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
Phototoxicity, also called photoirritation, is a chemically induced skin irritation, requiring light, that does not involve the immune system. It is a type of photosensitivity.
The skin response resembles an exaggerated sunburn. The involved chemi ...
).
PDT is popularly used in treating
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
. It is used clinically to treat a wide range of medical conditions, including
wet age-related macular degeneration
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
, psoriasis, atherosclerosis and has shown some efficacy in anti-viral treatments, including
herpes
Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected.
Oral herpes involves the face or mouth. It may result in small blisters in groups often called cold ...
. It also treats malignant
cancers
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
including head and neck, lung, bladder and particular skin.
The technology has also been tested for treatment of prostate cancer, both in a dog model and in human prostate cancer patients.
It is recognised as a treatment strategy that is both minimally invasive and minimally toxic. Other
light-based and laser therapies such as laser wound healing and rejuvenation, or
intense pulsed light
Intense pulsed light (IPL) is a technology used by cosmetic and medical practitioners to perform various skin treatments for aesthetic and therapeutic purposes, including hair removal, photorejuvenation (e.g. the treatment of skin pigmentation ...
hair removal do not require a photosensitizer.
Photosensitisers have been employed to sterilise blood plasma and water in order to remove blood-borne viruses and microbes and have been considered for agricultural uses, including herbicides and insecticides.
Photodynamic therapy's advantages lessen 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.
Basics
PDT applications involve three components:
a
photosensitizer
Photosensitizers produce a physicochemical change in a neighboring molecule by either donating an electron to the substrate or by abstracting a hydrogen atom from the substrate. At the end of this process, the photosensitizer eventually returns t ...
, a
light source
Light or visible light is electromagnetic radiation that can be perceived by the human eye. Visible light is usually defined as having wavelengths in the range of 400–700 nanometres (nm), corresponding to frequencies of 750–420 terah ...
and tissue
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
. The wavelength of the light source needs to be appropriate for exciting the photosensitizer to produce radicals and/or
reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
. These are
free radicals (Type I) generated through electron abstraction or transfer from 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 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.
[ ]
This article contains quotations from this source, which is available under an Attribution 3.0 Unported (CC BY 3.0) license.
Reactive oxygen species
In air and tissue, molecular oxygen (O
2) occurs in a
triplet state
In quantum mechanics, a triplet is a quantum state of a system with a spin of quantum number =1, such that there are three allowed values of the spin component, = −1, 0, and +1.
Spin, in the context of quantum mechanics, is not a mechanical r ...
, 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 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.
Photochemical processes
When a photosensitiser is in its excited state (3Psen*) it can interact with molecular triplet oxygen (
3O
2) and produce radicals and reactive oxygen species (ROS), crucial to the Type II mechanism. These species include singlet oxygen (
1O
2),
hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydro ...
radicals (•OH) and
superoxide
In chemistry, a superoxide is a compound that contains the superoxide ion, which has the chemical formula . The systematic name of the anion is dioxide(1−). The reactive oxygen ion superoxide is particularly important as the product of t ...
(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).
Photochemical mechanisms
When a
chromophore molecule, such as a cyclic tetrapyrrolic molecule, absorbs a photon, one of its
electron
The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family,
and are generally thought to be elementary particles because they have no ...
s 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
Internal conversion is a non-radioactive, atomic decay process where an excited nucleus interacts electromagnetically with one of the orbital electrons of an atom. This causes the electron to be emitted (ejected) from the atom. Thus, in internal ...
(IC) to populate the first excited singlet state (S1), before quickly relaxing back to the ground state.
The decay from the excited singlet state (S1) to the ground state (S0) is via
fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, tha ...
(S1 → S0). Singlet state lifetimes of excited fluorophores are very short (''τ''fl. = 10
−9–10
−6 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 the lower-energy first excited triplet state (T1) via
intersystem crossing Intersystem crossing (ISC) is an isoenergetic radiationless process involving a transition between the two electronic states with different spin multiplicity.
Excited Singlet and Triplet States
When an electron in a molecule with a singlet ground ...
(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
Phosphorescence is a type of photoluminescence related to fluorescence. When exposed to light (radiation) of a shorter wavelength, a phosphorescent substance will glow, absorbing the light and reemitting it at a longer wavelength. Unlike fluo ...
(T1→ S0). Owing to the spin-forbidden triplet to singlet transition, the lifetime of phosphorescence (''τP'' = 10
−3 − 1 second) is considerably longer than that of fluorescence.
Photosensitisers and photochemistry
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.
Photochemical reactions
Excited triplet-state photosensitisers can react via Type-I and Type-II processes. Type-I processes can involve 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 (
3O
2,
3Σ
g).
Type-I processes
Type-I processes can be divided into Type I(i) and Type I(ii). Type I (i) involves 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 (
3O
2) to generate a
superoxide radical anion (O
2•
−), which can go on to produce the highly reactive
hydroxyl radical
The hydroxyl radical is the diatomic molecule . The hydroxyl radical is very stable as a dilute gas, but it decays very rapidly in the condensed phase. It is pervasive in some situations. Most notably the hydroxyl radicals are produced from the ...
(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 a complex mixture of reactive oxygen intermediates, including reactive
peroxide
In chemistry, peroxides are a group of compounds with the structure , where R = any element. The group in a peroxide is called the peroxide group or peroxo group. The nomenclature is somewhat variable.
The most common peroxide is hydrogen ...
s.
Type-II processes
Type-II processes involve the direct interaction of the excited triplet state photosensitiser (3Psen*) with ground state molecular oxygen (
3O
2,
3Σ
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, a process of
triplet-triplet annihilation takes place (3Psen* ''→''1Psen and
3O
2 ''→''
1O
2). This inverts the spin of one oxygen molecule's (
3O
2) outermost
antibonding electrons, generating two forms of singlet oxygen (
1Δ
g and
1Σ
g), while simultaneously depopulating the photosensitiser's excited triplet state (T1 → S0). The higher-energy singlet oxygen state (
1Σ
g, 157kJ mol−1 >
3Σ
g) is very short-lived (
1Σ
g ≤ 0.33 milliseconds (methanol), undetectable in H
2O/D
2O) and rapidly relaxes to the lower-energy excited state (
1Δ
g, 94kJ mol
−1 >
3Σ
g). It is, therefore, this lower-energy form of singlet oxygen (
1Δ
g) that is implicated in cell injury and cell death.
The highly-reactive singlet oxygen species (
1O
2) produced via the Type-II process act near to their site generation and within 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
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
residues in proteins, such as
tryptophan
Tryptophan (symbol Trp or W)
is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...
; unsaturated lipids like
cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
and
nucleic acid bases, particularly
guanosine
Guanosine (symbol G or Guo) is a purine nucleoside comprising guanine attached to a ribose ( ribofuranose) ring via a β-N9- glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate (GMP), cyclic guanosine monophosphate ...
and
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is c ...
derivatives, with 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 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
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the d ...
). Certain skin cells are somewhat resistant to PDT in the absence of molecular oxygen; further supporting 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 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.
Photosensitizers
Many photosensitizers for PDT exist. They divide into
porphyrin
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
s,
chlorin
In organic chemistry, chlorins are tetrapyrrole pigments that are partially hydrogenated porphyrins. The parent chlorin is an unstable compound which undergoes air oxidation to porphine.
The name chlorin derives from chlorophyll. Chlorophyll ...
s and
dyes.
Examples include
aminolevulinic acid (ALA), Silicon Phthalocyanine Pc 4,
m-tetrahydroxyphenylchlorin (mTHPC) and mono-L-aspartyl
chlorin
In organic chemistry, chlorins are tetrapyrrole pigments that are partially hydrogenated porphyrins. The parent chlorin is an unstable compound which undergoes air oxidation to porphine.
The name chlorin derives from chlorophyll. Chlorophyll ...
e6 (
NPe6).
Photosensitizers commercially available for clinical use include Allumera,
Photofrin,
Visudyne,
Levulan,
Foscan
Temoporfin (INN) is a photosensitizer (based on chlorin) used in photodynamic therapy for the treatment of squamous cell carcinoma of the head and neck
.
It is marketed in the European Union under the brand name Foscan. The U.S. Food and Drug ...
,
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 is the parts of the cell that they target. Unlike in
radiation therapy
Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Radi ...
, 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 chromophores
Cyclic
tetrapyrrolic molecules are
fluorophores
A fluorophore (or fluorochrome, similarly to a chromophore) is a fluorescent chemical compound that can re-emit light upon light excitation. Fluorophores typically contain several combined aromatic groups, or planar or cyclic molecules with sev ...
and photosensitisers. Cyclic tetrapyrrolic derivatives have an inherent similarity to the naturally occurring porphyrins present in living matter.
Porphyrins
Porphyrin
Porphyrins ( ) are a group of heterocyclic macrocycle organic compounds, composed of four modified pyrrole subunits interconnected at their α carbon atoms via methine bridges (=CH−). The parent of porphyrin is porphine, a rare chemical com ...
s 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
Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored i ...
and have applications in fields ranging from fluorescent imaging to medicine. Porphyrins are tetrapyrrolic molecules, with the heart of the skeleton a heterocyclic macrocycle, known as a
porphin
Porphine or porphin is an organic chemical compound with formula . The molecule, which is flat, consists of four pyrrole-like rings joined by four methine (= C H−) groups to form a larger macrocycle ring, which makes it the simplest of the tet ...
e. 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
In organic chemistry, a methine group or methine bridge is a trivalent functional group , derived formally from methane. It consists of a carbon atom bound by two single bonds and one double bond, where one of the single bonds is to a hydrogen. ...
(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 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
Trifluoroacetic acid (TFA) is an organofluorine compound with the chemical formula CF3CO2H. It is a structural analogue of acetic acid with all three of the acetyl group's hydrogen atoms replaced by fluorine atoms and is a colorless liquid with ...
affording a dicationic intermediate. The
tetradentate
In chemistry, tetradentate ligands are ligands that bind four donor atoms to a central atom to form a coordination complex. This number of donor atoms that bind is called denticity and is a method of classifying ligands.
Tetradentate ligands ar ...
anionic species can readily form complexes with most metals.
= Absorption spectroscopy
=
Porphyrin's highly conjugated skeleton produces 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 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).
Ideal photosensitisers
The key characteristic of 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:
* Strong absorption with a high extinction coefficient in the red/near infrared region of the electromagnetic spectrum (600–850 nm)—allows deeper tissue penetration. (Tissue is much more transparent at longer wavelengths (~700–850 nm). Longer wavelengths allow the light to penetrate deeper
and treat larger structures.)
* Suitable photophysical characteristics: a high-quantum yield of triplet formation (ΦT ≥ 0.5); a high singlet oxygen quantum yield (ΦΔ ≥ 0.5); a relatively long triplet state lifetime (''τ''T, μs range); and a high triplet-state energy (≥ 94 kJ mol
−1). Values of ΦT= 0.83 and ΦΔ = 0.65 (haematoporphyrin); ΦT = 0.83 and ΦΔ = 0.72 (etiopurpurin); and ΦT = 0.96 and ΦΔ = 0.82 (tin etiopurpurin) have been achieved
* Low dark toxicity and negligible cytotoxicity in the absence of light. (The photosensitizer should not be harmful to the target tissue until the treatment beam is applied.)
* Preferential accumulation in diseased/target tissue over healthy tissue
* Rapid clearance from the body post-procedure
* High chemical stability: single, well-characterised compounds, with a known and constant composition
* Short and high-yielding synthetic route (with easy translation into multi-gram scales/reactions)
* Simple and stable formulation
* Soluble in biological media, allowing intravenous administration. Otherwise, a hydrophilic delivery system must enable efficient and effective transportation of the photosensitiser to the target site via the bloodstream.
* Low
photobleaching
In optics, photobleaching (sometimes termed fading) is the photochemical alteration of a dye or a fluorophore molecule such that it is permanently unable to fluoresce. This is caused by cleaving of covalent bonds or non-specific reactions between ...
to prevent degradation of the photosensitizer so it can continue producing singlet oxygen
* Natural
fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation. It is a form of luminescence. In most cases, the emitted light has a longer wavelength, and therefore a lower photon energy, tha ...
(Many optical dosimetry techniques, such as
fluorescence spectroscopy
Fluorescence spectroscopy (also known as fluorimetry or spectrofluorometry) is a type of electromagnetic spectroscopy that analyzes fluorescence from a sample. It involves using a beam of light, usually ultraviolet light, that excites the electro ...
, depend on fluorescence.)
First generation
Porfimer Sodium
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 calle
Photofrin
PDT was first discovered more than a century ago in Germany, it was not unti
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 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 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.
Second generation
5-Aminolaevulinic acid
5-Aminolaevulinic acid (ALA) 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
Heme, or haem (pronounced /Help:IPA/English, hi:m/ ), is a precursor (chemistry), precursor to hemoglobin, which is necessary to bind oxygen in the bloodstream. Heme is biosynthesized in both the bone marrow and the liver.
In biochemical terms, ...
.
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
Protoporphyrin IX is an organic compound, classified as a porphyrin, that plays an important role in living organisms as a precursor to other critical compounds like heme (hemoglobin) and chlorophyll. It is a deeply colored solid that is not solu ...
(PPIX), an effective photosensitiser. Haem itself 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
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
and
succinyl coenzyme A
Succinyl-coenzyme A, abbreviated as succinyl-CoA () or SucCoA, is a thioester of succinic acid and coenzyme A.
Sources
It is an important intermediate in the citric acid cycle, where it is synthesized from α-ketoglutarate by α-ketoglutarate d ...
(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 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
Protoporphyrin ferrochelatase (EC 4.98.1.1, formerly EC 4.99.1.1, or ferrochelatase; systematic name protoheme ferro-lyase (protoporphyrin-forming)) is an enzyme encoded by the FECH gene in humans. Ferrochelatase catalyses the eighth and termin ...
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 the treatment of malignant and non-malignant dermatological conditions, including psoriasis,
Bowen's disease
Squamous-cell skin cancer, also known as cutaneous squamous-cell carcinoma (cSCC), is one of the main types of skin cancer along with basal cell cancer and melanoma. It usually presents as a hard lump with a scaly top but can also form an ulcer. O ...
and
Hirsutism
Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a "male" pattern of hair growth in a female that ...
(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 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
In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group () group.
Nomenclature
In IUPAC nomenclature, the prefix benzyl refers to a substi ...
(Benvix) and hexyl ester (
Hexvix) derivatives are used for gastrointestinal cancers and for the diagnosis of bladder cancer.
Verteporfin
Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular dege ...
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 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 is rapidly cleared from the body, minimising patient photosensitivity (1–2 days).
Purlytin
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
Restenosis is the recurrence of stenosis, a narrowing of a blood vessel, leading to restricted blood flow. Restenosis usually pertains to an artery or other large blood vessel that has become narrowed, received treatment to clear the blockage and s ...
.
Chlorins are distinguished from 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 a photoreaction 7–14 days post-administration.
Foscan
Tetra(''m''-hydroxyphenyl)chlorin (''m''THPC) is in clinical trials for head and neck cancers under the trade name
Foscan
Temoporfin (INN) is a photosensitizer (based on chlorin) used in photodynamic therapy for the treatment of squamous cell carcinoma of the head and neck
.
It is marketed in the European Union under the brand name Foscan. The U.S. Food and Drug ...
. 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.
Lutex
Lutetium texaphyrin, marketed under the trade name Lutex and Lutrin, is a large porphyrin-like molecule.
Texaphyrin
Texaphyrin is a sub-class of heterocyclic macrocycle molecules known as porphyrins. The molecule was invented by University of Texas at Austin professor Jonathan Sessler. The name texaphryin arose because some of the molecules have a shape that ...
s 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.
A Lutex derivative, Antrin, has undergone Phase I clinical trials for the prevention of restenosis of vessels after cardiac
angioplasty
Angioplasty, is also known as balloon angioplasty and percutaneous transluminal angioplasty (PTA), is a minimally invasive endovascular procedure used to widen narrowed or obstructed arteries or veins, typically to treat arterial atheroscle ...
by photoinactivating foam cells that accumulate within arteriolar plaques. A second Lutex derivative, Optrin, is in Phase I trials for AMD.
Texaphyrins also have potential as radiosensitisers (
Xcytrin) and chemosensitisers. Xcytrin, a gadolinium texaphyrin (motexafin gadolinium), has been evaluated in Phase III clinical trials against brain metastases and Phase I clinical trials for primary brain tumours.
ATMPn
9-Acetoxy-2,7,12,17-tetrakis-(''β''-methoxyethyl)-porphycene has been evaluated as an agent for dermatological applications against psoriasis vulgaris and superficial non-melanoma skin cancer.
Zinc phthalocyanine
A liposomal formulation of zinc phthalocyanine
CGP55847 has undergone clinical trials (Phase I/II, Switzerland) against squamous cell carcinomas of the upper aerodigestive tract. Phthalocyanines (PCs) are related to tetra-aza porphyrins. Instead of four bridging carbon atoms at the ''meso-''positions, as for the porphyrins, PCs have four nitrogen atoms linking the pyrrolic sub-units. PCs also have an extended conjugate pathway: a
benzene ring
Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atom ...
is fused to the ''β''-positions of each of the four-pyrrolic sub-units. These rings strengthen the absorption of the chromophore at longer wavelengths (with respect to porphyrins). The absorption band of PCs is almost two orders of magnitude stronger than the highest Q band of haematoporphyrin. These favourable characteristics, along with the ability to selectively functionalise their peripheral structure, make PCs favourable photosensitiser candidates.
A sulphonated aluminium PC derivative (Photosense) has entered clinical trials (Russia) against skin, breast and lung malignancies and cancer of the gastrointestinal tract. Sulphonation significantly increases PC solubility in polar solvents including water, circumventing the need for alternative delivery vehicles.
PC4 is a silicon complex under investigation for the sterilisation of blood components against human colon, breast and ovarian cancers and against glioma.
A shortcoming of many of the metallo-PCs is their tendency to aggregate in aqueous buffer (pH 7.4), resulting in a decrease, or total loss, of their photochemical activity. This behaviour can be minimised in the presence of detergents.
Metallated cationic porphyrazines (PZ), including PdPZ
+, CuPZ
+, CdPZ
+, MgPZ
+, AlPZ
+ and GaPZ
+, have been tested ''in vitro'' on V-79 (Chinese hamster lung fibroblast) cells. These photosensitisers display substantial dark toxicity.
Naphthalocyanines
Naphthalocyanines (NCs) are an extended PC derivative. They have an additional benzene ring attached to each
isoindole
In organic chemistry and heterocyclic chemistry, isoindole consists of a benzene ring fused with pyrrole. The compound is an isomer of indole. Its reduced form is isoindoline. The parent isoindole is a rarely encountered in the technical lite ...
sub-unit on the periphery of the PC structure. Subsequently, NCs absorb strongly at even longer wavelengths (approximately 740–780 nm) than PCs (670–780 nm). This absorption in the near infrared region makes NCs candidates for highly pigmented tumours, including melanomas, which present significant absorption problems for visible light.
However, problems associated with NC photosensitisers include lower stability, as they decompose in the presence of light and oxygen. Metallo-NCs, which lack axial ligands, have a tendency to form H-aggregates in solution. These aggregates are photoinactive, thus compromising the photodynamic efficacy of NCs.
Silicon naphthalocyanine attached to copolymer PEG-PCL (poly(ethylene glycol)-''block''-poly(ε-caprolactone)) accumulates selectively in cancer cells and reaches a maximum concentration after about one day. The compound provides real time near-infrared (NIR) fluorescence imaging with an extinction coefficient of 2.8 × 10
5 M
−1 cm
−1 and combinatorial phototherapy with dual photothermal and photodynamic therapeutic mechanisms that may be appropriate for
adriamycin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toget ...
-resistant tumors. The particles had a hydrodynamic size of 37.66 ± 0.26 nm (polydispersity index = 0.06) and surface charge of −2.76 ± 1.83 mV.
Functional groups
Altering the peripheral functionality of porphyrin-type chromophores can affect photodynamic activity.
Diamino platinum porphyrins show high anti-tumour activity, demonstrating the combined effect of the cytotoxicity of the platinum complex and the photodynamic activity of the porphyrin species.
Positively charged PC derivatives have been investigated. Cationic species are believed to selectively localise in the mitochondria.
Zinc and copper cationic derivatives have been investigated. The positively charged zinc complexed PC is less photodynamically active than its neutral counterpart ''in vitro'' against V-79 cells.
Water-soluble cationic porphyrins bearing
nitrophenyl,
aminophenyl,
hydroxyphenyl and/or pyridiniumyl functional groups exhibit varying cytotoxicity to cancer cells ''in vitro'', depending on the nature of the metal ion (Mn, Fe, Zn, Ni) and on the number and type of functional groups. The manganese pyridiniumyl derivative has shown the highest photodynamic activity, while the nickel analogue is photoinactive.
Another metallo-porphyrin complex, the iron chelate, is more photoactive (towards HIV and simian immunodeficiency virus in MT-4 cells) than the manganese complexes; the zinc derivative is photoinactive.
The hydrophilic sulphonated porphyrins and PCs (AlPorphyrin and AlPC) compounds were tested for photodynamic activity. The disulphonated analogues (with adjacent substituted sulphonated groups) exhibited greater photodynamic activity than their di-(symmetrical), mono-, tri- and tetra-sulphonated counterparts; tumour activity increased with increasing degree of sulphonation.
Third generation
Many photosensitisers are poorly soluble in aqueous media, particularly at physiological pH, limiting their use.
Alternate delivery strategies range from the use of oil-in-water (o/w) emulsions to carrier vehicles such as liposomes and nanoparticles. Although these systems may increase therapeutic effects, the carrier system may inadvertently decrease the "observed" singlet oxygen quantum yield (ΦΔ): the singlet oxygen generated by the photosensitiser must diffuse out of the carrier system; and since singlet oxygen is believed to have a narrow radius of action, it may not reach the target cells. The carrier may limit light absorption, reducing singlet oxygen yield.
Another alternative that does not display the scattering problem is the use of
moieties. Strategies include directly attaching photosensitisers to biologically active molecules such as
antibodies.
Metallation
Various metals form into complexes with photosensitiser macrocycles. Multiple second generation photosensitisers contain a chelated central metal ion. The main candidates are
transition metal
In chemistry, a transition metal (or transition element) is a chemical element in the d-block of the periodic table (groups 3 to 12), though the elements of group 12 (and less often group 3) are sometimes excluded. They are the elements that ca ...
s, although photosensitisers co-ordinated to
group 13
The Group 13 network ( pl, Trzynastka, Yiddish: ''דאָס דרײַצענטל'') was a Jewish Nazi collaborationist organization in the Warsaw Ghetto during the German occupation of Poland in World War II. The rise and fall of the Group ...
(Al, AlPcS
4) and
group 14
The carbon group is a periodic table group consisting of carbon (C), silicon (Si), germanium (Ge), tin (Sn), lead (Pb), and flerovium (Fl). It lies within the p-block.
In modern IUPAC notation, it is called group 14. In the field of semicon ...
(Si, SiNC and Sn, SnEt
2) metals have been synthesised.
The metal ion does not confer definite photoactivity on the complex. Copper (II), cobalt (II), iron (II) and zinc (II) complexes of Hp are all photoinactive in contrast to metal-free porphyrins. However,
texaphyrin
Texaphyrin is a sub-class of heterocyclic macrocycle molecules known as porphyrins. The molecule was invented by University of Texas at Austin professor Jonathan Sessler. The name texaphryin arose because some of the molecules have a shape that ...
and PC photosensitisers do not contain metals; only the metallo-complexes have demonstrated efficient photosensitisation.
The central metal ion, bound by a number of photosensitisers, strongly influences the photophysical properties of the photosensitiser. Chelation of paramagnetic metals to a PC chromophore appears to shorten triplet lifetimes (down to nanosecond range), generating variations in the triplet quantum yield and triplet lifetime of the photoexcited triplet state.
Certain heavy metals are known to enhance inter-system crossing (ISC). Generally, diamagnetic metals promote ISC and have a long triplet lifetime. In contrast, paramagnetic species deactivate excited states, reducing the excited-state lifetime and preventing photochemical reactions. However, exceptions to this generalisation include copper octaethylbenzochlorin.
Many metallated paramagnetic texaphyrin species exhibit triplet-state lifetimes in the nanosecond range. These results are mirrored by metallated PCs. PCs metallated with diamagnetic ions, such as Zn
2+, Al
3+ and Ga
3+, generally yield photosensitisers with desirable quantum yields and lifetimes (ΦT 0.56, 0.50 and 0.34 and ''τ''T 187, 126 and 35 ''μ''s, respectively). Photosensitiser ZnPcS
4 has a singlet oxygen quantum yield of 0.70; nearly twice that of most other mPCs (ΦΔ at least 0.40).
Expanded metallo-porphyrins
Expanded porphyrins have a larger central binding cavity, increasing the range of potential metals.
Diamagnetic metallo-texaphyrins have shown photophysical properties; high triplet quantum yields and efficient generation of singlet oxygen. In particular, the zinc and cadmium derivatives display triplet quantum yields close to unity. In contrast, the paramagnetic metallo-texaphyrins, Mn-Tex, Sm-Tex and Eu-Tex, have undetectable triplet quantum yields. This behaviour is parallel with that observed for the corresponding metallo-porphyrins.
The cadmium-texaphyrin derivative has shown ''in vitro'' photodynamic activity against human leukemia cells and
Gram positive
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
Gram-positive bact ...
(''
Staphylococcus'') and
Gram negative
The gram (originally gramme; SI unit symbol g) is a unit of mass in the International System of Units (SI) equal to one one thousandth of a kilogram.
Originally defined as of 1795 as "the absolute weight of a volume of pure water equal to th ...
(''
Escherichia coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus '' Esc ...
'') bacteria. Although follow-up studies have been limited with this photosensitiser due to the toxicity of the complexed cadmium ion.
A zinc-metallated ''seco''-
porphyrazine
Porphyrazines, or tetraazaporphyrins, are tetrapyrrole macrocycles similar to porphyrins and phthalocyanines. Pioneered by Sir R. Patrick Linstead as an extension of his work on phthalocyanines, porphyrazines differ from porphyrins in that they c ...
has a high quantum singlet oxygen yield (ΦΔ 0.74). This expanded porphyrin-like photosensitiser has shown the best singlet oxygen photosensitising ability of any of the reported ''seco-''porphyrazines. Platinum and palladium derivatives have been synthesised with singlet oxygen quantum yields of 0.59 and 0.54, respectively.
Metallochlorins/bacteriochlorins
The tin (IV) purpurins are more active when compared with analogous zinc (II) purpurins, against human cancers.
Sulphonated benzochlorin derivatives demonstrated a reduced phototherapeutic response against murine leukemia
L1210 L1210 is a mouse lymphocytic leukemia cell line which is derived from the ascitic fluid of 8-month-old female DBA/2 strain mice. While they are lymphocytic B-cells they are more like lymphoblasts in morphology, develop massive tumours in nude mice ...
cells ''in vitro'' and transplanted urothelial cell carcinoma in rats, whereas the tin (IV) metallated benzochlorins exhibited an increased photodynamic effect in the same tumour model.
Copper octaethylbenzochlorin demonstrated greater photoactivity towards leukemia cells ''in vitro'' and a rat bladder tumour model. It may derive from interactions between the cationic
iminium
In organic chemistry, an iminium cation is a polyatomic ion with the general structure . They are common in synthetic chemistry and biology.
Structure
Iminium cations adopt alkene-like geometries. The central C=N unit is nearly coplanar with al ...
group and biomolecules. Such interactions may allow electron-transfer reactions to take place via the short-lived excited singlet state and lead to the formation of radicals and radical ions. The copper-free derivative exhibited a tumour response with short intervals between drug administration and photodynamic activity. Increased ''in vivo'' activity was observed with the zinc benzochlorin analogue.
Metallo-phthalocyanines
PCs properties are strongly influenced by the central metal ion. Co-ordination of transition metal ions gives metallo-complexes with short triplet lifetimes (nanosecond range), resulting in different triplet quantum yields and lifetimes (with respect to the non-metallated analogues). Diamagnetic metals such as zinc, aluminium and gallium, generate metallo-phthalocyanines (MPC) with high triplet quantum yields (ΦT ≥ 0.4) and short lifetimes (ZnPCS
4 ''τ''T = 490 Fs and AlPcS4 ''τ''T = 400 Fs) and high singlet oxygen quantum yields (ΦΔ ≥ 0.7). As a result, ZnPc and AlPc have been evaluated as second generation photosensitisers active against certain tumours.
Metallo-naphthocyaninesulfobenzo-porphyrazines (M-NSBP)
Aluminium (Al
3+) has been successfully coordinated to M-NSBP. The resulting complex showed photodynamic activity against EMT-6 tumour-bearing Balb/c mice (disulphonated analogue demonstrated greater photoactivity than the mono-derivative).
Metallo-naphthalocyanines
Work with zinc NC with various amido substituents revealed that the best phototherapeutic response (
Lewis lung carcinoma in mice) with a tetrabenzamido analogue. Complexes of silicon (IV) NCs with two axial ligands in anticipation the ligands minimise aggregation. Disubstituted analogues as potential photodynamic agents (a siloxane NC substituted with two methoxyethyleneglycol ligands) are an efficient photosensitiser against Lewis lung carcinoma in mice. SiNC
2-n-C18H37">Si(i-Bu)2-n-C18H37sub>2 is effective against Balb/c mice MS-2 fibrosarcoma cells. Siloxane NCs may be efficacious photosensitisers against EMT-6 tumours in Balb/c mice. The ability of metallo-NC derivatives (AlNc) to generate singlet oxygen is weaker than the analogous (sulphonated) metallo-PCs (AlPC); reportedly 1.6–3 orders of magnitude less.
In porphyrin systems, the zinc ion (Zn
2+) appears to hinder the photodynamic activity of the compound. By contrast, in the higher/expanded ''π''-systems, zinc-chelated dyes form complexes with good to high results.
An extensive study of metallated texaphyrins focused on the lanthanide (III) metal ions, Y, In, Lu, Cd, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm and Yb found that when diamagnetic Lu (III) was complexed to texaphyrin, an effective photosensitiser (Lutex) was generated. However, using the paramagnetic Gd (III) ion for the Lu metal, exhibited no photodynamic activity. The study found a correlation between the excited-singlet and triplet state lifetimes and the rate of ISC of the diamagnetic texaphyrin complexes, Y(III), In (III) and Lu (III) and the atomic number of the cation.
Paramagnetic metallo-texaphyrins displayed rapid ISC. Triplet lifetimes were strongly affected by the choice of metal ion. The diamagnetic ions (Y, In and Lu) displayed triplet lifetimes ranging from 187, 126 and 35 ''μ''s, respectively. Comparable lifetimes for the paramagnetic species (Eu-Tex 6.98 ''μ''s, Gd-Tex 1.11, Tb-Tex < 0.2, Dy-Tex 0.44 × 10−3, Ho-Tex 0.85 × 10−3, Er-Tex 0.76 × 10−3, Tm-Tex 0.12 × 10−3 and Yb-Tex 0.46) were obtained.
Three measured paramagnetic complexes measured significantly lower than the diamagnetic metallo-texaphyrins.
In general, singlet oxygen quantum yields closely followed the triplet quantum yields.
Various diamagnetic and paramagnetic texaphyrins investigated have independent photophysical behaviour with respect to a complex's magnetism. The diamagnetic complexes were characterised by relatively high fluorescence quantum yields, excited-singlet and triplet lifetimes and singlet oxygen quantum yields; in distinct contrast to the paramagnetic species.
The +2 charged diamagnetic species appeared to exhibit a direct relationship between their fluorescence quantum yields, excited state lifetimes, rate of ISC and the atomic number of the metal ion. The greatest diamagnetic ISC rate was observed for Lu-Tex; a result ascribed to the heavy atom effect. The heavy atom effect also held for the Y-Tex, In-Tex and Lu-Tex triplet quantum yields and lifetimes. The triplet quantum yields and lifetimes both decreased with increasing atomic number. The singlet oxygen quantum yield correlated with this observation.
Photophysical properties displayed by paramagnetic species were more complex. The observed data/behaviour was not correlated with the number of unpaired electrons located on the metal ion. For example:
* ISC rates and the fluorescence lifetimes gradually decreased with increasing atomic number.
* Gd-Tex and Tb-Tex chromophores showed (despite more unpaired electrons) slower rates of ISC and longer lifetimes than Ho-Tex or Dy-Tex.
To achieve selective target cell destruction, while protecting normal tissues, either the photosensitizer can be applied locally to the target area, or targets can be locally illuminated. Skin conditions, including
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
,
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...
and also
skin cancer
Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
s, can be treated topically and locally illuminated. For internal tissues and cancers, intravenously administered photosensitizers can be illuminated using
endoscopes
An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are inse ...
and
fiber optic
An optical fiber, or optical fibre in Commonwealth English, is a flexible, transparent fiber made by drawing glass (silica) or plastic to a diameter slightly thicker than that of a human hair. Optical fibers are used most often as a means t ...
catheters
In medicine, a catheter (/ˈkæθətər/) is a thin tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. Cat ...
.
Photosensitizers can target viral and microbial species, including
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
and
MRSA
Methicillin-resistant ''Staphylococcus aureus'' (MRSA) is a group of Gram-positive bacteria that are genetically distinct from other strains of ''Staphylococcus aureus''. MRSA is responsible for several difficult-to-treat infections in humans. ...
.
Using PDT, pathogens present in samples of blood and
bone marrow can be decontaminated before the samples are used further for transfusions or transplants. PDT can also eradicate a wide variety of pathogens of the skin and of the oral cavities. Given the seriousness that drug resistant pathogens have now become, there is increasing research into PDT as a new antimicrobial therapy.
Applications
Acne
PDT is currently in clinical trials as a treatment for severe
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...
. Initial results have shown for it to be effective as a treatment only for severe acne. A systematic review conducted in 2016 found that PDT is a "safe and effective method of treatment" for acne. The treatment may cause severe redness and moderate to severe pain and burning sensation in some people. ''(see also:
Levulan)'' One phase II trial, while it showed improvement, was not superior to blue/violet light alone.
Cancer
The FDA has approved photodynamic therapy to treat: actinic keratosis, advanced cutaneous T-cell lymphoma, Barrett esophagus, basal cell skin cancer, esophageal (throat) cancer, non-small cell lung cancer, squamous cell skin cancer (Stage 0). Photodynamic therapy is also used to relieve symptoms of some cancers, including: esophageal cancer when it blocks the throat and non-small cell lung cancer when it blocks the airways.
When cells that have absorbed photosensitizers are exposed to a specific wavelength of light, the photosensitizer produces a form of oxygen, called an oxygen radical, that kills them.Photodynamic therapy (PDT) may also damage blood vessels in the tumor, which prevents it from receiving the blood it needs to keep growing. PDT may trigger the immune system to attack tumor cells, even in other areas of the body.
PDT is a minimally invasive treatment that is used to treat many conditions including: acne, psoriasis, age related macular degeneration, and several cancers such as skin, lung, brain, mesothelioma, bladder, bile-duct, esophageal, and head and neck cancers.
How photodynamic therapy treats cancer: When cells that have absorbed photosensitizers are exposed to a specific wavelength of light, the photosensitizer produces an oxygen radical, that kills them.
Photodynamic therapy may also damage blood vessels in the tumor, which prevents it from receiving the blood it needs to keep growing. PDT may trigger the immune system to attack tumor cells, even in other areas of the body.
In February 2019, medical scientists announced that
iridium
Iridium is a chemical element with the symbol Ir and atomic number 77. A very hard, brittle, silvery-white transition metal of the platinum group, it is considered the second-densest naturally occurring metal (after osmium) with a density of ...
attached to
albumin
Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water-soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Albumins ...
, creating a
photosensitized molecule, can penetrate
cancer cells and, after being irradiated with light, destroy the cancer cells.
Ophthalmology
As cited above, verteporfin was widely approved for the treatment of wet AMD beginning in 1999. The drug targets the neovasculature that is caused by the condition.
Photoimmunotherapy
Photoimmunotherapy
Photoimmunotherapy (PIT) is an oncological treatment that combines photodynamic therapy of tumor with immunotherapy treatment. Combining photodynamic therapy with immunotherapy enhances the immunostimulating response and has synergistic effects for ...
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.
Vascular targeting
Some photosensitisers naturally accumulate in the
endothelial cells of
vascular tissue
Vascular tissue is a complex conducting tissue, formed of more than one cell type, found in vascular plants. The primary components of vascular tissue are the xylem and phloem. These two tissues transport fluid and nutrients internally. The ...
allowing 'vascular targeted' PDT.
Verteporfin
Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular dege ...
was shown to target the neovasculature resulting from macular degeneration in the macula within the first thirty minutes after intravenous administration of the drug.
Compared to normal tissues, most types of cancers are especially active in both the uptake and accumulation of photosensitizers agents, which makes cancers especially vulnerable to PDT.
[
]
Since photosensitizers can also have a high affinity for
vascular
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
endothelial cells.
[
]
Antimicrobial Photodynamic Therapy (aPDT) or Photodisinfection
Numerous studies and literature reviews have found that photodynamic disinfection is effective at killing a broad spectrum of pathogens, including drug-resistant bacteria, viruses, and fungi, while also inactivating inflammatory cytokines, helping speed the process of healing. Photodynamic disinfection remains fully effective after many repeat treatments, showing no sign of engendering resistance formation. aPDT can effectively treat CRS polymicrobial antibiotic resistant Pseudomonas aeruginosa and MRSA biofilms in a maxillary sinus cavity model.
Some photosensitizers have been chemically modified to incorporate into the mycomembrane of mycobacteria. These molecules show promising in vitro activity and are potential candidates for targeted delivery of photosensitizers.
Furthermore, antibacterial photodynamic therapy has the potential to kill multidrug-resistant pathogenic bacteria very effectively and is recognized for its low potential to induce drug resistance in bacteria, which can be rapidly developed against traditional antibiotic therapy.
Antitumor Vaccines
Preclinical studies have shown that photodynamic therapy (PDT) of tumors augments the host antitumor immune response. However, the role of the PDT effect on tumor cells as opposed to the host tissues has not been determined. Research shows that the PDT-generated tumor cell lysates were potent vaccines and that PDT-generated vaccines may be more effective than other modes of creating whole tumor vaccines. PDT vaccines are tumor specific and appear to induce a cytotoxic T-cell response. Results show that PDT effects on tumor cells alone are sufficient to generate an antitumor immune response, indicating that the direct tumor effects of PDT play an important role in enhancing that host antitumor immune response. Studies also suggest that PDT-generated vaccines may have clinical potential as an adjuvant therapy.
History
Modern era
In the late nineteenth century. Finsen successfully demonstrated phototherapy by employing heat-filtered light from a
carbon-arc lamp (the "Finsen lamp") in the treatment of a tubercular condition of the skin known as ''
lupus vulgaris
Lupus vulgaris (also known as tuberculosis luposa) are painful cutaneous tuberculosis skin lesions with nodular appearance, most often on the face around the nose, eyelids, lips, cheeks, ears and neck. It is the most common ''Mycobacterium tuberc ...
'', for which he won the 1903
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accord ...
.
In 1913 another German scientist, Meyer-Betz, described the major stumbling block of photodynamic therapy. After injecting himself with haematoporphyrin (Hp, a photosensitiser), he swiftly experienced a general skin sensitivity upon exposure to sunlight—a recurrent problem with many photosensitisers.
The first evidence that agents, photosensitive synthetic dyes, in combination with a light source and oxygen could have potential therapeutic effect was made at the turn of the 20th century in the laboratory of
Hermann von Tappeiner in Munich, Germany. Germany was leading the world in industrial dye synthesis at the time.
While studying the effects of
acridine
Acridine is an organic compound and a nitrogen heterocycle with the formula C13H9N. Acridines are substituted derivatives of the parent ring. It is a planar molecule that is structurally related to anthracene with one of the central CH groups re ...
on
paramecia cultures, Oscar Raab, a student of von Tappeiner observed a toxic effect. Fortuitously Raab also observed that light was required to kill the paramecia. Subsequent work in von Tappeiner's laboratory showed that oxygen was essential for the 'photodynamic action' – a term coined by von Tappeiner.
Von Tappeiner and colleagues performed the first PDT trial in patients with skin carcinoma using the photosensitizer,
eosin
Eosin is the name of several fluorescent acidic compounds which bind to and form salts with basic, or eosinophilic, compounds like proteins containing amino acid residues such as arginine and lysine, and stains them dark red or pink as a resul ...
. Of six patients with a facial
basal cell carcinoma
Basal-cell carcinoma (BCC), also known as basal-cell cancer, is the most common type of skin cancer. It often appears as a painless raised area of skin, which may be shiny with small blood vessels running over it. It may also present as a raise ...
, treated with a 1% eosin solution and long-term exposure either to sunlight or arc-lamp light, four patients showed total tumour resolution and a relapse-free period of 12 months.
In 1924 Policard revealed the diagnostic capabilities of hematoporphyrin fluorescence when he observed that
ultraviolet radiation
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
excited red fluorescence in the
sarcomas
A sarcoma is a malignant tumor, a type of cancer that arises from transformed cells of mesenchymal (connective tissue) origin. Connective tissue is a broad term that includes bone, cartilage, fat, vascular, or hematopoietic tissues, and sarco ...
of laboratory rats. Policard hypothesized that the fluorescence was associated with endogenous hematoporphyrin accumulation.
In 1948 Figge and co-workers showed on laboratory animals that porphyrins exhibit a preferential affinity to rapidly dividing cells, including malignant, embryonic and regenerative cells. They proposed that porphyrins could be used to treat cancer.
Photosensitizer
Haematoporphyrin Derivative (HpD), was first characterised in 1960 by Lipson. Lipson sought a diagnostic agent suitable for tumor detection. HpD allowed Lipson to pioneer the use of
endoscopes
An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are inse ...
and HpD fluorescence. HpD is a porphyrin species derived from haematoporphyrin, Porphyrins have long been considered as suitable agents for tumour photodiagnosis and tumour PDT because cancerous cells exhibit significantly greater uptake and affinity for porphyrins compared to normal tissues. This had been observed by other researchers prior to Lipson.
Thomas Dougherty and co-workers at
Roswell Park Comprehensive Cancer Center
Roswell Park Comprehensive Cancer Center is a cancer research and treatment center located in Buffalo, New York. Founded by surgeon Roswell Park in 1898, the center was the first in the United States to specifically focus on cancer research. The ...
in
Buffalo, New York
Buffalo is the second-largest city in the U.S. state of New York (behind only New York City) and the seat of Erie County. It is at the eastern end of Lake Erie, at the head of the Niagara River, and is across the Canadian border from Sou ...
, clinically tested PDT in 1978. They treated 113 cutaneous or subcutaneous malignant tumors with HpD and observed total or partial resolution of 111 tumors. Dougherty helped expand clinical trials and formed the International Photodynamic Association, in 1986.
John Toth, product manager for Cooper Medical Devices Corp/Cooper Lasersonics, noticed the "photodynamic chemical effect" of the therapy and wrote the first white paper naming the therapy "Photodynamic Therapy" (PDT) with early clinical argon dye lasers circa 1981. The company set up 10 clinical sites in Japan where the term "radiation" had negative connotations.
HpD, under the brand name
Photofrin, was the first PDT agent approved for clinical use in 1993 to treat a form of bladder cancer in Canada. Over the next decade, both PDT and the use of HpD received international attention and greater clinical acceptance and led to the first PDT treatments approved by U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
Japan and parts of Europe for use against certain cancers of the oesophagus and non-small cell lung cancer.
Photofrin had the disadvantages of prolonged patient photosensitivity and a weak long-wavelength absorption (630 nm). This led to the development of second generation photosensitisers, including
Verteporfin
Verteporfin (trade name Visudyne), a benzoporphyrin derivative, is a medication used as a photosensitizer for photodynamic therapy to eliminate the abnormal blood vessels in the eye associated with conditions such as the wet form of macular dege ...
(a
benzoporphyrin derivative, also known as Visudyne) and more recently, third generation targetable photosensitisers, such as antibody-directed photosensitisers.
In the 1980s, David Dolphin, Julia Levy and colleagues developed a novel photosensitizer, verteporfin. Verteporfin, a porphyrin derivative, is activated at 690 nm, a much longer wavelength than Photofrin. It has the property of preferential uptake by neovasculature. It has been widely tested for its use in treating skin cancers and received FDA approval in 2000 for the treatment of wet age related macular degeneration. As such it was the first medical treatment ever approved for this condition, which is a major cause of vision loss.
Russian scientists pioneered a photosensitizer called Photogem which, like HpD, was derived from haematoporphyrin in 1990 by Mironov and coworkers. Photogem was approved by the Ministry of Health of Russia and tested clinically from February 1992 to 1996. A pronounced therapeutic effect was observed in 91 percent of the 1500 patients. 62 percent had total tumor resolution. A further 29 percent had >50% tumor shrinkage. In early diagnosis patients 92 percent experienced complete resolution.
[
]
Russian scientists collaborated with NASA scientists who were looking at the use of LEDs as more suitable light sources, compared to lasers, for PDT applications.
Since 1990, the Chinese have been developing clinical expertise with PDT, using domestically produced photosensitizers, derived from Haematoporphyrin. China is notable for its expertise in resolving difficult-to-reach tumours.
Photodynamic and photobiology organizations
International Photodynamic Association (IPA)*
American Society for Photobiology (ASP)
PanAmerican PDT Association
European Society for Photobiology (ESP)
Notable PDT researchers
* Heidi Abrahamse
* Stephen Bown
Thomas Doughertyref name=":1" />
* Sandra Gollnick
* Colin Hopper
* David Kessel
* Herwig Kostron
*
Tayyaba Hasan
* Barbara Henderson
* Harubumi Kato
*
Julia Levy
*
Tebello Nyokong
Miscellany
PUVA therapy
PUVA (psoralen and UVA) is an ultraviolet light therapy treatment for skin diseases: eczema, psoriasis, graft-versus-host disease, vitiligo, mycosis fungoides, large plaque parapsoriasis, and cutaneous T-cell lymphoma, using the sensitizing ef ...
uses
psoralen
Psoralen (also called psoralene) is the parent compound in a family of naturally occurring organic compounds known as the linear furanocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered ...
as photosensitiser and UVA
ultraviolet
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation ...
as light source, but this form of therapy is usually classified as a separate form of therapy from photodynamic therapy.
To allow treatment of deeper tumours some researchers are using internal
chemiluminescence to activate the photosensitiser.
See also
*
Blood irradiation therapy
Blood irradiation therapy is an alternative medical procedure in which the blood is exposed to low level light (often laser light) for therapeutic reasons. The practice was originally developed in the United States, but most recent research on i ...
*
Laser medicine
Laser medicine consists in the use of lasers in medical diagnosis, treatments, or therapies, such as laser photodynamic therapy, photorejuvenation, and laser surgery.
Lasers
Lasers used in medicine include in principle any type of laser, bu ...
*
Light Harvesting Materials
*
Photoimmunotherapy
Photoimmunotherapy (PIT) is an oncological treatment that combines photodynamic therapy of tumor with immunotherapy treatment. Combining photodynamic therapy with immunotherapy enhances the immunostimulating response and has synergistic effects for ...
*
Photomedicine
*
Photopharmacology
Photopharmacology, an emerging approach in medicine, involves activating and deactivating photoswitchable molecules with light for target drug delivery. Clinicians use the energy of light to change the shape and chemical properties of a drug, res ...
*
Photostatin Photostatins are inhibitors that can be switched on and off ''in vivo'' by visible light, to optically control microtubule dynamics. Photostatins are a form of photopharmacology.
As a cell prepares to divide, its microtubules, arrange themselves ...
*
Sonodynamic therapy
Sonodynamic therapy (SDT) is a noninvasive treatment, often used for tumor irradiation, that utilizes a sonosensitizer and the deep penetration of ultrasound to treat lesions of varying depths by reducing target cell number and preventing future t ...
*
Photosensitizer
Photosensitizers produce a physicochemical change in a neighboring molecule by either donating an electron to the substrate or by abstracting a hydrogen atom from the substrate. At the end of this process, the photosensitizer eventually returns t ...
*
Nanodumbbells, being studied for possible use in photodynamic therapy
References
External links
International Photodynamic AssociationPhotodynamic Therapy for Cancerfrom the NCI
{{DEFAULTSORT:Photodynamic Therapy
Cancer treatments
Medical physics
Laser medicine
Light therapy