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Ocular Pharmacology and Pharmacy, Dr. Rajendra Prasad Center for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
9.2.1 Introduction/Definition
Also known as photochemotherapy, it is a form of phototherapy using a photosensitizer (a nontoxic light-sensitive chemical which when selectively exposed to light becomes toxic) and causes damage to target malignant and other diseased cells. This method is used for both disease diagnosis and treatment (Jia and Jia 2012).
The spectrum of possible applications of PDT encompasses the entire range of infectious (viral, bacterial, fungal, protozoal) disorders, epidermal and dermal inflammatory diseases, tumors of lymphocytes, adnexal diseases, and premature skin aging due to sun exposure. With PDT, it is possible to eradicate pathogens in simple locations such as oral cavities as well as in deep-seated bone marrow. Nowadays’ PDT is being explored as a new line of antimicrobial therapy in order to eradicate drug-resistant pathogens.
Photodynamic therapy (PDT) has also recently grown as a proven method of treatment for various types of cancers with a proven potential to target even HIV and MRSA (methicillin-resistant Staphylococcus aureus). Another key indication is for small areas of cancer that are unsuitable for or have persisted or recurred after conventional management. It can be applied in areas already exposed to the maximum safe dose of radiotherapy. Photodynamic therapy (PDT) is of particular value for precancer and early cancers of the skin and mouth because of good cosmetic and functional results.
PDT also has considerable potential in arterial diseases for preventing restenosis after balloon angioplasty and in the treatment of infectious diseases, where the responsible organisms are accessible to both the photosensitizer and light. New developments on the horizon include techniques for increasing the selectivity for cancers, such as coupling photosensitizers to antibodies, and for stimulating immunological responses, but many further preclinical and clinical studies are needed to establish PDT’s role in routine clinical practice (Bown 2013).
9.2.2 Photodynamic Therapy Process
Most PDT applications involve three key components: a photosensitizer, a light source, and tissue oxygen. A photosensitizer is a chemical compound that gets converted to an excited state upon absorption of light and forms free radicals which react with oxygen to produce a highly reactive state of oxygen (reactive oxygen species (ROS)) known as singlet oxygen. Exposure of cell to light energy wavelengths is typically in the visible region. ROS produces cell inactivation and death through modification of intracellular components thus becoming highly cytotoxic within few microseconds of activation. Generally, the photosensitizer is applied locally to target area or the photosensitive targets are locally excited with light. In the localized treatment of internal tissues and cancers, photosensitizers are administered intravenously and light is delivered through endoscopes or fiber-optic catheters. Once the photosensitizer is localized to the intended area (tissue/organ), an appropriate wavelength of light is chosen in order to excite the photosensitizer.
9.2.2.1 Mechanism of Photodynamic Therapy
Photodynamic process begins when photosensitizer absorbs a photon and gets converted into an excited (singlet) state. This singlet state of photosensitizer undergoes simultaneous or sequential decay resulting in intramolecular energy transfer reactions which are of three types. Type I reaction involves photooxidation by radicals, type II reaction involves photooxidation by singlet oxygen, and in type III reaction, photoreaction does not involve oxygen. Photosensitizer in excited singlet state readily decays back to the ground state with the emission of light (fluorescence) or heat. Sometimes it goes into a “triplet state.” In addition, excited molecules also undergo type III reactions. Photosensitizer in triplet state reacts with ground state oxygen to produce singlet state oxygen, then decay to ground state by phosphorescence, or undergo type I and III reactions. Singlet oxygen generated during the process is a highly reactive form of oxygen and is highly damaging species with the potential to cause blood flow stasis, vascular collapse, and/or vascular leakage ultimately leading to tumor ablation. PDT has also been demonstrated to induce apoptosis causing orderly elimination of unwanted cells (Sibata et al. 2000).
9.2.2.2 Light Used
The light source for PDT can range from an ordinary light bulb to a diode array (emitting a broad band incoherent spectrum) or a laser. Broad-spectrum light sources such as xenon arc lamps or slide projectors equipped with red filters (to eliminate short wavelengths) are used for in vitro and preclinical in vivo studies of tumors. Lasers are standard light sources for PDT as they are monochromatic, have high power output, and can be easily coupled to fiber optics for endoscopic light delivery to localized areas in body cavity. The most common lasers are tunable dye lasers (Sibata et al. 2000). Argon lasers have been employed for the treatment of human corneal neovascularization (Sheppard et al. 2006) and neovascular maculopathy (Barbara et al. 1991). Copper-pumped dye laser, a double laser consisting of KTP (potassium titanyl phosphate/YAG (yttrium aluminum garnet)) medium, has been used in dermatology and in facial telangiectasias (Cassuto et al. 2000), while LED (light-emitting diode) has been used in treatment of viral warts (Ohtsuki et al. 2009).
9.2.2.3 Dyes Used
Photofrin was the first US FDA-approved photosensitizer for treatment of cancer. Thereafter, a variety of dye sensitizers have been developed and approved for PDT treatment of skin and organ diseases ranging from simple bacterial infections (acne vulgaris) to more serious cancers. Some of the very common dyes used in the treatment of photodynamic therapy are listed as follows:
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Psoralen compounds in conjunction with UVA (300–400 nm) radiation are used in the treatment of psoriasis, atopic dermatitis, seborrheic dermatoses, histiocytosis, lichen planus, mycosis fungoides, polymorphous light eruption, pityriasis lichenoides, lymphomatoid papulosis, prurigo, palmar and plantar pustulosis, and vitiligo. Examples of psoralen photosensitizers include 5-methoxypsoralen, 8-methoxypsoralen, and trioxsalen.
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Porphyrinoid photosensitizers porphyrin, chlorin, bacteriochlorin, pheophorbide, bacteriopheophorbide, texaphyrin, porphycene, and phthalocyanine.
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Non-porphyrin dyes are anthraquinones, phenothiazines, xanthenes, cyanines, and curcuminoids.
9.2.2.4 Molecules Used
Photofrin is the only photosensitizer approved by US FDA for palliation of various types of cancer such as cancer of the esophagus and Barrett esophagus, endobronchial cancer, certain skin cancers such as basal cell carcinoma and squamous cell carcinoma, and some tumors of the vagina, vulva, and cervix that can be reached by activating light. Aminolevulinic acid has been approved for the treatment of actinic keratosis of face or scalp. Methyl ester of ALA has been approved by US FDA in July 2004 for treatment of some types of actinic keratoses of face and scalp. Verteporfin (Visudyne) had been approved for treatment of pathologic myopia, ocular histoplasmosis, and for age-related macular degeneration.
9.2.2.5 Side Effects
Photofrin comes with the side effects of accumulation. Also skin and eyes of the patient become photosensitive with Photofrin treatment. Application of aminolevulinic acid causes redness and tingling or burning sensation to skin. Photosensitivity reactions can also be observed with methyl ester of ALA, and therefore, this drug is not recommended for people whose skin is sensitive to light, in immunosuppressed individuals, and those with peanut or almond allergy.
Some of the other general adverse effects include burns, swelling, pain, and scarring of surrounding tissues (Dolmans et al. 2003). Skin and eyes become sensitive to light. Stenosis and perforation of hollow organs have also been observed in some cases (Wittmann et al. 2014). PDT has also been reported to cause damage to DNA such as strand breaks, degradation, DNA-protein cross-links, and chromosomal aberrations and mutations. Other shortcomings include limitation of treatment depth due to ineffective penetration of light. Revascularization of treated areas is one of the biggest adverse effects that pose threat to benefits of PDT. In some cases, damage to vascular endothelium leading to increased vascular permeability, platelet aggregation, blood flow stasis, vasoconstriction, and ultimately vascular occlusion has been observed. Vascular damage further leads to hypoxia-related re-angiogenesis necessitating re-treatment (Verteporfin in Photodynamic Therapy Study Group 2001).
9.2.2.6 Advantages of PDT
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It has no long-term side effects when used properly.
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It is less invasive than surgery.
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It usually takes only a short time and is most often done as an outpatient.
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It can be targeted very precisely.
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It can be used to treat one lesion at a time.
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Unlike radiation, PDT can be repeated many times at the same site if needed.
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Since this therapy uses nonionizing radiation, there is relatively rapid recovery.
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There is little or no scarring after the site heals.
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It often costs less than other cancer treatments.
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It can also be used in combination with other therapies so as to achieve synergistic effects.
Calculations for doses applied/based on body surface area: Successful treatment with PDT is highly dependent upon the light dose delivered to the target tissue. The unit of total energy of light is joule (J) and is determined by watt (W) multiplied by time (s). The number of photons (N) in a joule depends on the wavelength (λ) of light. If two different wavelengths of light are used, the number of photons per joule varies as the inverse ratio of the wavelength (hc/λ, where h = 6.623 × 10–34 J is Planck’s constant and c = 2.998 × 108 m/s is the speed of light). Another factor that needs to be considered is fluence rate (i.e., rate of light delivered; fluence rate = W/area). Fluence rate, and thus treatment time, depends on the light source used. It the light is delivered at a high rate, significant heating of the tissue and its surrounding may take place. Generally, fluence rates less than 200 mW/cm2 (for microlens) or 400 mW/cm (for cylindrical diffusers) should be used in order to avoid thermal damage to the normal tissues (Sibata et al. 2000).
9.2.2.7 Photodynamic Therapy in Ophthalmic Disorders
PDT finds widespread use in treatment of ocular diseases. In ophthalmology, PDT is used to treat ARMD and malignant cancers. This is because maintaining the mechanical integrity of hollow organs is easy with PDT therapy since its biological effect is different from surgery, radiotherapy, and chemotherapy as connective tissues like collagen are largely unaffected. In ophthalmology, it is established for all types of ARMD such as nonexudative, exudative, dry, and wet ARMD. PDT with verteporfin along with laser photocoagulation and administration of pegaptanib sodium is known to reduce the risk of vision loss in selected cases of neovascular ARMD as well as wet ARMD (55–56). PDT with verteporfin causes stabilization or improvement of visual acuity in patients suffering from chorioretinal anastomosis (Silva et al. 2004).
Some of the other applications of PDT are in treatment of ocular herpes using antimetabolites ara A and F3T (Pavan-Langston and Langston 1975), to reduce subretinal fluid in choroidal nevus with serous macular detachment (Garcia-Arumi et al. 2012), to induce closure of superficial vasculature of pigmented choroidal melanoma with verteporfin (Tuncer et al. 2012) and with bevacizumab (Canal-Fontcuberta et al. 2012), for the treatment of progressive keratoconus using collagen cross-linking by the photosensitizer riboflavin and UVA light (Wollensak 2006), for the treatment of chronic cases of central serous chorioretinopathy with verteporfin (64–66), for the treatment of polypoidal choroidal vasculopathy [using ICGA-guided photodynamic therapy (PDT) with verteporfin, combined PDT, and antivascular endothelial growth factor (VEGF) therapy (anti-VEGF therapy)] (Wong and Lai 2013). PDT with intravitreal bevacizumab has also shown good visual improvements in cases of polypoidal choroidal vasculopathy (Fan et al. 2014). Preoperative PDT has also been useful in reducing the potential of bleeding at the time of tissue biopsy (Canal-Fontcuberta et al. 2012).
9.2.3 Photodynamic Therapy in Angiogenesis
PDT is clinically approved for the treatment of angiogenic disorders, including certain forms of cancer and neovascular eye diseases. PDT for ocular angiogenesis is generally a two-step process, consisting initially of an intravenous (within the vein) injection of photosensitizer followed by laser treatment to the targeted sites of neovascularization in the retina after 15 min. The laser treatment is intended to selectively damage the vascular endothelium. In case choroidal neovascularization persists, patients are re-treated. In some cases, PDT is combined with angiostatic agents intended to target various parts of angiogenic pathway: mRNA, VGEFs, endothelial cell proliferation, migration, and proteolysis. Some of the angiostatic agents under study are verteporfin, pegaptanib, ranibizumab, bevacizumab, anecortave acetate, squalamine, vatalanib, and triamcinolone acetonide. Some of the typical cases of angiogenesis treated with PDT are:
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Subfoveal and juxtafoveal choroidal neovascularization: Choroidal neovascularization is the most common vision-threatening complication of high myopia. In this disease, new vessels grow under the retina distorting vision and leading to scarring. Photodynamic therapy (PDT) is a new experiment treatment for CNV that combines the application of low-intensity light with a photosensitizing agent in the presence of oxygen to produce tissue effects. It uses the noninvasive potential of the laser light to cause a nonthermal localized chemotoxic reaction and obtain highly selective occlusion of the neovascular channels while sparing the overlying photoreceptors (Donati et al. 1999). Verteporfin photodynamic therapy is used in these cases due to its angio-occlusive mechanism of action that reduces visual acuity loss and underlying leakage associated with lesions. Verteporfin PDT has also been associated with encouraging treatment outcomes in case studies involving patients with choroidal vascular disorders such as polypoidal choroidal vasculopathy, central serous chorioretinopathy, choroidal hemangioma, angioid streaks, and inflammatory CNV (Chan et al. 2010). Verteporfin photodynamic therapy has also been found to be beneficial as a part of triple therapy for neovascular ARMD (Ehmann and Garcia 2010). PDT therapy has been found to effectively induce tumor regression and resolution of exudative subretinal fluid, improving or stabilizing vision in circumscribed choroidal hemangioma (Elizalde et al. 2012). Visudyne has already been approved by US FDA for the treatment of subfoveal choroidal neovascularization (Rivellese and Baumal 2000) and juxtafoveal neovascularization (Blair et al. 2004).
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Corneal neovascularization (CNV): It is excessive ingrowth of blood vessels from the limbal vascular plexus into the cornea as a result of oxygen deprivation. CNV causes significant visual loss because of the scarring and lipid deposition that frequently accompany it and is generally induced by nonspecific inflammatory stimuli mediated primarily by polymorphonuclear neutrophils. CNV can also be caused due to specific corneal immune reactions such as herpes simplex keratitis. Photodynamic therapy with argon laser following intravenous injection of hematoporphyrin derivative or purified dihematoporphyrin ether (DHE) has been used to suppress tumor growth and blood vessel growth in the eye (Epstein et al. 1987; Sheppard et al. 2006). Currently, verteporfin in conjunction with photodynamic therapy has been reported to be effective against CNV (Al-Torbak 2012).
9.2.3.1 Mechanism of Action of Molecules Used for PDT in Angiogenesis
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Verteporfin: it is composed of two semisynthetic porphyrin isomers and is four times more powerful as compared to porphyrin sensitizers when used alone. It is a chlorin-type molecule and an efficient generator of singlet oxygen. It has a maximum absorption in the UVA range with an additional absorption peak between 680 and 695 nm. Therefore, it can be activated with a low-power light that can penetrate blood, melanin, and fibrotic tissue. It binds with LDL to form a complex within abnormally proliferating cells. Thereafter, it becomes bound to intracellular or membrane components and, when activated through light, causes cellular damage (Schmidt-Erfurth and Hasan 2000).
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Pegaptanib: it is a pegylated anti-VGEF aptamer (single strand of nucleic acid that binds with a particular target). It is a selective antagonist of 165 isoform of VGEF. As a result, growth of blood vessels is curtailed to control leakage and swelling in angiogenesis (Ng et al. 2006).
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Bevacizumab: it is the first monoclonal antibody synthesized for treatment of angiogenesis in cancer. It is a recombinant monoclonal antibody that blocks VGEF-A, which is an angiogenesis stimulator. It finds application in treatment of certain metastatic cancers such as colon cancer, ovarian cancer, and renal cancer. In eye diseases, it is used in the treatment of diabetic retinopathy (Agarwal et al. 2014), neovascular glaucoma (Jiang et al. 2014), diabetic macular edema (Stewart 2014), and retinopathy of prematurity.
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Anecortave acetate: it is a unique angiostatic agent derived from glucocorticoid cortisol acetate and is a nonselective inhibitor of different angiogenic factors. It is useful in the treatment of iatrogenic glaucoma (Razeghinejad and Katz 2012) and wet ARMD (Augustin 2006) and shows promise in the treatment of choroidal neovascularization (Slakter 2006).
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Squalamine: it is an aminosterol compound obtained from dogfish shark. It has potent antimicrobial activity. It is a cationic peptide that binds to phospholipid membranes and interacts with plasma membranes of infective bacteria to prevent their function. It shows promise in the treatment of neovascular ARMD (Emerson and Lauer 2007) and exudative ARMD (Connolly et al. 2006).
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Triamcinolone acetonide: it is a synthetic fluorinated corticosteroid and is about eight times more potent as compared to prednisone. It possesses good anti-inflammatory action and therefore used in the management of ocular inflammatory disease. Its use is being explored in the treatment of diabetic macular edema (Ciulla et al. 2014).
Recently, the concept of angiostatic targeted therapy is under rapid development. It involves use of clinically effective angiogenesis inhibitors in combination with PDT (Weiss et al. 2012). However, this therapy has not got a full-fledged entrance into the clinical management of cancer mainly because of secondary complications such as inflammation and neoangiogenesis.
The recent development of anti-VEGF substances for use in clinical routine has markedly improved the prognosis of patients with neovascular ARMD. Intravitreal treatment with substances targeting all isotypes of vascular endothelial growth factor (VEGF), for the first time in the history of ARMD treatments, results in a significant increase in visual acuity in patients with neovascular ARMD. Overall, antiangiogenic approaches provide vision maintenance in over 90 % and substantial improvement in 25–40 % of patients. The combination with occlusive therapies like photodynamic therapy (PDT) potentially offers a reduction of re-treatment frequency and long-term maintenance of the treatment benefit.
9.3 Summary
Photodynamic therapy is a unique treatment modality wherein a photosensitizer localized to specific tissue/organ is activated by use of light of specific wavelength. This method has revolutionized therapeutic strategies for the treatment of several infectious as well as angiogenic diseases. It also finds promising applications in several malignant as well as nonmalignant conditions of the ocular system.
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