oxygen intermediates, including reactive peroxides . Type-II processes involve the direct interaction of the excited triplet state photosensitiser (3Psen*) with ground state molecular oxygen ( O 2 , Σ g ); a spin allowed transition—the excited state photosensitiser and ground state molecular oxygen are of the same spin state (T). When the excited photosensitiser collides with molecular oxygen,

230-401: A fast internal conversion. This ability to transform the excitation energy of photon into heat can be a crucial property for photoprotection by molecules such as melanin . Fast internal conversion reduces the excited state lifetime, and thereby prevents bimolecular reactions. Bimolecular electron transfer always produces a reactive chemical species, free radicals . Nucleic acids (precisely

276-429: A photon, one of its electrons is promoted into a higher-energy orbital , elevating the chromophore from the ground state ( S0 ) into a short-lived, electronically excited state (S n ) composed of vibrational sub-levels (S n ′). The excited chromophore can lose energy by rapidly decaying through these sub-levels via internal conversion (IC) to populate the first excited singlet state (S1), before quickly relaxing back to

322-675: A photoreaction 7–14 days post-administration. Tetra( m -hydroxyphenyl)chlorin ( m THPC) is in clinical trials for head and neck cancers under the trade name Foscan . It has also been investigated in clinical trials for gastric and pancreatic cancers, hyperplasia, field sterilisation after cancer surgery and for the control of antibiotic-resistant bacteria. Foscan has a singlet oxygen quantum yield comparable to other chlorin photosensitisers but lower drug and light doses (approximately 100 times more photoactive than Photofrin). Foscan can render patients photosensitive for up to 20 days after initial illumination. Lutetium texaphyrin , marketed under

368-1006: A photosensitiser is not exclusively dependent upon a Type-II process. Multiple photosensitisers display excited triplet lifetimes that are too short to permit a Type-II process to occur. For example, the copper metallated octaethylbenzochlorin photosensitiser has a triplet state lifetime of less than 20 nanoseconds and is still deemed to be an efficient photodynamic agent. Many photosensitizers for PDT exist. They divide into porphyrins , chlorins and dyes . Examples include aminolevulinic acid (ALA), Silicon Phthalocyanine Pc 4, m-tetrahydroxyphenylchlorin (mTHPC) and mono-L-aspartyl chlorin e6 ( NPe6 ). Photosensitizers commercially available for clinical use include Allumera, Photofrin , Visudyne , Levulan , Foscan , Metvix , Hexvix , Cysview and Laserphyrin , with others in development, e.g. Antrin , Photochlor , Photosens , Photrex, Lumacan, Cevira , Visonac, BF-200 ALA, Amphinex and Azadipyrromethenes . The major difference between photosensitizers

414-460: A photosensitiser is the ability to preferentially accumulate in diseased tissue and induce a desired biological effect via the generation of cytotoxic species. Specific criteria: Porfimer sodium Porfimer sodium is a drug used to treat some types of cancer. When absorbed by cancer cells and exposed to light, porfimer sodium becomes active and kills the cancer cells. It is a type of photodynamic therapy (PDT) agent and also called Photofrin. PDT

460-415: A process of triplet-triplet annihilation takes place (3Psen* → 1Psen and O 2 → O 2 ). This inverts the spin of one oxygen molecule's ( O 2 ) outermost antibonding electrons, generating two forms of singlet oxygen ( Δ g and Σ g ), while simultaneously depopulating the photosensitiser's excited triplet state (T1 → S0). The higher-energy singlet oxygen state ( Σ g , 157kJ mol−1 > Σ g )

506-571: A radius of approximately 20 nm, with a typical lifetime of approximately 40 nanoseconds in biological systems. It is possible that (over a 6 μs period) singlet oxygen can diffuse up to approximately 300 nm in vivo . Singlet oxygen can theoretically only interact with proximal molecules and structures within this radius. ROS initiate reactions with many biomolecules, including amino acid residues in proteins, such as tryptophan ; unsaturated lipids like cholesterol and nucleic acid bases, particularly guanosine and guanine derivatives, with

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552-419: A red-shifted and intensified long-wavelength absorption maxima at approximately 690 nm. Tissue penetration by light at this wavelength is 50% greater than that achieved for Photofrin ( λ max. = 630 nm). Verteporfin has further advantages over the first generation sensitiser Photofrin. It is rapidly absorbed by the tumour (optimal tumour-normal tissue ratio 30–150 minutes post-intravenous injection) and

598-500: A specified period. The light dose supplies sufficient energy to stimulate the photosensitiser, but not enough to damage neighbouring healthy tissue. The reactive oxygen kills the target cells. In air and tissue, molecular oxygen (O 2 ) occurs in a triplet state , whereas almost all other molecules are in a singlet state. Reactions between triplet and singlet molecules are forbidden by quantum mechanics , making oxygen relatively non-reactive at physiological conditions. A photosensitizer

644-425: A strong electronic transition from the ground state to the second excited singlet state (S0 → S2); whereas the Q band is a result of a weak transition to the first excited singlet state (S0 → S1). The dissipation of energy via internal conversion (IC) is so rapid that fluorescence is only observed from depopulation of the first excited singlet state to the lower-energy ground state (S1 → S0). The key characteristic of

690-418: A substrate molecule and highly reactive state of oxygen known as singlet oxygen (Type II). PDT is a multi-stage process. First a photosensitiser, ideally with negligible toxicity other than its phototoxicity, is administered in the absence of light, either systemically or topically. When a sufficient amount of photosensitiser appears in diseased tissue, the photosensitiser is activated by exposure to light for

736-470: Is a prodrug used to treat and image multiple superficial cancers and tumours. ALA a key precursor in the biosynthesis of the naturally occurring porphyrin, haem . Haem is synthesised in every energy-producing cell in the body and is a key structural component of haemoglobin, myoglobin and other haemproteins . The immediate precursor to haem is protoporphyrin IX (PPIX), an effective photosensitiser. Haem itself

782-503: Is a stub . You can help Misplaced Pages by expanding it . Photodynamic therapy Photodynamic therapy ( PDT ) is a form of phototherapy involving light and a photosensitizing chemical substance used in conjunction with molecular oxygen to elicit cell death ( phototoxicity ). PDT is used in treating acne , wet age-related macular degeneration , psoriasis , and herpes . It is used to treat malignant cancers , including head and neck, lung, bladder and skin. Advantages lessen

828-503: Is a chemical compound that can be promoted to an excited state upon absorption of light and undergo intersystem crossing (ISC) with oxygen to produce singlet oxygen . This species is highly cytotoxic , rapidly attacking any organic compounds it encounters. It is rapidly eliminated from cells, in an average of 3 μs. When a photosensitiser is in its excited state (3Psen*) it can interact with molecular triplet oxygen ( O 2 ) and produce radicals and reactive oxygen species (ROS), crucial to

874-399: Is a transition from a higher to a lower electronic state in a molecule or atom. It is sometimes called "radiationless de-excitation", because no photons are emitted. It differs from intersystem crossing in that, while both are radiationless methods of de-excitation, the molecular spin state for internal conversion remains the same, whereas it changes for intersystem crossing. The energy of

920-405: Is also excreted more rapidly from the body (~24 hours) than other photosensitisers, minimising photosensitivity side effects. Esterified ALA derivatives with improved bioavailability have been examined. A methyl ALA ester ( Metvix ) is now available for basal cell carcinoma and other skin lesions. Benzyl (Benvix) and hexyl ester ( Hexvix ) derivatives are used for gastrointestinal cancers and for

966-406: Is not a photosensitiser, due to the coordination of a paramagnetic ion in the centre of the macrocycle, causing significant reduction in excited state lifetimes. The haem molecule is synthesised from glycine and succinyl coenzyme A (succinyl CoA). The rate-limiting step in the biosynthesis pathway is controlled by a tight (negative) feedback mechanism in which the concentration of haem regulates

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1012-455: Is rapidly cleared from the body, minimising patient photosensitivity (1–2 days). Chlorin photosensitiser tin etiopurpurin is marketed as Purlytin. Purlytin has undergone Phase II clinical trials for cutaneous metastatic breast cancer and Kaposi's sarcoma in patients with AIDS (acquired immunodeficiency syndrome). Purlytin has been used successfully to treat the non-malignant conditions psoriasis and restenosis . Chlorins are distinguished from

1058-454: Is the parts of the cell that they target. Unlike in radiation therapy , where damage is done by targeting cell DNA, most photosensitizers target other cell structures. For example, mTHPC localizes in the nuclear envelope. In contrast, ALA localizes in the mitochondria and methylene blue in the lysosomes. Cyclic tetrapyrrolic molecules are fluorophores and photosensitisers. Cyclic tetrapyrrolic derivatives have an inherent similarity to

1104-485: Is very short-lived ( Σ g ≤ 0.33 milliseconds (methanol), undetectable in H 2 O/D 2 O) and rapidly relaxes to the lower-energy excited state ( Δ g , 94kJ mol > Σ g ). It is, therefore, this lower-energy form of singlet oxygen ( Δ g ) that is implicated in cell injury and cell death. The highly-reactive singlet oxygen species ( O 2 ) produced via the Type-II process act near to their site generation and within

1150-537: The meso- and β -hydrogens are substituted with non-hydrogen atoms or groups, the resulting compounds are known as porphyrins. The inner two protons of a free-base porphyrin can be removed by strong bases such as alkoxides , forming a dianionic molecule; conversely, the inner two pyrrolenine nitrogens can be protonated with acids such as trifluoroacetic acid affording a dicationic intermediate. The tetradentate anionic species can readily form complexes with most metals. Porphyrin's highly conjugated skeleton produces

1196-487: The Type II mechanism. These species include singlet oxygen ( O 2 ), hydroxyl radicals (•OH) and superoxide (O 2 ) ions. They can interact with cellular components including unsaturated lipids, amino acid residues and nucleic acids. If sufficient oxidative damage ensues, this will result in target-cell death (only within the illuminated area). When a chromophore molecule, such as a cyclic tetrapyrrolic molecule, absorbs

1242-436: The Type-II photo-oxygenation process predominates in the induction of cell damage, a consequence of the interaction between the irradiated photosensitiser and molecular oxygen. Cells in vivo may be partially protected against the effects of photodynamic therapy by the presence of singlet oxygen scavengers (such as histidine ). Certain skin cells are somewhat resistant to PDT in the absence of molecular oxygen; further supporting

1288-497: The US for high grade dysplasia in Barrett's Esophagus. Disadvantages associated with first generation photosensitisers include skin sensitivity and absorption at 630 nm permitted some therapeutic use, but they markedly limited application to the wider field of disease. Second generation photosensitisers were key to the development of photodynamic therapy. 5-Aminolaevulinic acid (ALA)

1334-419: The diagnosis of bladder cancer. Benzoporphyrin derivative monoacid ring A (BPD-MA), marketed as Visudyne ( Verteporfin , for injection), has been approved by health authorities in multiple jurisdictions, including US FDA, for the treatment of wet AMD beginning in 1999. It has also undergone Phase III clinical trials (USA) for the treatment of cutaneous non-melanoma skin cancer. The chromophore of BPD-MA has

1380-413: The electronically excited state is given off to vibrational modes of the molecule. The excitation energy is transformed into heat. A classic example of this process is the quinine sulfate fluorescence , which can be quenched by the use of various halide salts . The excited molecule can de-excite by increasing the thermal energy of the surrounding solvated ions . Several natural molecules perform

1426-531: The excited singlet or triplet photosensitiser (1Psen*, S1; 3Psen*, T1), however due to the short lifetime of the excited singlet state, the photosensitiser can only react if it is intimately associated with a substrate. In both cases the interaction is with readily oxidisable or reducible substrates. Type-II processes involve the direct interaction of the excited triplet photosensitiser (3Psen*, T1) with molecular oxygen ( O 2 , Σ g ). Type-I processes can be divided into Type I(i) and Type I(ii). Type I (i) involves

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1472-574: The ground state. The decay from the excited singlet state (S1) to the ground state (S0) is via fluorescence (S1 → S0). Singlet state lifetimes of excited fluorophores are very short ( τ fl. = 10 –10 seconds) since transitions between the same spin states (S → S or T → T) conserve the spin multiplicity of the electron and, according to the Spin Selection Rules, are therefore considered "allowed" transitions. Alternatively, an excited singlet state electron (S1) can undergo spin inversion and populate

1518-457: The heart of the skeleton a heterocyclic macrocycle, known as a porphine . The fundamental porphine frame consists of four pyrrolic sub-units linked on opposing sides ( α -positions, numbered 1, 4, 6, 9, 11, 14, 16 and 19) through four methine (CH) bridges (5, 10, 15 and 20), known as the meso -carbon atoms/positions. The resulting conjugated planar macrocycle may be substituted at the meso - and/or β -positions (2, 3, 7, 8, 12, 13, 17 and 18): if

1564-467: The latter base more susceptible to ROS. These interactions cause damage and potential destruction to cellular membranes and enzyme deactivation, culminating in cell death. It is probable that in the presence of molecular oxygen and as a direct result of the photoirradiation of the photosensitiser molecule, both Type-I and II pathways play a pivotal role in disrupting cellular mechanisms and cellular structure. Nevertheless, considerable evidence suggests that

1610-594: The lifetime of phosphorescence ( τP = 10 − 1 second) is considerably longer than that of fluorescence. Tetrapyrrolic photosensitisers in the excited singlet state (1Psen*, S>0) are relatively efficient at intersystem crossing and can consequently have a high triplet-state quantum yield. The longer lifetime of this species is sufficient to allow the excited triplet state photosensitiser to interact with surrounding bio-molecules, including cell membrane constituents. Excited triplet-state photosensitisers can react via Type-I and Type-II processes. Type-I processes can involve

1656-410: The lower-energy first excited triplet state (T1) via intersystem crossing (ISC); a spin-forbidden process, since the spin of the electron is no longer conserved. The excited electron can then undergo a second spin-forbidden inversion and depopulate the excited triplet state (T1) by decaying to the ground state (S0) via phosphorescence (T1→ S0). Owing to the spin-forbidden triplet to singlet transition,

1702-480: The naturally occurring porphyrins present in living matter. Porphyrins are a group of naturally occurring and intensely coloured compounds, whose name is drawn from the Greek word porphura , or purple. These molecules perform biologically important roles, including oxygen transport and photosynthesis and have applications in fields ranging from fluorescent imaging to medicine. Porphyrins are tetrapyrrolic molecules, with

1748-520: The need for delicate surgery and lengthy recuperation and minimal formation of scar tissue and disfigurement. A side effect is the associated photosensitisation of skin tissue. PDT applications involve three components: a photosensitizer , a light source and tissue oxygen . The wavelength of the light source needs to be appropriate for exciting the photosensitizer to produce radicals and/or reactive oxygen species . These are free radicals (Type I) generated through electron abstraction or transfer from

1794-573: The parent porphyrins by a reduced exocyclic double bond, decreasing the symmetry of the conjugated macrocycle. This leads to increased absorption in the long-wavelength portion of the visible region of the electromagnetic spectrum (650–680 nm). Purlytin is a purpurin; a degradation product of chlorophyll. Purlytin has a tin atom chelated in its central cavity that causes a red-shift of approximately 20–30 nm (with respect to Photofrin and non-metallated etiopurpurin, λ max.SnEt2 = 650 nm). Purlytin has been reported to localise in skin and produce

1840-511: The photosensitizer porfimer sodium for palliative treatment of advanced esophageal cancer, specifically the palliation of patients with completely obstructing esophageal cancer, or for patients with partially obstructing esophageal cancer. Porfimer Sodium is also FDA-approved for the treatment of types of lung cancer, more specifically for the treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated and also FDA approved in

1886-429: The production of ALA. However, this controlled feedback can be by-passed by artificially adding excess exogenous ALA to cells. The cells respond by producing PPIX (photosensitiser) at a faster rate than the ferrochelatase enzyme can convert it to haem. ALA, marketed as Levulan , has shown promise in photodynamic therapy (tumours) via both intravenous and oral administration, as well as through topical administration in

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1932-410: The proposal that the Type-II process is at the heart of photoinitiated cell death. The efficiency of Type-II processes is dependent upon the triplet state lifetime τ T and the triplet quantum yield (ΦT) of the photosensitiser. Both of these parameters have been implicated in phototherapeutic effectiveness; further supporting the distinction between Type-I and Type-II mechanisms. However, the success of

1978-532: The trade name Lutex and Lutrin, is a large porphyrin-like molecule. Texaphyrins are expanded porphyrins that have a penta-aza core. It offers strong absorption in the 730–770 nm region. Tissue transparency is optimal in this range. As a result, Lutex-based PDT can (potentially) be carried out more effectively at greater depths and on larger tumours. Lutex has entered Phase II clinical trials for evaluation against breast cancer and malignant melanomas. Internal conversion (chemistry) Internal conversion

2024-484: The transfer of an electron (oxidation) from a substrate molecule to the excited state photosensitiser (Psen*), generating a photosensitiser radical anion (Psen• ) and a substrate radical cation (Subs• ). The majority of the radicals produced from Type-I(i) reactions react instantaneously with molecular oxygen (O 2 ), generating a mixture of oxygen intermediates. For example, the photosensitiser radical anion can react instantaneously with molecular oxygen ( O 2 ) to generate

2070-452: The treatment of malignant and non-malignant dermatological conditions, including psoriasis, Bowen's disease and Hirsutism (Phase II/III clinical trials). ALA accumulates more rapidly in comparison to other intravenously administered sensitisers. Typical peak tumour accumulation levels post-administration for PPIX are usually achieved within several hours; other (intravenous) photosensitisers may take up to 96 hours to reach peak levels. ALA

2116-514: Was first discovered more than a century ago in Germany, it was not until Thomas Dougherty's when PDT became more mainstream. Prior to Dr. Dougherty, researchers had ways of using light-sensitive compounds to treat disease. Dougherty successfully treated cancer with PDT in preclinical models in 1975. Three years later, he conducted the first controlled clinical study in humans. In 1994, the FDA approved PDT with

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