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Photodynamic Therapy (PDT) 2 SERIES I ARTICLE Photodynamic Therapy (PDT) 2. Old and New Photosensitizers Bhaskar G Maiya In this article, key aspects related to the design and deve­ lopment of drugs for use in photodynamic therapy are considered. The chemistry, photochemistry and photobi­ ology of porphyrinic and non-porphyrinic photosensitiz­ ers, as relevant to their application in clinical PDT are discussed in detail. Bhaskar G Maiya is in the School of Chemistry, Introduction University of Hyderabad, Hyderabad. Application In the first article of this series,l we discussed the basic prin­ of photophysical ciples of photodynamic therapy (PDT) and also the relevant principles to problems at the interface of chemistry physical and biochemical mechanisms associated with it. PDT and biology is a unifying involves irradiation of a tissue-bound photosensitizer which theme of his current goes to its triplet excited state and generates, upon energy research. transfer to oxygen, the cytotoxic singlet oxygen (102) resulting in cell necrosis. Thus, the photosensitizer plays a key role in this modern cancer management protocol. Naturally, the qualities of the photosensitizer matter most in realizing an efficient photodynamic action. In this article, we focus on the drug design strategies involved in PDT. Recall, however, that the drug in PDT is actually 'photosensitizer + light'. Therefore, besides the chemistry, photochemistry and photobiology of old and new photo sensitizers, this article also discusses, albeit briefly, the 'light-related' aspects (i.e., light sources, irradiation strate­ gies, etc.) of PDT. Qualities of a Good Photosensitizer for PDT By definition, photosensitizers are compounds that are capable of absorbing light of specific wavelength (chromophores) and Previous part of this series transforming it into useful energy. In the case of PDT, this 1. The Basic Principles of PDT, would involve the production of lethal cytotoxic agents. Going Resonance, Vol. 5, No.4, p. 6, by this definition, there are hundreds of natural and synthetic 2000. --------~-------- RESONANCE I June 2000 15 SERIES I ARTICLE For visible dyes ranging from plant extracts to complex synthetic wavelength, macrocycles that, in principle, can function as photosensitizers hemoglobin and for PDT. However, a good PDT photosensitizer is expected to melanin are the fulfill the following minimum criteria. It should primary (a) have a strong absorbance with high extinction coefficient c endogenous at longer wavelengths (600-850 nm) where tissue penetration of chromophores in light is at a maximum and still energetic enough to produce 102' the skin. (b) have excellent photochemical reactivity, with high triplet state yields (<I>T) and long triplet state lifetimes (<I>T) and be able to effectively produce 102 and other reactive oxygen species, (c) have minimal dark toxicity and only be cytotoxic in the presence of light, (d) be preferentially retained by the target tissue, (e) be rapidly excreted from the body, thus inducing a low systemic toxicity, and (f) be chemically pure and of known specific composition. Among these six major guidelines, the first two are the most important ones and the rationale behind such stringent optical and photophysical criteria are discussed below. For visible wavelength, hemoglobin and melanin are the pri­ mary endogenous chromophores in the skin. Hemoglobin has strong absorption bands near 418,542 and 577 nmand melanin absorbs over a broad range with a maximum in the 300-500 nm region, but decreasing steadily in the visible range. Thus, it is necessary that the illumination wavelengths be greater than 600 nm to have significant light penetration past the dermal capil­ lary plexi. At wavelengths longer than - 1000 nm, light absorp­ tion by water molecules becomes substantial. Therefore, there is a 600-1000 nm 'therapeutic window' that permits significant light penetration into the tissue as illustrated in Figure 1. Within this window, longer wavelengths penetrate more deeply because of decreasing tissue absorbance and decreasing light scattering. However, for wavelengths greater than 850-900 nm, the photons -16-------------------------------~~-------------R-E-S-O-N-A-N-C-E--I-J-U-ne--2-0-o-0 SERIES I ARTICLE Figure 1. Illustration of the 'absorption spectrum of a human hand' that clearly shows the PDT' therapeutic window' Tissue chro­ 7.0 mophores (viz., amino ac­ ids, nucleotides, heme, 6.0 melanin, etc.) absorb light 0.0. of ca. < 600 nm (UV-vis­ ible). At longer wave­ lengths, the all-pervading water molecules start ab­ sorbing light (infra-red). Thus, an ideal photosensi­ tizer for PDT has to absorb light in the pure visible re­ WAVELENGTH (NM) gion ofthe electromagnetic spectrum, towards the red end. may not have sufficient energy to participate in photochemical reactions. Thus, the available wavelengths for photodynamic sensitizers are 600-850 nm (red light). In general, the use of sensitizers with stronger absorption (large extinction coeffi­ cient) offers the possibility to inject smaller drug doses. Besides being able to strongly absorb red-light, a good PDT photosensitizer should also possess favorable triplet state prop­ erties. The effectiveness of photodynamic activity has notable dependence on the triplet state quantum yield and its lifetime. A long triplet state lifetime and a high triplet quantum yield are both considered as preconditions for efficient photosensitiza­ tion. This is obvious because longer life times permit diffusion of the reactants (i.e. the triplet sensitizer and molecular oxygen) to form the initial encounter complex which ultimately relaxes to the products (i.e. ground state photosensitizer and 102)' Similarly, copious amount ofl02 can be generated if the precur­ sor triplet itself is produced in large quantities. Indeed, the quantity S ll' which is the ratio of the singlet oxygen yield and the triplet quantum yield (SII = <I>(l02)/(<I>T)' is a well acknowledged photophysical bench mark for a good PDT photosensitizer. --------~-------- RESONANCE I June 2000 17 SERIES I ARTICLE Porphyrins, by Finally, it is not only triplet lifetime and yield, but also its virtue of their energy that is an important factor which enables a given sensi­ robust aromatic tizer to be a good PDT agent. This is because compounds 1 18n -electron having triplet state energy which is about 8 kJ mol- lower than 1 system and their that of 102 (94 kJ mol- ) are generally unable to transfer their rich redox and excitation energy to molecular oxygen. Therefore, energy of the photophysical first excited triplet state of a photosensitizer should be approxi­ 1 activity as well as mately greater than 86 kJ mol- to promote a type II mechanism; biocompatibility, the corresponding ground state absorption for such photosensi­ fulfill most of the tizers does not, usually, extend beyond ca.850 nm. criteria ·for an ideal While it is imperative that any good PDT agent should be photosensitizer. minimally toxic in the dark and should be activated only in the presence of light (criterion c), criteria (d) to (f) are true for any drug, light activated or not. Old and New Porphyrin-based PDT Agents Porphyrins, by virtue of their robust aromatic I8n-electron system and their rich redox and photophysical activity as well as biocompatibility, fulfill most of the criteria for an ideal photo­ sensitizer. Indeed, hematoporphyrin derivative (HpD or Photofrin II®, see Figure 3 in the first article of this series) is currently being marketed as an anti-cancer drug. HpD was originally synthesized by combining hematoporphyrin with 95% sulphuric acid in acetic acid at room temperature and neutralizing the resulting mixture with an aqueous base. This procedure led to the formation of a complex mixture of dimers and oligomers primarily involving ester and ether linkages. Partial purification of the most active of these oligomers by high performance liquid chromatography (HPLC) or size exclusion gel chromatography led to Photofrin II®, 90-95% of which is the genuinely active component. Notwithstanding this messy syn­ thetic route and its unknown structure, Photofrin II® is ap­ proved by regulatory bodies all over the world, and is currently marketed for the treatment of early and late-stage lung cancer, superficial and advanced oesophageal cancer, bladder cancer and cervical dysplasia (a precancerous condition) with promis- 18-------------------------------~~·-------------R-E-S-O-N-A-N-C-E--I-J-U-n-e--2o-0-0 SERIES I ARTICLE Box 1. Seeing is Believing! A typical complete remission case of early central bronchial cancer treated by PDT. a: squamous cell carcinoma of a 78-year-old man. b: 1 week after PDT, covered by necrosis tissue. Approximately 48 h. following intravenous injection of2.0 mg/kg of body weight ofPhotofrin II®, broncho­ scopic PDT was performed under topical anesthesia using light from an argon dye laser and fiber optic light­ delivery device. c: 3 years after PDT, no evidence of recurrence (extracted, with permission from Yamamoto and others, Curro Sci., 77, 894, 1999). ing clinical results. An illustration of the successful clinical use of Photofrin II® is given in Box 1. Despite its apparent success, Photofrin II® (HpD) has two very important disadvantages. First of all, it is readily taken up and retained by cutaneous tissue for up to ten weeks post-injection. This is not desirable since it causes a marked skin photo toxicity that requires the patient to avoid bright sunlight for several weeks. Secondly, while there exists a number of absorption bands between 400-650 nm, the weakest absorption band of Photofrin II® at 630 nm wavelength is often used to excite this photosensitizer (remember: tissue penetration of light increases at longer wavelengths). Moreover, there is considerable uncer­ tainty about the chemical 'purity' and also the structure of Photofrin II® resulting in 'batch to batch' variation in its photo­ dynamic activity thus rendering the fixation of the dosage diffi­ cult. Put together, these disadvantages of Photofrin II® have necessitated the development of other photosensitizers for use in PDT.
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