Photodynamic therapy (PDT) employs a photosensitizing agent that preferentially accumulates, at least to some degree, in malignant tissues and the tumor vasculature. The photosensitizer (PS) is then activated by light of a specific wavelength and intensity (termed fluence). Upon the photosensitizer’s capture of light energy, the energy is transferred and translated into chemical reactions in the presence of molecular oxygen. These reactions produce singlet oxygen and/or superoxide ions, and they induce cell damage through direct and indirect mechanisms. These highly reactive forms of oxygen can be damaging and ultimately destructive to the tumor and its blood supply. The interplay between light, oxygen and photosensitizer results in a complex whole-body process that ultimately may involve increased activity of the immune system against residual cancer cells and metastases.
PDT has received increased attention in recent years due to the limitations of traditional cancer therapies and thanks to the regulatory approvals granted for several photosensitizing drugs and light applicators worldwide. Nevertheless, despite the publication of thousands of peer-reviewed articles on the clinical application and basic science of PDT, the total number of approved clinical indications for PDT remains extremely small. Moreover, despite the fact that numerous natural or synthetic structures have been found to be photosensitizing agents, only a handful of these agents have undergone clinical trial evaluation. Even fewer have been approved for clinical use and are commercially available.
The specific choice of photosensitizer, along with a compatible light source, may be considered the most critical elements in PDT. The future evolution of PDT will depend largely on the development of more effective photosensitizers. A recent review of PDT by Ron Allison, MD, the current editor-in-chief of the medical journal Photodiagnosis and Photodynamic Therapy, proposes that a successful photosensitizing agent should meet most of the following criteria:
- High quantum yield, allowing for rapid generation of singlet oxygen and thus shorter treatment times (measured in minutes);
- Targeting, with the photosensitizer showing a strong affinity for malignant or diseased tissue, minimizing oxidative damage to normal tissue as far less photosensitizer is present in normal tissue; no photosensitizer has yet achieved perfect targeting or a perfect therapeutic index (ratio of photosensitizer in tumor tissue versus normal tissue);
- Rapid pharmokinetics, which allows the photosensitizer to concentrate in the lesion quickly so therapy can start shortly after its application, as well as rapid elimination of the photosensitizer to minimize the risk of photosensitivity or other unintended consequences of photodynamic reactions;
- Minimal skin photosensitivity, meaning that minimal photosensitizer should be found in the skin and other organs in order to reduce the risk of adverse effects in those tissues (sunlight is strong enough to activate any photosensitizer, and precautions to prevent skin burn may be needed);
- Optical window, allowing light of various wavelengths to activate the photosensitizer. Whereas longer wavelengths are needed for deeper tissue penetration, shorter wavelengths can be used for treatment of superficial lesions;
- Lack of dark toxicity, with activation of the photosensitizer occurring only upon illumination or light exposure;
- Fluorescence, allowing for visualization of the borders or extent of the cancer (tumor margins) and, critically, as a means of enabling accurate dosimetry;
- Amphiphilicity, allowing for ease of systemic distribution of the photosensitizer to the target tissue, without the need for carriers to facilitate transport and uptake by the target tissue;
- Lack of toxic degradation products, with the photosensitizer being degraded during PDT, and without the creation of downstream toxic byproducts.
Other key criteria pertain to the pragmatic, logistical, and regulatory aspects of the photosensitizer:
- Ease of administration, a safe, painless formulation allowing for oral, topical or intravenous modes of administration;
- Painless, a pain-free therapy that enables outpatient, cost-effective treatment while also avoiding the substantial costs incurred by hospitalization, anesthesia and recovery;
- Synthetic purity, so that each batch of photosensitizer produced by the manufacturer will perform in an identical manner;
- Ease of production, allowing for commercialization of the product and the capacity to meet a potentially large demand;
- Stability during storage, allowing for transport of the product to the treatment facility;
- Commercial availability, with regulatory agency approval of the photosensitizer (“clinically approved”) and thus market authorization for clinical use.
Several commercially available, clinically approved photosensitizers have resulted in successful treatment outcomes for certain cancers and precancers. Nevertheless, none of the photosensitizers currently available on the market meet all of these criteria. The lack of optimal features or characteristics in the currently approved photosensitizing agents has probably impeded the advancement of PDT. Other reasons for the lack of progress in this area have to do excessive specialization among oncologists, along with a large cancer care infrastructure that is biased toward surgery, radiotherapy and chemotherapy as the “established” modalities for modern cancer treatment.
Categories of Photosensitizers
Photosynthesizers for PDT are broady divided into first-, second-, and third-generations. First-generation PDT agents, such as Photofrin®, lack long wavelength absorption and thus do not allow the photodynamic treatment to penetrate deeply into tissues. Moreover, these agents are not cleared easily from the body and thus can lead to prolonged photosensitivity reactions in the skin. Second-generation photosensitizers exhibit an absorption band in the longer wavelength region, allowing for deeper penetration of the light treatment into tissues. These agents also have fewer side effects than the first-generation photosensitizers.
More recently, nanotechnology has introduced various targeting strategies, such as the use of liposome encapsulation, in order to further boost the affinity of the photosensitizer for tumor tissue. This can result in a heightened ability to selectively concentrate in the tumors as well as to selectively target subcellular structures such as the mitochondria. Such nanoscale targeting strategies have led to the evolution of third-generation photosensitizers; however, research is lacking as to whether the third-generation agents confer any major advantages over second-generation agents.
Photosensitizers can be further categorized according to their chemical origins and structures. In general, they can be divided into three broad groups: (1) porphyrins or porphyrin-based photosensitizers; (2) chlorophylls or chlorophyll-based photosensitizers (e.g., chlorins, bacteriochlorins, purpurins), and (3) dyes such as napthalocyanine and phtalocyanine. Most of the currently approved clinical photosensitizers and most second-generation photosensitizers are in the first group, the porphyrin-based agents. Porphyrins comprise the backbone of hemoglobin and chlorophyll.
The chlorins, an important group of chlorophyll-derived agents, are highly successful photosensitizing agents and may soon surpass porphyrins as the photosensitizers of choice for the treatment of lung cancer, esophageal cancer, stomach cancer, and other solid tumor types. In particular, chlorin-based agents such as Bremachlorin® and Temoporfin® appear to be the most effective second-generation photosensitizers.
In summary, photosensitizers tend to vary widely in the ways they are metabolized and utilized by the body. The ideal photosensitzing agent is taken up easily by cancer cells (or other diseased or abnormal cells) and then retained within the tumor (or other diseased tissues). At the same time, the agent is rapidly excreted or cleared from normal, healthy tissues. When the concentration of the photosensitizer is much higher in malignant than in normal tissues, this can lead to the highly targeted destruction of cancerous and precancerous tissues, with very few if any side effects. This ability to more selectively target the cancer has provided a powerful impetus for studying PDT as a major modality for the treatment of cancer, one that can help reduce the need for toxic chemotherapy and radiotherapy.
The Challenge of Comparing Different Photosensitizers
A central question is how the various photosensitizers compare to each other. Unfortunately, even at the in vitro level, only a few studies have compared the currently used photosensitizers. One example of such research was a cell culture study by Berlanda and colleagues at the University of Salzburg (Austria) that involved a comparison of the six most widely used photosensitizers. The Berlanda study found that Foscan and a similar formulation called Fospeg exhibited the lowest LD50 values (a measure of the lethal dose). This finding alone would indicate that Foscan and Fospeg are better photosensitizers. However, the respective IC50 values (a measure of how much of a particular drug is needed to inhibit a given biological process by half) for Foscan and Fospeg were higher than those of the other photosensitizers—an unfavorable finding.
In the Berlanda study, a number of significant differences were found between the various photosensitizers. Overall, however, the results of this study were too mixed to offer any meaningful conclusions. This study helps highlight some of the challenges involved in choosing the best photosensitizer for a given clinical purpose. First, a truly meaningful comparative study can only take place at the clinical level, with humans receiving PDT with different photosensitizers. The very poor tolerability of Foscan in humans places helps place the findings from the Berlanda study in the proper perspective. The ability of a drug to destroy tumors must be counterbalanced by its side effects profile. Any drug with a large number of side effects should be considered a poor choice for PDT, especially when photosensitizers with similar tumor-killing effects and far better tolerability are available.
Preclinical studies that seek to address the effects of photosensitizers for specific therapeutic outcomes, such as the killing of specific types of cancer or disease-causing bacteria, may offer some preliminary insights into the value of such agents. For example, a 2012 study by biochemists at the University of Aveiro (Portugal) sought to compare the effects of a porphyrin photosensitizer to those of a chlorin-based photosensitizer. The chlorin agent showed superior ability to destroy antibiotic-resistant bacteria, particularly with longer wavelengths of light, which allow for deeper tissue penetration. Such studies could also be done at the in vivo level to asses the ability to kill specific tumor types.
Ultimately, however, comparative studies of different photosensitizers must be done at the clinical level. The ideal study would assess the effects of different photosensitizers in different groups of patients who have the same diagnosis, such as early-stage lung cancer or recurrent bladder cancer. Unfortunately, the patient numbers in many clinical trials involving PDT tend to be very small, and most clinical trials focus only on one drug rather than a comparison of different photosensitizers.
In order to understand the relative strengths and limitations of photosensitizers currently in use or in development, we have constructed the following overview comparing seven different photosensitizers. It is hoped that such comparisons may improve the process of choosing better photosensitizers in the future.
Staron J, Boron B, Karcz D, Szczygiel M, Fiedor L. Recent Progress in Chemical Modifications of Chlorophylls and Bacteriochlorophylls for the Applications in Photodynamic Therapy. Curr Med Chem. 2015;22(26):3054-74.
O’Connor AE, Gallagher WM, Byrne AT. Porphyrin and nonporphyrin photosensitizers in oncology: preclinical and clinical advances in photodynamic therapy. Photochem Photobiol. 2009 Sep-Oct;85(5):1053-74.
Garland MJ, Cassidy CM, Woolfson D, Donnelly RF. Designing photosensitizers for photodynamic therapy: strategies, challenges and promising developments. Future Med Chem. 2009 Jul;1(4):667-91.
Josefsen LB, Boyle RW. Photodynamic therapy: novel third-generation photosensitizers one step closer? Br J Pharmacol. 2008 May;154(1):1-3
Berlanda, J., T. Kiesslich, V. Engelhardt, B. Krammer and K. Plaetzer. Comparative in vitro study on the characteristics of different photosensitizers employed in PDT. J. Photochem. Photobiol. B:Biol. 2010; 100, 173–180.
Costa DC1, Gomes MC, Faustino MA, Neves MG, Cunha A, Cavaleiro JA, Almeida A, Tomé JP. Comparative photodynamic inactivation of antibiotic resistant bacteria by first and second generation cationic photosensitizers. Photochem Photobiol Sci. 2012 Dec;11(12):1905-13