Handbook of Photodynamic Therapy

The following sections are included:

• Contents
• Preface

The work summarized in this chapter is focused on the chemical constituents of Photofrin, its limitations and the strategy to take the advantage of porphyrins and reduced porphyrin-based compounds in developing improved imaging and image-guided dual function agents. Advantages of polyacrylamide (PAA)-based nanoparticles (NPs) for enhancing the tumor-avidity are also discussed. Such an approach under proper strategies could help in developing other targeted multifunctional, biodegradable, biocompatible and non-toxic NPs for cancer-imaging and therapy, which is otherwise difficult to achieve.

The design and synthesis of covalently linked photosensitizer-peptide conjugates are reviewed in this chapter. Peptides of relatively small size (<50 amino acids) are most commonly used for enhancing the photosensitizer targeting specificity, due to their straightforward synthesis and ease of conjugation to photosensitizers. Porphyrin, chlorin and phthalocyanine macrocycles are the most common PDT photosensitizers used in the conjugation reactions to peptides, generally via a low molecular weight linker, following either solution or solid phase protocols. These so-called third-generation photosensitizers have shown increased selectivity for targeting specific cell enzymes or receptors, and enhanced PDT efficacy compared with unconjugated photosensitizers.

meso-Substituted porphyrins present a readily accessible class of porphyrins which has found wide applications in biomedical sciences. Contemporary syntheses allow the generation of large libraries of compounds with variable meso-substituents or the preparation of bioconjugates. This chapter summarizes current synthetic strategies and medicinal chemistry applications of meso-substituted porphyrins in photodynamic therapy (PDT).

The synthesis, photophysical properties, biological properties, and phototoxicity in vitro and in vivo are summarized for core-modified porphyrins in which pyrrolic NH groups are replaced with O, S, Se, or Te atoms at the 21- or 21, 23-positions.

Photodynamic therapy (PDT) is a form of phototherapy using nontoxic, light-sensitive compounds that upon exposure to light generate toxic, reactive oxygen species (ROS) targeting malignant and other diseased cells (phototoxicity). Most modern PDT applications involve three key components: A photosensitizer (PS), a light source and molecular oxygen. PDT is used clinically to treat a wide range of medical conditions, including wet age-related macular degeneration and various cancers, and it is recognised as a treatment strategy that is both minimally invasive and minimally toxic. Phthalocyanines (Ps) and its derivatives are structurally related to porphyrins. They have been advanced as PS for PDT due to their strong absorption in the visible region (strong Q band bands around 670 nm) and high quantum yield for the generation of ROS. To optimize PDT efficacy for selected applications their lipophilic and hydrophilic properties can be modulated by modifying peripheral substituants and the central metal ion. Furthermore their target specificity can be improved through conjugation to biomolecules. In this chapter we address potential structure-activity relationships of phthalocyanine-based PS and review their clinical potential.

Phthalocyanines represent a versatile class of functional dyes. Owing to their desirable spectroscopic and photophysical properties, high photostability, and ease of chemical and physical modification, these compounds have emerged as promising photosensitizers for photodynamic therapy. This chapter aims to summarize the recent development of molecular phthalocyanine-based photosensitizers being reported over the last five years, including hydrophilic analogues with non-ionic, cationic, or anionic moieties, and bioconjugated derivatives substituted with carbohydrates, peptides, nucleic acids, polyamines, or folic acid. Novel phthalocyanines that exhibit dual functions and can be activated by tumor-associated stimuli are also described. The review will focus on their molecular design, synthesis, photophysical characteristics, and in vitro and in vivo photodynamic activities.

Phototherapies including photodynamic therapy (PDT) and photothermal therapy (PTT) are extensively investigated as potent alternative therapeutic modalities for cancer treatment. Porphyrins, the nature existed chromophores, have a rich history of phototherapy, especially for PDT. Paramount efforts have been involved in the development of porphyrin-based photosensitizers to enhance therapeutic efficacy and decrease toxicity. The union of porphyrin and nanotechnology offers new perspective to improve the safety and efficacy of porphyrin-based PDT. Various nanovectors, both organic and inorganic, have been investigated on porphyrin delivery for high payload photosensitizers, protection from pre-mature release and tumor-selective targeting. Most recently, the development of porphyrin-based “one-for-all” nanoparticles has opened up a brand new avenue for rational design of multifunctional nanoconstruct with multimodal imaging and therapeutic capabilities. When porphyrin is utilized as built-in elements to form the nanostructure, the high densely packed or orderedly aggregated porphyrin produce new photonic properties beyond porphyrin monomer, such as photoacoustic and photothermal properties. Marching on the frontline of cancer theranostics, porphyrin nanotechnology is turning one of nature's most fascinating molecules into powerful imaging and therapeutic platforms.

This chapter uses a glossary format to introduce the reader to fundamental concepts in the dosimetry of photodynamic therapy (PDT). Each term is defined in the context of PDT dosimetry and its importance is discussed in the light of current knowledge and recent developments. The goal of the chapter is to make the literature in the field accessible to those without an extensive background in optics, photophysics, or radiation transport. The chapter concludes with a discussion of the importance of dosimetry in the future of PDT.

Photodynamic therapy (PDT) elicits a variety of signals that can lead to both cell death and cytoprotection. The irreversible process of apoptosis is readily initiated by mechanisms involving mitochondrial or lysosomal photodamage. An often competing process is autophagy, a pathway that can lead to recycling of photodamaged organelles before they can initiate apoptosis. There can be crosstalk between these processes with sometimes unpredictable results. The net effect is that a relatively minor degree of photodamage can result in a significant level of cell death. More recent studies point to the possibility that combinations of PDT with chemotherapy, or even involving multiple photosensitizers can promote PDT efficacy.

The localized damage of tumor vasculature contributes to the therapeutic effect of photodynamic therapy (PDT) in many of its oncologic uses. As a function of the treatment protocol, vascular effects can manifest as vasoconstriction, vasodilation, hemostasis, and/or hyperpermeability, among other hemodynamic changes. The extent and nature of vascular damage will depend on treatment-specific factors, such as the photosensitizer used (targeted or untargeted, pharmacokinetics and dosing), drug-light interval, and illumination fluence and fluence rate. Moreover, microenvironmental factors specific to the pre-existing structure (e.g., stromal composition) and function (e.g., flow velocity) of tumor blood vessels may determine their sensitivity to PDT. PDT-created vascular damage is integral to the inflammatory response that can accompany it, and may also play a role in the development of anti-tumor immunity. Simultaneous with vascular and immune effects, survival signaling can be activated by PDT, potentially detracting from tumor response. Indeed, combination therapies that include molecular targeting of PDT-upregulated pathways, such as those involved in angiogenesis, have proven beneficial to long-termtumor response. The advantages and limitations of PDT-triggered vascular damage are also evident in its clinical application. Looking ahead, the incorporation of hemodynamic monitoring in clinical trials of PDT may provide a means for individualized optimization of treatment.

A derivative of Nile Blue, a small molecule dye which selectively stains tumors, EtNBS has in recent decades become a popular photosensitizer in photodynamic therapy (PDT). Its structure has been designed to maximize its photosensitization capability and to improve upon the shortcomings of earlier porphyrin-based photosensitizers. EtNBS rapidly localizes to the lysosome and efficiently absorbs light at a wavelength of 652 nm. Unlike many photosensitizers, it can operate via both oxygen-dependent and oxygen-independent pathways with remarkable efficiency. As a result, PDT with EtNBS has shown particular promise in the eradication of entire tumors, including the hypoxic, acidic cores of nodules that have traditionally been unresponsive to most therapeutic regimens. EtNBS has also been investigated, with success, as a possible treatment for Gram-negative and Gram-positive bacterial infections, leishmaniasis, tuberculosis, and fungal infections, among many other diseases.

Many malignant tumors exploit endogenously generated nitric oxide (NO) as a pro-survival molecule, a role often linked to constitutive expression of inducible nitric oxide synthase (iNOS). NO is known to antagonize the antitumor effects of ionizing radiation, chemotherapeutic agents, and also photodynamic therapy (PDT), the latter effect recognized relatively recently. This chapter will focus on low level NO as a tumor-promoting signaling molecule and how it can compromise PDT efficacy by stimulating tumor microvasculature relaxation or more directly by enhancing tumor cell resistance to photokilling and also proliferation, migration, and invasiveness of surviving cells. To be discussed (along with its troubling implications) is the striking observation that for certain cancer cell types, these negative effects are attributable more to PDT stress-induced iNOS/NO than to preexisting iNOS/NO. Approaches for overcoming NO's still poorly recognized anti-PDT activity through pharmacologic use of appropriate iNOS inhibitors will also be discussed.

The introduction of Visudyne-photodynamic therapy (PDT) to the treatment of choroidal neovascular, (CNV) age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) has rescued millions of patients from vision loss and blindness. Especially in the case of PCV, the clinical results obtained with PDT, in combination with angiogenesis inhibitors, vascular disrupting agents, or/and anti-inflammatory compounds as adjuvant therapies, may well keep PDT as one the main treatment options. In the present article we review past and very recent data on PDT in PCV, including combination therapies.

Photodynamic therapy (PDT) is a FDA approved minimally invasive medical treatment modality that utilizes light in the presence of oxygen to activate photosensitizing agents that are relatively selectively concentrated in abnormal or neoplastic cells resulting in cell death. At the present time, PDT has been approved for clinical treatment in the United States, European Union, Canada, Russia, and Japan. In the EU Foscan has been approved for the treatment of early head and neck cancers and palliative treatment of head and neck cancer. In the United States, PDT treatment of head and neck cancer is performed off label using Photofrin, as to date there are no photosensitizers approved by the U.S. FDA for the treatment of head and neck cancers.

PDT is an excellent minimally invasive modality for the treatment of carcinomas of the head and neck as the treatment preserves normal tissue. First and second generation photosensitizer PDT has been effective in the treatment of early head and neck cancers, including severe premalignant dysplasia, Tis, T1, and T2 cancers of the oral cavity, pharynx and larynx with complete response rates of 71–90%. In addition, combination therapies and targeted therapies are being investigated that may improve the therapeutic efficacy of PDT to treat later stage disease and recurrent cancers of the head and neck, including ChemoPDT and Photoimmunotherapy (PIT).

Patients suffering from advanced esophageal cancer ineligible for curative surgery still have a poor prognosis. Photodynamic Therapy (PDT) represents a gentle and effective approach beneath the different palliative treatment options for this aggressive malignancy. The mechanism of function is based on the illumination of malignant esophageal tumor tissue after selective accumulation of the specific photosensitizer in these tumor cells. As a result of this photochemical reaction distinct necrosis of the endoluminal tumor load develops quickly and sustainably. In case of esophageal cancer, PDT is performed endoscopically under general anaesthesia. By means of PDT, considerable reduction of the endoluminal tumor load associated with increased quality of life can be achieved which helps conditioning the patient for further palliative treatment procedures. However, local endoluminal palliation with the aim to improve swallowing, decreament of dysphagia and therefore improvement of the patient´s quality of life are the main therapeutic goals of PDT in case of inoperable esophageal cancer. Therefore, PDT has become an accepted as well as safe, feasible and efficient endoscopic treatment option within the various multimodal treatment procedures for advanced inoperable esophageal cancer.

Photodynamic therapy (PDT) for lung cancer is becoming increasingly common. In Japan, PDT is recommended as a treatment option for centrally located early-stage lung cancers (CLELCs). The second generation photosensitizer, Laserphyrin has strong anti-tumor effects with much less photosensitivity than Photofrin. Moreover, the laser equipment is compact and portable, and Laserphyrin is now the current mainstay of PDT for lung cancer. For successful PDT, accurate evaluation of tumor extent and bronchial invasion is crucial. Detailed examination of the tumor using autofluorescence bronchoscopy (AFB) and endobronchial ultrasonography (EBUS) or optical coherence tomography is extremely useful before PDT. At present, PDT has become the first choice of treatment for CLELC in institutions with the necessary equipment. It can also be effective for advanced lung cancer causing tracheobronchial obstruction. With such advances in PDT for CLELC, we are expanding the indications of PDT for not only CLELC, but also peripheral type lung cancer.

Today the increasing resistance of bacteria against antibiotics is one of the most important clinical challenges. Beside the investigation and development of new drugs, it is absolutely necessary to focus also on other antibacterial approaches like antimicrobial photodynamic therapy (PDT). In the photodynamic process, visible light is absorbed in a harmless dye molecule (photosensitizer), which transfers the absorbed light energy mainly to adjacent oxygen molecules generating highly reactive oxygen species (ROS). In case the photosensitizer is a cationic molecule, it can attach to the negatively charged surface of bacteria. Then, ROS are generated directly at the bacteria cell wall upon light irradiation. Bacteria are killed via oxidative damage and killing efficacy is independent of bacterial resistance pattern. Due to the simple oxidative mechanisms, the development of resistance against antimicrobial PDT is very unlikely. The photodynamical produced ROS can be permanently applied on surfaces to kill bacteria which settle down on such a surface.

The incidence and prevalence of bacterial and fungal infections will continue to increase because of (i) more frequent use of broad-spectrum antibiotics and antifungals as well as immunosuppressive medications (ii) increased number of invasive medical procedures and (iii) higher incidence of neutropenia and HIV infections. In addition to the adverse side effects, the growing resistance against both antibiotic and antifungal agents has driven the continuing search for alternative treatment modalities. One promising option is photodynamic therapy (PDT). Numerous in vitro studies have clearly demonstrated activity of PDT against viruses, bacteria, yeast-like fungi and dermatophytes, using photosensitizers that include phenothiaziniums, porhyrins and phthalocyanines. Our lab has demonstrated that PDT sensitized by silicon phthalocyanine (Pc) 4 can efficiently induce cell death of Candida albicans, Trichophyton rubrum and Staphylococcus aureus. Because of the mechanism of action of PDT, which involves oxidative damage to cell membranes, microbial killing was observed in all species, regardless of their susceptibility or resistance to standard antimicrobial agents.

There are numerous clinical and scientific individuals carrying out Photodynamic Therapy (PDT) on patients throughout the world, but most have no idea how to go about obtaining permission to use new drugs or treatments for these patients. In this paper one example of this process by a new, small company is described. You will find that approval for patient treatment is daunting even when you think you are doing this correctly.

The following sections is included:

• Index