Photodynamic therapies

Photodynamic action, in which photochemical reactions are used to destroy microorganisms and affected tissues by the combination of photosensitizer, oxygen, and visible or near infrared light have been well known for more than 100 years, and are being developed as antitumor agents [26]. 

In the early stage of investigation with porphyrin compounds, haematoporphyr-ins, were used as photosensitizers [27]. These compounds exhibit absorption maximum in the region from 590 nm to 680 nm. To improve the penetration depth in 

Photosensitizers used for photodynamic therapy must of course be nontoxic to tissue, so that they can absorb light with a wavelength longer than 630 nm, so as to accumulate selectively in the tissues and have high efficiency to generate singlet oxygen. 

Phthalocyanine compounds may be extremely promising materials in this application [28]. Sulfonic acid derivatives of chloroaluminum phthalocyanine and zinc phthalocyanine have been investigated in detail. Sulfonic-acid substituents appear to add optimum value. For zinc phthalocyanine, disulfonic acid is the most effective. In most cases, these materials are reported to be highly selective in tissue accumulation, and be more sensitive than porphyrin compounds. 

Phthalocyanine compounds exhibit many kinds of electronic, optical, magnetic, and optoelectronic characteristics. To hyperbolize, phthalocyanine compounds can do anything. But, viewed in practical terms, every characteristic of phthalocyanine compounds meets the competitive materials in the market. We have referred principally to application fields where phthalocyanine compounds have superiority over competition. So, for example, electroconductivity, including many works of Hanack [29] and photovoltaic characteristics are not mentioned. The development of new phthalocyanine compounds with expanded 7t-electron systems, such as two-dimensionally polymerized phthalocyanine compounds [30] and dendritic structures [31], have also not been considered. 

Photodynamic therapy (PDT) is a developing approach to the treatment of cancer and certain other diseases, such as age-related macular degeneration, which uses a combination of a photosensitizing dye and laser light to obtain a therapeutic effect [75], There is also an absolute requirement for oxygen. If any of the 

The application of PDT to a patient is simple. The photosensitizing dye is administered to the patient, who is then kept in the dark for up to 48 h, during which the dye becomes optimally located in any tumor tissue. A predetermined dose of laser light is delivered, typically for ca. 15 min. This is believed to produce highly reactive singlet oxygen and/or radicals, which kill the tumor [76], 

Some of the key properties of a photosensitizer are high efficiency of singlet-oxygen generation, strong absorption in the red and particularly near-IR (660-800 nm), preferential affinity for tumor rather than healthy tissue, and rapid clearance from the body. Porphyrin and phthalocyanine dyes fit these criteria best, and much work has been done on these dye types [76], Photofrin, a hemato-porphyrin derivative, was the first photosensitizer to be approved for clinical use. It is a complex mixture of monomeric porphyrins (protoporphyrin, hematopor-phyrin (84), and hydroxyethylvinyldeuteroporphyrin) and oligomers of these porphyrins. 

Second-generation photosensitizers include chlorins such as rnela -tctrahy-droxyphenyl chlorin (85) and A-aspartylchlorin [76], and phthalocyanines such as the zinc phthalocyanines (86) [77] and (87) [78], 

Photodynamic therapy (PDT) has been the subject of an immense body of research over the last 30 years or more and has emerged as 

Recently, a photocytotoxic activity of a series of dirhodium(II/II) complexes, [ Rh2(q-OOCCH3)4(dppz)I.] (where L = CH3OH, bpy, or dppz), has been demonstrated in in vitro tests [164-166], It was found that some of the derivatives show pronounced cytotoxicity on irradiation and can be good candidates for phototherapy. It is believed that they can photocleave DNA however, the exact mechanism of photochemical reaction and the nature of the reactive excited states remain unclarified. 

Phototherapy is the generic term covering therapies which use light either with or without a sensitiser. Those that do not require a sensitiser use the natural chromophores within the tissue to perform this function e.g. treatment of vitamin D deficiency in rickets, and neonatal jaundice). Those that do use an added sensitiser include photochemotherapy (largely psoriasis and skin disorders) and photodynamic therapy (currently mainly cancer). Photodynamic therapy is differentiated from photochemotherapy by its additional requirement for the presence of oxygen at molecular or ambient levels.In this text we will deal only with photodynamic therapy since, at the present time, this is the main driving force in phototherapy. °  

Work during the last ten years on photodynamic therapy (PDT) has established the methodology as effective in the early treatment of cancers, and in the treattnent of certain skin disorders and viral infections. Approval by the regulatory authorities for sensitisers in this process began in 1993 when Canada allowed the use of Photofrin (QLT Therapeutics), an action followed later by most countries around the world. Now many other companies have sensitisers at late stage clinical dials (2001), see below in Table 4.5. An excellent introduction to the chemistry of this topic is provided in the book written by Bonnett.  

Out of the vast number of applications in the field of medicine and biology involving laser chemical aspects, we are able to present only a handful of examples. One particularly interesting, now well-established, practical application is that of cancer treatment by photodynamic therapy (PDT), and all the monitoring processes around it examples are given in Sections 30.1 and 30.2. The analysis of the gases taken in and released in respiration is probably one of the most accessible fields for laser analytical techniques, and thus we discuss some relevant examples in Section 30.3. It has to be noted that the laser is used as an analytical tool here to add to the understanding of many of the fundamental processes in our metabolism the tech- 

For centuries, solar radiation has been used to cure a variety of diseases (e.g. rickets and psoriasis). Indeed, phototherapy was used as far back as 3000 years ago and was known to the Egyptians, the Indians and the Chinese. In Greece, heliotherapy was used in the 2nd century bc for the restoration of health (e.g. Patrice, 2003). 

Laser Chemistry Spectroscopy, Dynamics and Applications Helmut H. Telle, Angel Gonzalez Urena Robert J. Donovan 2007 John Wiley Sons, Ltd ISBN 978-0-471-48570-4 (HB) ISBN 978-0-471-48571-1 (PB) 

In the simplest forms of phototherapy, light is administered to a patient in a controlled way to achieve a specific purpose. A good example is the treatment of newborn babies suffering from jaundice with artificial daylight from a lamp the light induces a chemical reaction that allows the babies bodies to eliminate the yellow pigment causing the jaundice. 

Recently, PDT, a form of photo-chemotherapy, has become accepted for the treatment of several forms of cancer, particularly those found in the area of the head and neck, but it can also be used for the treatment of colon, bladder, oesophageal, lung, pancreatic and cervical cancers e.g. see Milgrom and MacRobert (1998) and Patrice (2003, 2006). 

Light is a versatile physical stimulus that can be localized with optical fibers whose penetration can be tuned using UV, near infrared (NIR) or two-photon sources. Photoresponsive polymers contain groups that aggregate or are cleaved after irradiation (for a recent review see [ 141 ]). Whereas the photoresponsive groups (photosensitizers) have minimal toxicity themselves, irradiation leads to generation of reactive oxygen species and cell death (photodynamic therapy, PDT). 

Even without administration in a pharmaceutical dosage form, specificity is imparted by choice of the area illuminated. Hydrophobicity of photosensitizers has been used to prepare self-assembled nanostructures that act in primary tumor targeting, after irradiation that induces destruction of the nanostructure and burst release of photosensitizer for maximal PDT [141]. 

Using porphyrin as the hydrophobic imit in a porphyrin core/arginine-substituted poly-L-Lysine shell (PP-PLLD-Arg) allowed solubilization of docetaxel in the core and complexation of MMP9 shRNA in the PLLD-Arg shell [142]. This promising copolymer demonstrated irradiation-controlled MMP9 siRNA expression as well as synergy in apoptosis induction between docetaxel and MMP9 shRNA in vitro. 

For further control of cancer cell selectivity, Zhu and coworkers developed tumor-hypoxia activated phototrigger systems using coumarin as the photosensitizer and nitro-imidazole as the hypoxia-sensitive imit [143]. Hypoxia-induced nitroimidazole reduction was required before photocleavage of coumarin and etoposide release for anticancer therapy. They showed cancer cell killing in vitro in aerobic conditions after illumination but not in a normal atmosphere. In aerobic tissues, nitroimidazole acts as an electron acceptor, preventing photocleavage and imspedfic drug release in normal tissues. 

Kataoka and coworkers recently evaluated the importance of the PEG corona for photodynamic therapy and verified the dependence of light-sensitive polymers on primary tumor accumulation [144]. A porphyrazine derivative was encapsulated in BVqMAA copolymers (polybutadiene-block-poly(l-methyl-2-vinyl pyridinium methyl sulfate)-block-poly(metacrylic add)). The nanoparticles were then PEGylated by electrostatic interaction between MAA and the poly-L-Lysine PEG copolymer. This resulted in better stability in blood, tumor accumulation and tumor regression after irradiation of PEGylated porphyrazine-loaded micelles over im-PEGylated micelles. 

These agents bind the copper so that it is solublized and excreted in the urine. They are effective because of their high affinity for copper(II) over other metals in the body. Although both isomers of penicillamine bind copper equally well it has been found that the L-form is toxic. Interestingly D-penicillamine is also used to treat rheumatoid arthritis where it acts to reduce collagen crosslinking the enzymes responsible for this process are largely copper centred. 

Porphyria, the disease from which Britain s King George III is believed to have suffered, arises through the accumulation of porphyrin decomposition products in the skin due to impaired enzyme function in the haem biosynthetic pathway [5], In addition to many other unpleasant side effects, porphyria renders the individual highly sensitive to light. The effects of porphyria, if they could be controlled and directed towards particular diseased tissue, would have the potential as a powerful therapeutic method. As the mechanism involves local, light-initiated generation of 

The early history of phthalocyanines is a quite bizarre and tragic. They are easily synthesized by a transition metal templated cyclocondensation of phthalonitrile, however, this was not how they were discovered. It is probable that a metal-free phthalocyanine was successfully prepared by Braun and Tcherniac in the early 1900s though it was not characterized [9], Given their synthetic methods it is also probable that de Diesbach and von der Weid were the first to prepare copper phthalocyanine but, again, their 1927 paper gives no characterization details [10]. 

The insolubilities of phthalocyanines made their analysis difficult and it took some time before a satisfactory structure was elucidated. Initial work was undertaken by the Linstead group at Imperial College in the 1930s that culminated in a series of six back to back papers published in 1934 [14], It was also Linstead who named the compounds in recognition of their synthesis from phthalic anhydride and similarity to the blue cyanine dyes. Definitive characterization of the nickel, platinum and copper phthalocyanine complexes, together with the metal-free compound, was revealed in 1935 following the publication of their X-ray structures by Robertson [15] the copper and metal-free compounds are illustrated in Fig. 7.5. 

In an extremely inventive approach, PDT with liposomes has been used to achieve localized delivery of highly toxic, short-lived, free radicals to neovascular tissue. A dye, photoporphorin, is encapsulated in liposomes which are injected intravenously. A laser fired into the eye simultaneously destabilizes the dye molecule causing it to form a free radical and destabilizes the liposome causing it to release the free radical. The free radical interacts with the first tissue it encounters, in this case the neovascular tissue. PDT is one of the only treatments currently available for age-related macular degeneration (see Chapter 6). 

The photosensitizer is hence a photocatalyst for the production of Oj. It is common practice to use a porphyrin photosensitizer, such as compounds derived from hematoporphyrin (7). However, much effort is being expended to develop better drugs with enhanced photochemical properties. 

A specific selection rule is a statement about which changes in quantum number may occur in a transition. 

CD Ih The exclusion rule states that ifthe molecule has a center of inversion, then no modes can be both infrared and Raman active. 

CD 13- In conventional microscopy, the diffraction limit prevents the study of specimens that are much smaller than the wavelength of light used as a probe. 

In fluorescence microscopy, images of biological cells at work are obtained by attaching a large number of fluorescent molecules to proteins, nucleic acids, and membranes, and then measuring the distribution of fluorescence intensity within the illuminated area. Special techniques permit the observation of fluorescence from single molecules in cells. 

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There are, indeed, many biological implications that have been triggered by the advent of fullerenes. They range from potential inhibition of HIV-1 protease, synthesis of dmgs for photodynamic therapy and free radical scavenging (antioxidants), to participation in photo-induced DNA scission processes [156, 157, 158, 159, 160, 161, 162 and 163]. These examples unequivocally demonstrate the particular importance of water-soluble fullerenes and are summarized in a few excellent reviews [141, 1751. 

The development of so-called photodynamic therapy uses lasers for treatment of cancer. The patient is injected with a substance called hematoporphyrin derivative [68335-15-9] which is preferentially localized in cancerous tissues. The patient is later irradiated with laser light, often with a dye laser at a wavelength around 630 nm. The light energy catalyticaHy photooxidizes the hematoporphyrin derivative, releasing materials which kill the nearby cancerous tissue. Normal tissue which did not retain the chemical is not harmed. Photodynamic therapy offers promise as a new form of cancer treatment. 

Use of coherent light sources in industrial appHcations has led to the field of photodynamic therapy as a photochemically based medical technology (9—11). The apphcation of photochemistry to information storage and communication processes is expected (12) (see Information storage materials Resist materials). 

Given stringent requirements for effective sensitizers and the desire to use wavelengths further to the red for therapeutic appHcations, definition of newer sensitizers has been a principal area of research since about 1987. Expanded theoretical and experimental understanding of photophysics has been a key element in identifying new classes of potential sensitizers (93—98). Research has focused on cationic derivatives of Nile Blue (93), metaHo-phthalocyanines (94), naphthalocyanines (95), chlorin-type compounds (96), expanded ring porphyrinoids (97), as well as porphyrins other than hematoporphyrin and its derivatives (98). This work has also been reviewed (10,91). Instmmentation for photodynamic therapy has been reviewed (99). 

S. L. Marcus, in C. J. Corner, ed., Euture Directions and Applications in Photodynamic Therapy, SPIE, Bellingham, Wash., 1990, pp. 5ff... 

Functional dyes (1) of many types are important photochemical sensitizers for oxidation, polymerization, (polymer) degradation, isomerization, and photodynamic therapy. Often, dye stmctures from several classes of materials can fulfiH a similar technological need, and reviewing several dye stmctures... 

Natural Sensitizing Dyes and Photodynamic Therapy. The chlorophylls are, of course, among the natural sensitizers for photosynthesis. Considerable iaterest exists ia chlorophyll and related pigments as photosensitizers ia biology and medicine (75), isomeric retinal chromophores as visual pigments (76,77), and the use of synthetic photosensitizers ia neurobiology (9), hematology (78), and photodynamic therapy (79). 

Porphyrin-based photosensitizers for use in photodynamic therapy 98T4151. 

Porphyrins, modified natural chlorophylls, chlorins, phthalocyanins, xanthenes, phenothiazine, and phenoxazine dyes as new sensitizers for photodynamic therapy 98MI50, 98MI51, 98MI52, 98MI53. 

Nitro ilkenes derived from galdctose or other carbohydrates are converted directly into pyrroles siibsdnited v/ith such carbohydrates at the fi-posidon. They are important precursors for water-soluble porphyrins fEq. 10.29. Such kmds of porphyrins are good candidates for photodynamic therapy of cancer and have been extensively snithed. 

Gold MH, Goldman MP (2004) 5-aminolevulinic acid photodynamic therapy where we have been and where we are going. Dermatol Surg 30 1077-1083... 

Pariser DM, Lowe NJ, Stewart DM, Jarratt MT, Lucky AW, Pariser RJ, Yamauchi PS (2003) Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis results of a prospective randomized multicenter trial. J Am Acad Dermatol 48 227-232... 

There is also evidence that individual chlorophyll derivatives exhibit cytostatic and cytotoxic activities against tumor cells. Studies have been started on electronic structures, in particular the electronic state of the phorphyrin macrocycle, and progress in this area is expected regarding photodynamic therapy for tumors, since the strong absorption of hght in the visible region is effective for laser excitation. Nevertheless, httle is known to date about the influences of peripheral groups on the electronic state of the macrocycle n system in chlorophyll derivatives. ... 

Wood, S.,et ah, Erythrosine is a potential photosensitizer for the photodynamic therapy of oral plaque biofihns, J. Antimicrob. Chemother., 57, 680, 2006. Hurlstone, D.P., et ah. Indigo carmine-assisted high-magnification chromoscopic colonoscopy for the detection and characterisation of intraepithelial neoplasia in ulcerative colitis a prospective evaluation. Endoscopy, 37,1186, 2005. 

Photodynamic therapy uses non-thermal red light to activate verteporfin, which produces reactive oxygen species that locally damage the neovascular endothelium.24 Verteporfin treatment reduces the risk of loss of visual acuity and legal blindness over 1 to 2 years. Long-term results are not yet available. Severe photosensitivity for 3 to 5 days after the procedure is common and some patients experience a severe loss of vision. Eventually, most patients have some visual recovery. This procedure requires multiple treatments over time.22... 

Figure 10.13 Photophysical mechanisms involved in photodynamic therapy...

Investigations of the kinetics of hole transfer in DNA by means of pulse radiolysis of synthetic ODNs have provided details about the hole transfer process, especially over 1 /is, including the multi-step hole transfer process. Based on the investigation of the kinetics of hole transfer in DNA, development of the DNA nanoelectronic devices is now expected. An active application of the hole transfer process is also desirable from a therapeutical point of view, since hole transfer may play a role in improvement of quantum yield and selectivity of DNA scission during photodynamic therapy. The kinetics of the hole transfer process is now being revealed, although there is still much research to be performed in this area. The kinetics of adenine hopping is another area of interest that should be explored in the future. 

LDMS is particularly well suited for the analysis of porphyrins.35-39 The heme molecule—a 22 rc-electron conjugated protoporphyrin system (Figure 8.1)—is an efficient photo-absorber in the visible and near UV (with an absorption maximum—the Soret band—near 400nm). This feature, concurrently with its low ionization potential, warrants that direct LDMS will possess extremely low limits for heme detection. The uses of IR or UV LDMS for structural characterization of natural porphyrins and their metabolites, synthetic monomeric porphyrins (e.g., used in photodynamic therapy), porphyrin polymers, and multimeric arrays, have been well documented.41148 In addition fast atom bombardment MS has been used to characterize purified hemozoin, isolated from the spleens and livers of Plasmodium yoelii infected mice.49... 

Miller, JW, Walsh, AW, Kramer, M, Hasan, T, Michaud, N, Flotte, TJ, Haimovici, R, and Gragoudas, ES, 1995. Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzo-porphyrin. Arch Ophthalmol 113, 810-818. 

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