Photodynamic therapy

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Photodynamic therapy
Close up of surgeons' hands in an operating room with a beam of light traveling along fiber optics for photodynamic therapy. Its source is a laser beam which is split at two different stages to create the proper therapeutic wavelength. A patient is given a photosensitive drug that is absorbed by cancer cells. During the surgery, the light beam is positioned at the tumor site, which then activates the drug that kills the cancer cells, thus photodynamic therapy (PDT).
Other names	photochemotherapy

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 popularly used in treating acne. It is used clinically to treat a wide range of medical conditions, including wet age-related macular degeneration, psoriasis, atherosclerosis and has shown some efficacy in anti-viral treatments, including herpes. It also treats malignant cancers 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 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, 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 a substrate molecule and highly reactive state of oxygen known as singlet oxygen (Type II).

PDT is a multi-stage process. First a photosensitiser with negligible dark toxicity is administered, either systemically or topically, in the absence of light. 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.

Reactive oxygen species

In air and tissue, molecular oxygen (O₂) 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 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 (³O₂) and produce radicals and reactive oxygen species (ROS), crucial to the Type II mechanism. These species include singlet oxygen (¹O₂), hydroxyl radicals (•OH) and superoxide (O₂⁻) 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 electrons is promoted into a higher-energy orbital, elevating the chromophore from the ground state (S0) into a short-lived, electronically excited state (Sn) composed of vibrational sub-levels (Sn′). 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 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 (τfl. = 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 (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, 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 (³O₂, 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 (O₂), generating a mixture of oxygen intermediates. For example, the photosensitiser radical anion can react instantaneously with molecular oxygen (³O₂) to generate a superoxide radical anion (O₂•⁻), 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 a complex mixture of reactive oxygen intermediates, including reactive peroxides.

Type-II processes

Type-II processes involve the direct interaction of the excited triplet state photosensitiser (3Psen*) with ground state molecular oxygen (³O₂, 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 ³O₂ →¹O₂). This inverts the spin of one oxygen molecule's (³O₂) 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 H₂O/D₂O) 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 (¹O₂) 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 residues in proteins, such as tryptophan; unsaturated lipids like cholesterol and nucleic acid bases, particularly guanosine and guanine 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). 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 τT 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 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 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 chromophores

Cyclic tetrapyrrolic molecules are fluorophores and photosensitisers. Cyclic tetrapyrrolic derivatives have an inherent similarity to the naturally occurring porphyrins present in living matter.

Porphyrins

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 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 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.

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 (τT, 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 to prevent degradation of the photosensitizer so it can continue producing singlet oxygen
• Natural fluorescence (Many optical dosimetry techniques, such as fluorescence spectroscopy, depend on fluorescence.)

First generation

Disadvantages associated with first generation photosensitisers HpD and Photofrin (skin sensitivity and weak 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.

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 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 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 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 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 the diagnosis of bladder cancer.

Verteporfin

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 (λmax. = 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.

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, λmax.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 (mTHPC) 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.

Lutex

Lutetium texaphyrin, marketed under 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.

A Lutex derivative, Antrin, has undergone Phase I clinical trials for the prevention of restenosis of vessels after cardiac angioplasty 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 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 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 × 10⁵ M⁻¹ cm⁻¹ and combinatorial phototherapy with dual photothermal and photodynamic therapeutic mechanisms that may be appropriate for adriamycin-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 metals, although photosensitisers co-ordinated to group 13 (Al, AlPcS₄) and group 14 (Si, SiNC and Sn, SnEt₂) 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 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 Zn²⁺, Al³⁺ and Ga³⁺, generally yield photosensitisers with desirable quantum yields and lifetimes (ΦT 0.56, 0.50 and 0.34 and τT 187, 126 and 35 μs, respectively). Photosensitiser ZnPcS₄ 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 (Staphylococcus) and Gram negative (Escherichia coli) 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 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 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 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 (ZnPCS₄ τT = 490 Fs and AlPcS4 τT = 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 (Al³⁺) 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[OSi(i-Bu)₂-n-C₁₈H₃₇]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 (Zn²⁺) 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 μs, respectively. Comparable lifetimes for the paramagnetic species (Eu-Tex 6.98 μs, 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, psoriasis and also skin cancers, can be treated topically and locally illuminated. For internal tissues and cancers, intravenously administered photosensitizers can be illuminated using endoscopes and fiber optic catheters.

Photosensitizers can target viral and microbial species, including HIV and MRSA.^[16] 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. 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

In February 2019, medical scientists announced that iridium attached to albumin, 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 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 allowing 'vascular targeted' PDT.

Verteporfin 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 endothelial cells.

Antimicrobial Photodynamic Therapy

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.

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, for which he won the 1903 Nobel Prize in Physiology or Medicine.

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 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. Of 6 patients with a facial basal cell carcinoma, treated with a 1% eosin solution and long-term exposure either to sunlight or arc-lamp light, 4 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 excited red fluorescence in the sarcomas 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 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 in Buffalo, New York, 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 Japa 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 (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 Archived 2017-12-30 at the Wayback Machine
• European Society for Photobiology (ESP)

Miscellany

PUVA therapy uses psoralen as photosensitiser and UVA ultraviolet 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.

Photoelectrochemistry

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Photoelectrochemistry 

Photoelectrochemistry is a subfield of study within physical chemistry concerned with the interaction of light with electrochemical systems. It is an active domain of investigation. One of the pioneers of this field of electrochemistry was the German electrochemist Heinz Gerischer. The interest in this domain is high in the context of development of renewable energy conversion and storage technology.

Historical approach

Photoelectrochemistry has been intensively studied in the 70-80s because of the first peak oil crisis. Because fossil fuels are non-renewable, it is necessary to develop processes to obtain renewable resources and use clean energy. Artificial photosynthesis, photoelectrochemical water splitting and regenerative solar cells are of special interest in this context. Discovered by Alexander Edmund Becquerel.

H. Gerischer, H. Tributsch, AJ. Nozik, AJ. Bard, A. Fujishima, K. Honda, PE. Laibinis, K. Rajeshwar, TJ Meyer, PV. Kamat, N.S. Lewis, R. Memming, JOM. Bockris are researchers which have contributed a lot to the field of photoelectrochemistry.

Semiconductor electrochemistry

Introduction

Semiconductor materials have energy band gaps, and will generate a pair of electron and hole for each absorbed photon if the energy of the photon is higher than the band gap energy of the semiconductor. This property of semiconductor materials has been successfully used to convert solar energy into electrical energy by photovoltaic devices.

In photocatalysis the electron-hole pair is immediately used to drive a redox reaction. However, the electron-hole pairs suffer from fast recombination. In photoelectrocatalysis, a differential potential is applied to diminish the number of recombinations between the electrons and the holes. This allows an increase in the yield of light's conversion into chemical energy.

Semiconductor-electrolyte interface

When a semiconductor comes into contact with a liquid (redox species), to maintain electrostatic equilibrium, there will be a charge transfer between the semiconductor and liquid phase if formal redox potential of redox species lies inside semiconductor band gap. At thermodynamic equilibrium, the Fermi level of semiconductor and the formal redox potential of redox species are aligned at the interface between semiconductor and redox species. This introduces an upward band bending in a n-type semiconductor for n-type semiconductor/liquid junction (Figure 1(a)) and an downward band bending in a p-type semiconductor for a p-type semiconductor/liquid junction (Figure 1(b)). This characteristic of semiconductor/liquid junctions is similar to a rectifying semiconductor/metal junction or Schottky junction. Ideally to get a good rectifying characteristics at the semiconductor/liquid interface, the formal redox potential must be close to the valence band of the semiconductor for a n-type semiconductor and close to the conduction band of the semiconductor for a p-type semiconductor. The semiconductor/liquid junction has one advantage over the rectifying semiconductor/metal junction in that the light is able to travel through to the semiconductor surface without much reflection; whereas most of the light is reflected back from the metal surface at a semiconductor/metal junction. Therefore, semiconductor/liquid junctions can also be used as photovoltaic devices similar to solid state p–n junction devices. Both n-type and p-type semiconductor/liquid junctions can be used as photovoltaic devices to convert solar energy into electrical energy and are called photoelectrochemical cells. In addition, a semiconductor/liquid junction could also be used to directly convert solar energy into chemical energy by virtue of photoelectrolysis at the semiconductor/liquid junction.

• 

  Figure 1(a) band diagram of n-type semiconductor/liquid junction

• 

  Figure 1(b) band diagram of p-type semiconductor/liquid junction

Experimental setup

Semiconductors are usually studied in a photoelectrochemical cell. Different configurations exist with a three electrode device. The phenomenon to study happens at the working electrode WE while the differential potential is applied between the WE and a reference electrode RE (saturated calomel, Ag/AgCl). The current is measured between the WE and the counter electrode CE (carbon vitreous, platinum gauze). The working electrode is the semiconductor material and the electrolyte is composed of a solvent, an electrolyte and a redox specie.

A UV-vis lamp is usually used to illuminate the working electrode. The photoelectrochemical cell is usually made with a quartz window because it does not absorb the light. A monochromator can be used to control the wavelength sent to the WE.

Main absorbers used in photoelectrochemistry

Semiconductor IV

C(diamond), Si, Ge, SiC, SiGe

Semiconductor III-V

BN, BP, BAs, AlN, AlP, AlAs, GaN, GaP, GaAs, InN, InP, InAs...

Semiconductor II-VI

CdS, CdSe, CdTe, ZnO, ZnS, ZnSe, ZnTe, MoS₂, MoSe₂, MoTe₂, WS₂, WSe₂

Metal oxides

TiO₂, Fe₂O₃, Cu₂O

Organic dyes

Methylene blue...

Organometallic dyes

Perovskites

Applications

Photoelectrochemical splitting of water

Photoelectrochemistry has been intensively studied in the field of hydrogen production from water and solar energy. The photoelectrochemical splitting of water was historically discovered by Fujishima and Honda in 1972 onto TiO₂ electrodes. Recently many materials have shown promising properties to split efficiently water but TiO₂ remains cheap, abundant, stable against photo-corrosion. The main problem of TiO₂ is its bandgap which is 3 or 3.2 eV according to its crystallinity (anatase or rutile). These values are too high and only the wavelength in the UV region can be absorbed. To increase the performances of this material to split water with solar wavelength, it is necessary to sensitize the TiO₂. Currently Quantum Dots sensitization is very promising but more research is needed to find new materials able to absorb the light efficiently.

Artificial photosynthesis

Photosynthesis is the natural process that converts CO₂ using light to produce hydrocarbon compounds such as sugar. The depletion of fossil fuels encourages scientists to find alternatives to produce hydrocarbon compounds. Artificial photosynthesis is a promising method mimicking the natural photosynthesis to produce such compounds. The photoelectrochemical reduction of CO2 is much studied because of its worldwide impact. Many researchers aim to find new semiconductors to develop stable and efficient photo-anodes and photo-cathodes.

Regenerative cells or Dye-sensitized solar cell (Graetzel cell)

Dye-sensitized solar cells or DSSCs use TiO₂ and dyes to absorb the light. This absorption induces the formation of electron-hole pairs which are used to oxidize and reduce the same redox couple, usually I⁻/I₃⁻. Consequently, a differential potential is created which induces a current.

Artificial photosynthesis

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Artificial_photosynthesis 

Artificial photosynthesis is a chemical process that biomimics the natural process of photosynthesis to convert sunlight, water, and carbon dioxide into carbohydrates and oxygen. The term artificial photosynthesis is commonly used to refer to any scheme for capturing and storing the energy from sunlight in the chemical bonds of a fuel (a solar fuel). Photocatalytic water splitting converts water into hydrogen and oxygen and is a major research topic of artificial photosynthesis. Light-driven carbon dioxide reduction is another process studied that replicates natural carbon fixation.

Research on this topic includes the design and assembly of devices for the direct production of solar fuels, photoelectrochemistry and its application in fuel cells, and the engineering of enzymes and photoautotrophic microorganisms for microbial biofuel and biohydrogen production from sunlight.

Overview

The photosynthetic reaction can be divided into two half-reactions of oxidation and reduction, both of which are essential to producing fuel. In plant photosynthesis, water molecules are photo-oxidized to release oxygen and protons. The second phase of plant photosynthesis (also known as the Calvin-Benson cycle) is a light-independent reaction that converts carbon dioxide into glucose (fuel). Researchers of artificial photosynthesis are developing photocatalysts that are able to perform both of these reactions. Furthermore, the protons resulting from water splitting can be used for hydrogen production. These catalysts must be able to react quickly and absorb a large percentage of the incident solar photons.

Natural (left) versus artificial photosynthesis (right)

Whereas photovoltaics can provide energy directly from sunlight, the inefficiency of fuel production from photovoltaic electricity (indirect process) and the fact that sunshine is not constant throughout the day sets a limit to its use. One way of using natural photosynthesis is for the production of a biofuel, which is an indirect process that suffers from low energy conversion efficiency (due to photosynthesis' own low efficiency in converting sunlight to biomass), the cost of harvesting and transporting the fuel, and conflicts due to the increasing need of land mass for food production. The purpose of artificial photosynthesis is to produce a fuel from sunlight that can be stored conveniently and used when sunlight is not available, by using direct processes, that is, to produce a solar fuel. With the development of catalysts able to reproduce the major parts of photosynthesis, water and sunlight would ultimately be the only needed sources for clean energy production. The only by-product would be oxygen, and production of a solar fuel has the potential to be cheaper than gasoline.

One process for the creation of a clean and affordable energy supply is the development of photocatalytic water splitting under solar light. This method of sustainable hydrogen production is a major objective for the development of alternative energy systems. It is also predicted to be one of the more, if not the most, efficient ways of obtaining hydrogen from water. The conversion of solar energy into hydrogen via a water-splitting process assisted by photosemiconductor catalysts is one of the most promising technologies in development. This process has the potential for large quantities of hydrogen to be generated in an ecologically sound manner. The conversion of solar energy into a clean fuel (H₂) under ambient conditions is one of the greatest challenges facing scientists in the twenty-first century.

Two methods are generally recognized for the construction of solar fuel cells for hydrogen production:

• A homogeneous system is one such that catalysts are not compartmentalized, that is, components are present in the same compartment. This means that hydrogen and oxygen are produced in the same location. This can be a drawback, since they compose an explosive mixture, demanding gas product separation. Also, all components must be active in approximately the same conditions (e.g., pH).
• A heterogeneous system has two separate electrodes, an anode and a cathode, making possible the separation of oxygen and hydrogen production. Furthermore, different components do not necessarily need to work in the same conditions. However, the increased complexity of these systems makes them harder to develop and more expensive.

Another area of research within artificial photosynthesis is the selection and manipulation of photosynthetic microorganisms, namely green microalgae and cyanobacteria, for the production of solar fuels. Many strains are able to produce hydrogen naturally, and scientists are working to improve them. Algae biofuels such as butanol and methanol are produced both at laboratory and commercial scales. This method has benefited from the development of synthetic biology, which is also being explored by the J. Craig Venter Institute to produce a synthetic organism capable of biofuel production. In 2017, an efficient process was developed to produce acetic acid from carbon dioxide using "cyborg bacteria".

History

Artificial photosynthesis was first anticipated by the Italian chemist Giacomo Ciamician during 1912. In a lecture that was later published in Science he proposed a switch from the use of fossil fuels to radiant energy provided by the sun and captured by technical photochemistry devices. In this switch he saw a possibility to lessen the difference between the rich north of Europe and poor south and ventured a guess that this switch from coal to solar energy would "not be harmful to the progress and to human happiness."

During the late 1960s, Akira Fujishima discovered the photocatalytic properties of titanium dioxide, the so-called Honda-Fujishima effect, which could be used for hydrolysis.

Visible light water splitting with a one piece multijunction semiconductor device (vs. UV light with titanium dioxide semiconductors) was first demonstrated and patented by William Ayers at Energy Conversion Devices during 1983. This group demonstrated water photolysis into hydrogen and oxygen, now referred to as an "artificial leaf" with a low cost, thin film amorphous silicon multijunction sheet immersed directly in water. Hydrogen evolved on the front amorphous silicon surface decorated with various catalysts while oxygen evolved from the back side metal substrate which also eliminated the hazard of mixed hydrogen/oxygen gas evolution. A polymer membrane above the immersed device provided a path for proton transport. The higher photovoltage available from the multijuction thin film device with visible light was a major advance over previous photolysis attempts with UV or other single junction semiconductor photoelectrodes. The group's patent also lists several other semiconductor multijunction compositions in addition to amorphous silicon.

The Swedish Consortium for Artificial Photosynthesis, the first of its kind, was established during 1994 as a collaboration between groups of three different universities, Lund, Uppsala and Stockholm, being presently active around Lund and the Ångström Laboratories in Uppsala. The consortium was built with a multidisciplinary approach to focus on learning from natural photosynthesis and applying this knowledge in biomimetic systems.

Research of artificial photosynthesis is experiencing a boom at the beginning of the 21st century. During 2000, Commonwealth Scientific and Industrial Research Organisation (CSIRO) researchers publicized their intent to emphasize carbon dioxide capture and its conversion to hydrocarbons. In 2003, the Brookhaven National Laboratory announced the discovery of an important intermediate part of the reduction of CO₂ to CO (the simplest possible carbon dioxide reduction reaction), which could result in better catalysts.

One of the disadvantages of artificial systems for water-splitting catalysts is their general reliance on scarce, expensive elements, such as ruthenium or rhenium. During 2008, with the funding of the United States Air Force Office of Scientific Research, MIT chemist and director of the Solar Revolution Project Daniel G. Nocera and postdoctoral fellow Matthew Kanan attempted to circumvent this problem by using a catalyst containing the cheaper and more abundant elements cobalt and phosphate. The catalyst was able to split water into oxygen and protons using sunlight, and could potentially be coupled to a hydrogen gas producing catalyst such as platinum. Furthermore, while the catalyst broke down during catalysis, it could self-repair. This experimental catalyst design was considered a major improvement by many researchers.

Whereas CO is the prime reduction product of CO₂, more complex carbon compounds are usually desired. During 2008, Andrew B. Bocarsly reported the direct conversion of carbon dioxide and water to methanol using solar energy in a very efficient photochemical cell.

While Nocera and coworkers had accomplished water splitting to oxygen and protons, a light-driven process to produce hydrogen is desirable. During 2009, the Leibniz Institute for Catalysis reported inexpensive iron carbonyl complexes able to do just that. During the same year, researchers at the University of East Anglia also used iron carbonyl compounds to achieve photoelectrochemical hydrogen production with 60% efficiency, this time using a gold electrode covered with layers of indium phosphide to which the iron complexes were linked. Both of these processes used a molecular approach, where discrete nanoparticles are responsible for catalysis.

During 2009, F. del Valle and K. Domen showed the effect of the thermal treatment in a closed atmosphere using Cd
_1-xZn
_xS photocatalysts. Cd
_1-xZn
_xS solid solution reports high activity in hydrogen production from water splitting under sunlight irradiation. A mixed heterogeneous/molecular approach by researchers at the University of California, Santa Cruz, during 2010, using both nitrogen-doped and cadmium selenide quantum dots-sensitized titanium dioxide nanoparticles and nanowires, also yielded photoproduced hydrogen.

Artificial photosynthesis remained an academic field for many years. However, in the beginning of 2009, Mitsubishi Chemical Holdings was reported to be developing its own artificial photosynthesis research by using sunlight, water and carbon dioxide to "create the carbon building blocks from which resins, plastics and fibers can be synthesized." This was confirmed with the establishment of the KAITEKI Institute later that year, with carbon dioxide reduction through artificial photosynthesis as one of the main goals.

During 2010, the United States Department of Energy established, as one of its Energy Innovation Hubs, the Joint Center for Artificial Photosynthesis. The mission of JCAP is to find a cost-effective method to produce fuels using only sunlight, water, and carbon-dioxide as inputs.  JCAP is managed by a team from the California Institute of Technology (Caltech), directed by Professor Nathan Lewis and brings together more than 120 scientists and engineers from Caltech and its main partner, Lawrence Berkeley National Laboratory. JCAP also draws on the expertise and capabilities of key partners from Stanford University, the University of California at Berkeley, UCSB, University of California, Irvine, and University of California at San Diego, and the Stanford Linear Accelerator.  Additionally, JCAP serves as a central hub for other solar fuels research teams across the United States, including 20 DOE Energy Frontier Research Center.  The program has a budget of $122M over five years, subject to Congressional appropriation.

Also during 2010, a team directed by professor David Wendell at the University of Cincinnati successfully demonstrated photosynthesis in an artificial construct consisting of enzymes suspended in a foam housing.

During 2011, Daniel Nocera and his research team announced the creation of the first practical artificial leaf. In a speech at the 241st National Meeting of the American Chemical Society, Nocera described an advanced solar cell the size of a poker card capable of splitting water into oxygen and hydrogen, approximately ten times more efficient than natural photosynthesis. The cell is mostly made of inexpensive materials that are widely available, works under simple conditions, and shows increased stability over previous catalysts: in laboratory studies, the authors demonstrated that an artificial leaf prototype could operate continuously for at least forty-five hours without a drop in activity. In May 2012, Sun Catalytix, the startup based on Nocera's research, stated that it will not be scaling up the prototype as the device offers few savings over other ways to make hydrogen from sunlight. (Sun Catalytix ended up later pivoting away from solar fuel to develop batteries to store energy for the power grid instead, and Lockheed bought the company for an undisclosed amount in 2014.) Leading experts in the field have supported a proposal for a Global Project on Artificial Photosynthesis as a combined energy security and climate change solution. Conferences on this theme have been held at Lord Howe Island during 2011, at Chicheley Hall in the UK in 2014 and at Canberra and Lord Howe island during 2016.

Current research

In energy terms, natural photosynthesis can be divided in three steps:

• Light-harvesting complexes in bacteria and plants capture photons and transduce them into electrons, injecting them into the photosynthetic chain.
• Proton-coupled electron transfer along several cofactors of the photosynthetic chain, causing local, spatial charge separation.
• Redox catalysis, which uses the aforementioned transferred electrons to oxidize water to dioxygen and protons; these protons can in some species be utilized for dihydrogen production.

A triad assembly, with a photosensitizer (P) linked in tandem to a water oxidation catalyst (D) and a hydrogen evolving catalyst (A). Electrons flow from D to A when catalysis occurs.

Using biomimetic approaches, artificial photosynthesis tries to construct systems doing the same type of processes. Ideally, a triad assembly could oxidize water with one catalyst, reduce protons with another and have a photosensitizer molecule to power the whole system. One of the simplest designs is where the photosensitizer is linked in tandem between a water oxidation catalyst and a hydrogen evolving catalyst:

• The photosensitizer transfers electrons to the hydrogen catalyst when hit by light, becoming oxidized in the process.
• This drives the water splitting catalyst to donate electrons to the photosensitizer. In a triad assembly, such a catalyst is often referred to as a donor. The oxidized donor is able to perform water oxidation.

The state of the triad with one catalyst oxidized on one end and the second one reduced on the other end of the triad is referred to as a charge separation, and is a driving force for further electron transfer, and consequently catalysis, to occur. The different components may be assembled in diverse ways, such as supramolecular complexes, compartmentalized cells, or linearly, covalently linked molecules.

Research into finding catalysts that can convert water, carbon dioxide, and sunlight to carbohydrates or hydrogen is a current, active field. By studying the natural oxygen-evolving complex (OEC), researchers have developed catalysts such as the "blue dimer" to mimic its function . Photoelectrochemical cells that reduce carbon dioxide into carbon monoxide (CO), formic acid (HCOOH) and methanol (CH₃OH) are under development. However, these catalysts are still inefficient.

Phycobilitproteins from algae are under development for renewable energy production.

Hydrogen catalysts

Hydrogen is the simplest solar fuel to synthesize, since it involves only the transference of two electrons to two protons. It must, however, be done stepwise, with formation of an intermediate hydride anion:

2 e⁻ + 2 H⁺ ⇌ H⁺ + H⁻ ⇌ H₂

The proton-to-hydrogen converting catalysts present in nature are hydrogenases. These are enzymes that can either reduce protons to molecular hydrogen or oxidize hydrogen to protons and electrons. Spectroscopic and crystallographic studies spanning several decades have resulted in a good understanding of both the structure and mechanism of hydrogenase catalysis. Using this information, several molecules mimicking the structure of the active site of both nickel-iron and iron-iron hydrogenases have been synthesized. Other catalysts are not structural mimics of hydrogenase but rather functional ones. Synthesized catalysts include structural H-cluster models, a dirhodium photocatalyst, and cobalt catalysts.

Water-oxidizing catalysts

Water oxidation is a more complex chemical reaction than proton reduction. In nature, the oxygen-evolving complex performs this reaction by accumulating reducing equivalents (electrons) in a manganese-calcium cluster within photosystem II (PS II), then delivering them to water molecules, with the resulting production of molecular oxygen and protons:

2 H₂O → O₂ + 4 H⁺ + 4e⁻

Without a catalyst (natural or artificial), this reaction is very endothermic, requiring high temperatures (at least 2500 K).

The exact structure of the oxygen-evolving complex has been hard to determine experimentally. As of 2011, the most detailed model was from a 1.9 Å resolution crystal structure of photosystem II. The complex is a cluster containing four manganese and one calcium ions, but the exact location and mechanism of water oxidation within the cluster is unknown. Nevertheless, bio-inspired manganese and manganese-calcium complexes have been synthesized, such as [Mn₄O₄] cubane-type clusters, some with catalytic activity.

Some ruthenium complexes, such as the dinuclear µ-oxo-bridged "blue dimer" (the first of its kind to be synthesized), are capable of light-driven water oxidation, thanks to being able to form high valence states. In this case, the ruthenium complex acts as both photosensitizer and catalyst. This complexes and other molecular catalysts still attract researchers in the field, having different advantages such as clear structure, active site, and easy to study mechanism. One of the main challenges to overcome is their short-term stability and their effective heterogenization for applications in artificial photosynthesis devices.

Many metal oxides have been found to have water oxidation catalytic activity, including ruthenium(IV) oxide (RuO₂), iridium(IV) oxide (IrO₂), cobalt oxides (including nickel-doped Co₃O₄), manganese oxide (including layered MnO₂ (birnessite), Mn₂O₃), and a mix of Mn₂O₃ with CaMn₂O₄. Oxides are easier to obtain than molecular catalysts, especially those from relatively abundant transition metals (cobalt and manganese), but suffer from low turnover frequency and slow electron transfer properties, and their mechanism of action is hard to decipher and, therefore, to adjust.

Recently Metal-Organic Framework (MOF)-based materials have been shown to be a highly promising candidate for water oxidation with first row transition metals. The stability and tunability of this system is projected to be highly beneficial for future development.

Photosensitizers

Structure of [Ru(bipy)₃]²⁺, a broadly used photosensitizer.

Nature uses pigments, mainly chlorophylls, to absorb a broad part of the visible spectrum. Artificial systems can use either one type of pigment with a broad absorption range or combine several pigments for the same purpose.

Ruthenium polypyridine complexes, in particular tris(bipyridine)ruthenium(II) and its derivatives, have been extensively used in hydrogen photoproduction due to their efficient visible light absorption and long-lived consequent metal-to-ligand charge transfer excited state, which makes the complexes strong reducing agents. Other noble metal-containing complexes used include ones with platinum, rhodium and iridium.

Metal-free organic complexes have also been successfully employed as photosensitizers. Examples include eosin Y and rose bengal. Pyrrole rings such as porphyrins have also been used in coating nanomaterials or semiconductors for both homogeneous and heterogeneous catalysis.

As part of current research efforts artificial photonic antenna systems are being studied to determine efficient and sustainable ways to collect light for artificial photosynthesis. Gion Calzaferri (2009) describes one such antenna that uses zeolite L as a host for organic dyes, to mimic plant's light collecting systems. The antenna is fabricated by inserting dye molecules into the channels of zeolite L. The insertion process, which takes place under vacuum and at high temperature conditions, is made possible by the cooperative vibrational motion of the zeolite framework and of the dye molecules. The resulting material may be interfaced to an external device via a stopcock intermediate.

Carbon dioxide reduction catalysts

In nature, carbon fixation is done by green plants using the enzyme RuBisCO as a part of the Calvin cycle. RuBisCO is a rather slow catalyst compared to the vast majority of other enzymes, incorporating only a few molecules of carbon dioxide into ribulose-1,5-bisphosphate per minute, but does so at atmospheric pressure and in mild, biological conditions. The resulting product is further reduced and eventually used in the synthesis of glucose, which in turn is a precursor to more complex carbohydrates, such as cellulose and starch. The process consumes energy in the form of ATP and NADPH.

Artificial CO₂ reduction for fuel production aims mostly at producing reduced carbon compounds from atmospheric CO₂. Some transition metal polyphosphine complexes have been developed for this end; however, they usually require previous concentration of CO₂ before use, and carriers (molecules that would fixate CO₂) that are both stable in aerobic conditions and able to concentrate CO₂ at atmospheric concentrations haven't been yet developed. The simplest product from CO₂ reduction is carbon monoxide (CO), but for fuel development, further reduction is needed, and a key step also needing further development is the transfer of hydride anions to CO.

Photobiological production of fuels

Some photoautotrophic microorganisms can, under certain conditions, produce hydrogen. Nitrogen-fixing microorganisms, such as filamentous cyanobacteria, possess the enzyme nitrogenase, responsible for conversion of atmospheric N₂ into ammonia; molecular hydrogen is a byproduct of this reaction, and is many times not released by the microorganism, but rather taken up by a hydrogen-oxidizing (uptake) hydrogenase. One way of forcing these organisms to produce hydrogen is then to annihilate uptake hydrogenase activity. This has been done on a strain of Nostoc punctiforme: one of the structural genes of the NiFe uptake hydrogenase was inactivated by insertional mutagenesis, and the mutant strain showed hydrogen evolution under illumination.

Many of these photoautotrophs also have bidirectional hydrogenases, which can produce hydrogen under certain conditions. However, other energy-demanding metabolic pathways can compete with the necessary electrons for proton reduction, decreasing the efficiency of the overall process; also, these hydrogenases are very sensitive to oxygen.

Several carbon-based biofuels have also been produced using cyanobacteria, such as 1-butanol.

Synthetic biology techniques are predicted to be useful for this topic. Microbiological and enzymatic engineering have the potential of improving enzyme efficiency and robustness, as well as constructing new biofuel-producing metabolic pathways in photoautotrophs that previously lack them, or improving on the existing ones. Another topic being developed is the optimization of photobioreactors for commercial application.

Employed research techniques

Research in artificial photosynthesis is necessarily a multidisciplinary topic, requiring a multitude of different expertise. Some techniques employed in making and investigating catalysts and solar cells include:

• Organic and inorganic chemical synthesis.
• Electrochemistry methods, such as photoelectrochemistry, cyclic voltammetry, electrochemical impedance spectroscopy, dielectric spectroscopy and bulk electrolysis.
• Spectroscopic methods:
  • fast techniques, such as time-resolved spectroscopy and ultrafast laser spectroscopy;
  • magnetic resonance spectroscopies, such as nuclear magnetic resonance, electron paramagnetic resonance;
  • X-ray spectroscopy methods, including x-ray absorption such as XANES and EXAFS, but also x-ray emission.
• Crystallography.
• Molecular biology, microbiology and synthetic biology methodologies.

Advantages, disadvantages, and efficiency

Advantages of solar fuel production through artificial photosynthesis include:

• The solar energy can be immediately converted and stored. In photovoltaic cells, sunlight is converted into electricity and then converted again into chemical energy for storage, with some necessary loss of energy associated with the second conversion.
• The byproducts of these reactions are environmentally friendly. Artificially photosynthesized fuel would be a carbon-neutral source of energy, which could be used for transportation or homes.

Disadvantages include:

• Materials used for artificial photosynthesis often corrode in water, so they may be less stable than photovoltaics over long periods of time. Most hydrogen catalysts are very sensitive to oxygen, being inactivated or degraded in its presence; also, photodamage may occur over time.
• The cost is not (yet) advantageous enough to compete with fossil fuels as a commercially viable source of energy.

A concern usually addressed in catalyst design is efficiency, in particular how much of the incident light can be used in a system in practice. This is comparable with photosynthetic efficiency, where light-to-chemical-energy conversion is measured. Photosynthetic organisms are able to collect about 50% of incident solar radiation, however the theoretical limit of photosynthetic efficiency is 4.6 and 6.0% for C3 and C4 plants respectively. In reality, the efficiency of photosynthesis is much lower and is usually below 1%, with some exceptions such as sugarcane in tropical climate. In contrast, the highest reported efficiency for artificial photosynthesis lab prototypes is 22.4%. However, plants are efficient in using CO₂ at atmospheric concentrations, something that artificial catalysts still cannot perform.