Photodynamic Therapy

Introduction

Photodynamic therapy (PDT) is an approved treatment for several types of tumors and certain benign diseases, based on the use of a light-­absorbing compound (photosensitizer) and light irradiation. Light-activation of the photosensitizer accumulated in cancer tissues leads to local production of reactive oxygen species that kill the tumor cells, in the presence of molecular oxygen.

PDT may also be called photoradiation therapy, phototherapy, or photochemotherapy. In respiratory care, it is used as a minimally invasive modality for treatment of premalignant and malignant lung tumors as a proven antitumor modality well tolerated and with few negative effects. The U.S. Food and Drug Administration approved PDT for the treatment of microinvasive endobronchial non-small cell lung cancer in early 1998 and for advanced partially obstructing endobronchial lung cancer in late 1998 [1]. The FDA also has approved photodynamic therapy to treat: actinic keratosis advanced, cutaneous T-cell

J. P. Díaz-Jiménez (*)

Interventional Pulmonary Department, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain

e-mail: pablodiaz@pablodiaz.org

A. N. Rodríguez

School of Medicine, National University of Mar del Plata, Buenos Aires, Argentina

lymphoma, Barrett esophagus, basal cell skin cancer, esophageal (throat) cancer, non-small cell lung cancer, squamous cell skin cancer (Stage 0).

Despite their known drawbacks, conventional interventions including surgery, radiation therapy, and chemotherapy remain the rst options in the oncologist’s toolbox for the treatment of patients. Photodynamic therapy (PDT) has been proven to be an interesting alternative to the three described treatment modalities in several indications [2, 3].

PDT can be used as solo therapy or in combination with surgery, chemotherapy, or standard radiation therapy. The primary indications are for obstructive disease and symptom palliation in patients with tumors that are not eligible for standard surgery and radiation therapy.

Photodynamic therapy is also used to relieve symptoms of some cancers, including esophageal cancer when it blocks the throat and non-small cell lung cancer when it blocks the airways [4].

Photosensitizers

Photosensitizer agents are natural or synthetic structures that transfer light energy. Although there are thousands of them that participate in nature processes such as photosynthesis, or derived from porphyrins or chlorophyll from plants and bacteria, only a few meet the necessary characteristics for PDT and only a few have been approved by the FDA for clinical use (Table 14.1). PDT has been studied for decades

and its usefulness has been recognized for a large variety of malignant tumors, but the photosensitivity phenomenon was already known in the early twentieth century.

Most of the early photosensitizers were derivatives of hematoporphyrins. Hematoporphyrins are tetrapyrrolic pigments, whose base is porphyrin, formed by four pyrrolic units linked by four methyl bridges, con guring a cyclic molecule.

In 1961, a group of physicians at Mayo Clinic reported that tumor fuorescence was enhanced when a derivative of hematoporphyrin was employed. Lipson, Baldes, and Olsen obtained “Hematoporphyrin Derivative” (HpD), a purer compound suitable for use in humans [5, 6]. In 1968 Gregory et al. published a recipe along with a report that this agent could be used to localize

neoplasia by the resulting tumor fuorescence. They administered intravenously hematoporphyrin derivative to 226 patients to study fuorescence of various lesions utilizing a Baldes activating blue violet light. One hundred seventy-­ three patients of them had malignant neoplasms and 53 patients had benign lesions. Result was that 132 (76.3%) of the malignant lesions showed tumor fuorescence, while only 12 of the benign had fuorescence (22.6%) [7].

In the mid-1970s, the rst successful treatment of animal tumors was performed at the Roswell Park Memorial Institute, using a xenon lamp as the light source. The introduction of laser equipment resulted in much faster progress in PDT. In the early 1980s, PDT was used to treat early stages of squamous cell lung cancer.

In 1983 Dougherty found a new component in HpD: bis-1,3 (I hydroxyethyl) deuteropor n 8 ethyl ether or dihematoporphyrin (DHE), which seemed to be responsible, among the mix of components of HpD, for the ability to sensitize tumors [8].

Another known sensitizer is tetraphenylsulfonate (TPPS), capable of being as active as HpD. Its neurotoxicity and its slow elimination from the serum mean that it cannot be applied clinically [9].

The correct choice of the photosensitizer is important for a successful response to PDT’s treatment. PS must be non-toxic for the cells in absence of light exposure and should be selectively retained by the target (malignant) cells. Also, PS should be able to induce an immunogenic response over treated cells as changes of surface glycoproteins receptors and consequently activate a cascade of immunologic cells response and malignant cells death [10].

An ideal photosensitizer should have the following qualities: signi cant chemical purity, effective absorption af nity at an appropriate wavelength between 400 and 800 nm, with high quantum yield singulate oxygen production, minimal toxicity in the dark, and delayed phototoxicity, easy dissolution in injectable solvents, good stability and selective tumor localization.

Based on their speci c characteristics and the time of development, PSs have been classi ed in generations.

First-Generation Photosensitizers

Por mer Sodium (Photofrin®). It is the most extensively studied photosensitizer. In January 1998, the Food and Drug Administration approved in the United States the use of Photofrin® (por mer sodium) for PDT in patients with microinvasive lung tumor who are ineligible for surgery or radiotherapy [11].

The palliation use of certain tumors was approved in 1997.

Photofrin® and its predecessor, hematoporphyrin derivative are obtained by a complex mixture of esters from hematoporphyrin. The cytotoxic effect for PDT is limited by the maxi-

mum penetration capacity of the laser light at 630 nm wavelength. This wavelength has the highest power to penetrate tissue from 3 to 5 mm.

Following the administration of Photofrin, there is a systemic photosensitivity period that can last up to 6 weeks.

However, its low light absorption within the therapeutic window (from 600 to 700 nm) and prolonged photosensitivity made that second-­ generation photosensitizers with better absorption features and fewer adverse reactions were developed.

Photofrin®-PDT proves to be effective as a palliative treatment in lung cancer, but is associated with prolonged photosensitivity of the skin. In addition, it is less effective with lesions larger than 1 cm.

Although the majority of photosensitizers at the preclinical stage are porphyrin derivatives, a diverse number of nonporphyrin photosensitizers also exist.

Second-Generation

Photosensitizers

Despite the fact that PDT has slowly progressed in its oncological therapeutic applications due to the low sensitivity and phototoxicity produced byrst-generation sensitizers, research into second-­ generation photosensitizers has meant that in recent years PDT, once again, has the place that it deserves as an effective and well-tolerated modality with fewer adverse effects than chemotherapy or radiotherapy in the treatment of cancer.

In order to improve the ef cacy of PDT, and specially to ensure that the photosensitizer reaches the malignant cell and destroys it avoiding secondary effects on healthy cells as much as possible, researchers also are trying to nd new photosensitizers that make it more selective and effective and with fewer adverse effects.

Several studies have recently been conducted to better characterize the ef cacy and selectivity of PSs. New photosensitizers of the second generation present advantages due to their characteristics of better penetration, developing agents with longer absorption wavelengths that allow

better penetration in the target tissues. The goal of using these second-generation PSs was to achieve better tumor selectivity and reduce the total drug dose. The advantage of using lower doses is that the product is eliminated faster and the photosensitivity of the skin can be reduced from weeks to days [12].

Benzoporphyrin Derivate (BPD)  It is a second-­ generation of PS, which is a hydrophobic molecule with a maximum absorbing peak at 690 nm, higher than the absorption of the hemoglobin. So it is not attenuated by the blood and has a maximum tissue penetration. Furthermore, BPD is quickly accumulated in the target tissue allowing a PDT treatment from 30 to 150 min after intravenous injection. It is also rapidly cleared from the body. Photosensibility of the skin does not extend more than a few days [13].

Aminolevulinic Acid (ALA)  Endogenous photosensitization induced byALA is a new approach for photodynamic therapy and tumor detection. It consists in a biosynthetic reaction to produce endogenous porphyrins Hem, particularly photopor rine IX, which is a very effective photosensitizer that accumulates in mucosal surfaces, such as skin, conjunctiva, oral, rectal, vaginal, endometrial, and ureteral mucosa [14].

It has been used with acceptable results to treat super cial tumors of the skin, such as the basal cell carcinoma, squamous cell carcinoma, and adenocarcinoma. Residual photosensitivity after treatment lasts about 48 h.

ALA has been also applied orally and by aerosol inhalation via jet nebulizer, showing that both modalities were well tolerated, allowing tumor visualization and after oral administration it was possible to perform photodynamic therapy. At 5 and 12 weeks after PDT, marked reduction in tumor volume and recanalization of the bronchus was observed bronchoscopically, with no associated adverse effects [15].

ALA fuorescence can be used in the detection of bladder lesions, early stage “in situ” lung carcinoma, and malignant glioma.

Chlorins have been extensively investigated for their potential to treat oral cancer. Extensive cellular damage and complete tumor regression within a week treatment have been reported [16].

Although chlorine exhibits good water solubility and stability, aqueous solutions did not represent the best delivery system in many tumors such as oral cavity or endobronchial tumors. A combination to a mucoadhesive delivery system shows to increase the absorption in the target tissue and improves the overall outcomes [17].

N-Aspartyl Chlorin e6 (NPE6)

(Talaporfn Sodium, Laserphyrin®),

Meiji Seika, Tokyo, Japan

NPE6 is a second-generation, water-soluble photosensitizer with a molecular weight of 799.69 and a chlorine annulus. Its maximum absorption peak is at a wavelength of 407 nm, and there is a second peak at 664 nm.

It belongs to the second generation of PS that stands out for its excellent antitumor effects and rapid skin clearance in laboratory animals. The Npe6 has a longer absorption band (664 nm) than Photofrin®, so it has a slight advantage in deep tumor treatment. The administered dose is 40 mg/ m2 and the laser power density is 100 J/cm2.Adverse effects are minimal and cutaneous photosensitivity disappears within 2 weeks after administration. It has been approved by the Japanese authorities (Japan Ministry of Health, Labor and Welfare) since 2004 for lung cancer treatment, and from early 2010 for advanced lung cancer treatment.

M-Tetrahidroxofenil Cloro (mTHPC) (Foscan®)

It is a synthetically pure chlorine derivative whose best quality is to produce a rapid photodynamic reaction. It is very effective at treating primary and recurrent head and neck cancers. The drug is so active that after administration, patients must stay in a dark room for 24 h, as room light will activate the drug and cause severe burns. The