3 juni 2018: lees ook dit artikel:
Op de website van een ziekenhuis in Leeds, gespecialiseerd in PDT staat een mooi overzicht van verschillende fotosensitizers - voor radachlorin en photostem kijk op deze pagina - die gebruikt worden bij PDT. Hieronder de tekst in het Engels, maar hopelijk kunt u dit wel begrijpen, zo niet gebuirk google vertaalmachine bovenaan deze pagina - maar als u naar deze website gaat kunt u ook de schema's en foto's erbij lezen:
Bron: afd. PDT - ziekenhuis Leeds
Types of Photosensitisers
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Haematoporphyrin and Photofrin
The first sensitiser used in clinical PDT was haematoporphyrin derivative and its purified fraction, Photofrin®. HpD was first described by Lipson et al in 1961 and is prepared by acetylation of haematoporphyrin (Hp), followed by neutralisation prior to alkaline hydrolysis. The resulting mixture is known to contain haematoporphyrin, hydroxyethylvinyldeuteroporphyrin (HVD) and protoporphyrin (Pp), as well as a complex dimeric and oligomeric fraction containing ester, ether and carbon-carbon linkages of haematoporphyrin. HpD is typically 45% monomeric/dimeric porphyrins and 55% oligomeric material , the latter being accountable for the tumour localising activity of HpD in vivo. This fraction has been partly purified in the commercial development of Photofrin®, which has been reported to be around 85% oligomeric material. The same compound was prepared in Leeds under the name Polyhaematoporphyrin or PHP. Investigations using HpD have highlighted several criteria that an ideal photosensitiser should fulfil.
Although the higher molecular mass fraction is responsible for tumour localisation in vivo, it has a low fluorescent quantum yield and a low efficiency in generation of reactive oxygen species.
Photofrin®-mediated PDT has proved curative for a range of cancers, but there are well-documented drawbacks to treatment with this photosensitiser. Because the compound is a complex mixture, there are questions concerning the identity of the active components and also the reproducibility of the synthetic process. Photofrin® is excited clinically with red light at 630 nm. This wavelength can only penetrate tissue to a depth of a few mm, making Photofrin® unsuitable for the treatment of deep-seated tumours. Illumination is usually carried out 48 h after systemic administration of Photofrin®, when the accumulation of sensitiser by tumour tissue is thought to be optimal. Depending on the particular clinical procedure, during this time the patient may be allowed home with the provision that they avoid bright light. Cutaneous photosensitivity following treatment can last for several weeks and patients are advised to avoid bright light during this period which may impose restrictions on normal activities.
Current efforts are aimed to produce a photosensitiser which:
Is a single compound
Has increased absorbance in the red region of visible light
Gives a high quantum yield of triplet formation
Has good cytotoxic oxygen species generation
Shows increased selectivity for malignant tissue over normal tissue
Exhibits no dark toxicity
New photosensitisers have been synthesised that have better properties than HpD. Single substances are preferred because they allow simplified studies into the relationship between photosensitiser and effect, and clinical approval is easier to obtain. The increased absorbance in the red region of the spectrum and the increased molar absorption coefficients give rise to more excited photosensitiser at deeper tissue sites and hence more tumour damage. However, photosensitiser properties (aggregation, ionic charge, solubility, partition between aqueous and lipid) are also important and should promote selectivity without long term retention.
Following the success of PDT a number of so called "second generation" photosensitisers have been developed. These include modified porphyrins, chlorins, bacteriochlorins, phthalocyanines, naphthalocyanines, pheophorbides and purpurins. These photosensitisers show increased efficacy in PDT for many different reasons, such as improved photophysical properties as demonstrated by their activation wavelengths, thus increasing tissue penetration.
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Chlorins and bacteriochlorins
In chlorins one of the exo-pyrrole double bonds of the porphyrin ring is hydrogenated, resulting in an intense absorption at wavelengths greater than 650 nm. In bacteriochlorins, two of the exo-pyrrole double bonds of the porphyrin ring are hydrogenated, yielding compounds with maximum absorption at even longer wavelengths. Because of these improved optical properties, chlorins and bacteriochlorins are being intensively studied as potential new drugs for PDT. In principle, they should allow for treatment of much deeper tumours than HpD. For example, bonellin, a naturally occurring chlorin (see Figure) has better photosensitising abilities than HpD.
meta-Tetra hydroxyphenyl chlorin
Meta-tetra hydroxyphenyl chlorin (m-THPC) is a second generation photosensitiser, developed for clinical use by Scotia QuantaNova. m-THPC is also known by several other names, Foscan and Temoporfin. It has a hydrophobic chlorin core and hydroxyphenyl groups at the meso position to increase solubility of the photosensitiser. The first clinical study with m-THPC began in 1990 for the treatment of human mesothelioma and it is currently in clinical trials for gynaecological, respiratory and head and neck cancers in USA, Europe and the UK.
The advantages of m-THPC are highlighted by comparison with Photofrin. m-THPC has been shown to be approximately 200 times more effective then Photofrin when considering photodynamic dose (i.e. a lower photosensitiser dose and shorter illumination times are required to achieve similar results). m-THPC is a single pure compound, rather than a mixture of porphyrins. It is excited at a longer wavelength and the molar absorbance coefficient for m-THPC is much higher than that of Photofrin, i.e. 22 400 M-1cm-1 at 652 nm and 1 170 M-1cm-1 at 630 nm respectively (in methanol). Furthermore, m-THPC has a longer half life in the triplet state generating more cytotoxic oxygen species, and is said to be more selective between tumour and normal tissue. m-THPC is more hydrophobic than Photofrin which thus increases cellular uptake leading to higher efficacy in vitro . However, the skin photosensitivity caused by m-THPC is only slightly less than that of Photofrin. The reasons for the high efficacy of m-THPC are not fully understood.
m-THPC is hydrophobic and is dissolved in polyethylene glycol 400 (PEG): ethanol: water, (3: 2: 5, v:v:v) for clinical use as recommended by Scotia QuantaNova. More recently a number of new formulations have been developed. Foscan® 2 is a pre-dissolved preparation of m-THPC using propylene glycol: ethanol, (6:4, v:v). The difference in the two solvents lies in the chain length for PEG: H(OCH2CH2)nOH (n = 8.2-9.1) whilst propylene glycol is CH3CHOHCH2OH. In addition, m-THPC has been covalently linked to PEG (SC102).
Mono-L-aspartyl chlorin e6
Mono-L-aspartyl chlorin e6 (NPe6 or MACE) is a highly water soluble chlorin-type photosensitiser. It has an absorbance peak at 654 nm (extinction coefficient of 40 000 M-1cm-1) and is effective in vitro and in vivo, shown by retention in the tumour, efficient photodynamic damage with little skin phototoxicity (probably due to its rapid clearance).
Bacteriochlorins
Currently, a number of centres and companies are developing bacteriochlorins, which have almost ideal optical properties in terms of tissue penetration. These compounds, which absorb light strongly above 740 nm show considerable promise as new PDT agents, although their stability remains in some doubt.
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Phthalocyanines
Phthalocyanines are highly coloured compounds which have found widespread commercial application. Recently phthalocyanines have been developed as photosensitising agents for PDT.
The pyrrole groups in phthalocyanines are conjugated to benzene rings and bridged by aza nitrogens rather than methine carbons. This causes the absorption spectrum to shift to longer wavelengths and the Q bands to become more intense than the Soret peak. The shift of this red absorption peak permits the use of longer wavelength light with increased tissue penetration to excite these compounds (typically around 680 nm), compared with the 630 nm light used to excite porphyrins.
A long-life triplet state is required for efficient photosensitisation and this criterion may be fulfilled by the incorporation of a dimagnetic metal such as Zn or Al into the phthalocyanine macrocycle. Metal-free compounds and phthalocyanines containing paramagnetic metals such as Cu, Co and Fe have a much shorter triplet lifetime and display minimal phototoxicity.
Phthalocyanines are generally hydrophobic compounds although water-soluble derivatives can be readily synthesised through substitution of the ring with moieties such as sulphonic acid, carboxylic acid and amino groups. The sulphonated compounds, and in particular chloro aluminium sulphonated phthalocyanine (AlPcS) have received the most attention with regard to photodynamic efficacy. Purification of these derivatives can be a problem and the final product is typically a mixture of mono- di- tri- and tetrasulphonated derivatives. Furthermore, these compounds have been observed to aggregate at relatively low concentrations in aqueous media which results in loss of photochemical activity.
AlPcS exhibits selective retention in some tumours. This coupled with negligble dark-toxicity, minimal cutaneous photosensitivity, and excellent photodynamic activity at increased wavelengths has led to the clinical evaluation of AlPcS for PDT.
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Benzoporphyrin derivative
Benzoporphyrin derivative mono-acid A (BPD) is another chlorin-type molecule that has been developed by QuadraLogic Technologies. It is a hydrophobic molecule that is distinguished by the presence of a mono-acid at either position 3 or 4 of the porphyrin ring. The absorbance peak for PDT occurs at 650 nm with an extinction coefficient of 34 000 M-1cm-1. Phase I and II clinical trials have shown it has rapid tumour accumulation and reduced skin photosensitivity.
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5-Aminolaevulinic acid (ALA)
An alternative to the administration of exogenous photosensitising compounds is to stimulate the cellular synthesis of endogenous photosensitisers. 5-Aminolaevulinic acid (ALA ) is a metabolic precursor in the biosynthesis of haem. The immediate precursor to haem in this pathway is protoporphyrin IX (PpIX) which is a natural photosensitiser associated with some types of porphyria. The rate of formation of PpIX is dependent on the rate of synthesis of ALA from glycine and succinyl CoA which is governed in a negative-feedback manner by the concentration of free haem. Since the conversion of PpIX to haem is relatively slow, administration of exogenous ALA can bypass the negative-feedback mechanism and cause the build-up of phototoxic levels of PpIX.
ALA-induced PpIX offers several advantages over haematoporphyrin derivative and Photofrin® for use in PDT. In particular the optimum therapeutic ratio is reached 2-4 h following ALA administration and there is rapid systemic clearance of ALA-induced PpIX within 24 h. This not only eliminates prolonged cutaneous photosensitivity but also allows repeated treatment as frequently as every 48 h without the risk of damage to normal tissue. The fact that the photosensitising effect is due almost exclusively to PpIX permits the in situ monitoring by fluorescence, affording an accurate analysis of sensitiser levels. PpIX rapidly undergoes photobleaching therefore it is the concentration of sensitiser in the tissue and not the administered light dose which determines the PDT effect. ALA can be administered systemically or topically, the latter being particularly useful for the local treatment of superficial skin lesions.
Certain types of tumour tissue exhibit increased accumulation of ALA-induced PpIX. The activity of the enzyme ferrochelatase, which catalyses the incorporation of iron into the porphyrin ring, is lower in some tumours. Consequently the final conversion to haem is slower, which results in prolonged elevation of PpIX levels. Furthermore, topically applied ALA cannot readily penetrate the keratinous layer of normal skin but can penetrate malignant lesions. This further enhances the tumour specificity whilst eliminating photosensitisation of healthy skin.
Although ALA-induced PpIX photosensitisation offers some advantages over HpD and Photofrin®, there are still drawbacks associated with the treatment. Because photosensitisation is still porphyrin-mediated, excitation of PpIX also occurs at 630 nm, offering no advantage over HpD in the depth of tissue penetration. The hydrophilic nature of ALA restricts drug penetration through the keratinous later of normal skin, however this problem may be alleviated by the use of lipophilic ALA esters which can penetrate cells more easily.
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Other potential photosensitisers
There are other synthetic photosensitisers which have been developed with improved photophysical properties or tumour selectivity, and research continues. These include: purpurins, porphycenes, pheophorbides and verdins. Purpurins are a class of porphyrin macrocycle with an absorption band at 630 nm to 715 nm, typified by tin etiopurpurin (SnET2) which has an extinction coefficient of 40 000 M-1cm-1 at 700 nm. Porphycenes, despite having activation wavelengths lower than other new photosensitisers (635nm), show fluorescence yields higher than HpD and therefore are potentially useful. Phorbides are derived from chlorophylls (e.g. pheophorbide) and have 20 times the effectiveness of HpD. Verdins contain a cyclohexanone ring fused to one of the pyrroles of the porphyrin ring and produce similar responses to HpD and purpurins.
Psoralens and their derivatives have been used for over 3000 years in the treatment of skin disorders and are still in use today. The cytotoxic action of these compounds stems from their ability to cross-link biomolecules, in particular DNA, following activation by ultraviolet light.
Anthracycline compounds exhibit reasonable tumour selectivity and members of this group such as Doxorubicin are used in chemotherapy, although adverse side effects are common. Some of these compounds have demonstrated additional phototoxicity, raising the potential of combination therapy in which comparable antitumour activity could be achieved with a lower drug dose thereby reducing harmful side effects.
Many synthetic non-porphyrin compounds demonstrate photosensitising ability. These include: phenothiazinium compounds such as methylene blue ; Toluidine blue , which has found widespread use in the diagnosis of oral disease; cyanines such as Merocyanine 540; acridine dyes as demonstrated by Raab in 1900; derivatives of the tumour marker, Nile blue; and rhodamines such as the mitochondria-specific Rhodamine 123.
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