Photodynamic therapy involves administration of a tumor-localizing photosensitizing agent, which may require metabolic synthesis (i.e., a prodrug), followed by activation of the agent by light of a specific wavelength. This therapy results in a sequence of photochemical and photobiologic processes that cause irreversible photodamage to tumor tissues. Results from preclinical and clinical studies conducted worldwide over a 25-year period have established photodynamic therapy as a useful treatment approach for some cancers. Since 1993, regulatory approval for photodynamic therapy involving use of a partially purified, commercially available hematoporphyrin derivative compound (Photofrin) in patients with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract has been obtained in Canada, The Netherlands, France, Germany, Japan, and the United States. We have attempted to conduct and present a comprehensive review of this rapidly expanding field. Mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed. Technical issues regarding light dosimetry are also considered.

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A novel nanoparticle-based drug carrier for photodynamic therapy is reported which can provide stable aqueous dispersion of hydrophobic photosensitizers, yet preserve the key step of photogeneration of singlet oxygen, necessary for photodynamic action. A multidisciplinary approach is utilized which involves (i) nanochemistry in micellar cavity to produce these carriers, (ii) spectroscopy to confirm singlet oxygen production, and (iii) in vitro studies using tumor cells to investigate drug-carrier uptake and destruction of cancer cells by photodynamic action. Ultrafine organically modified silica-based nanoparticles (diameter approximately 30 nm), entrapping water-insoluble photosensitizing anticancer drug 2-devinyl-2-(1-hexyloxyethyl) pyropheophorbide, have been synthesized in the nonpolar core of micelles by hydrolysis of triethoxyvinylsilane. The resulting drug-doped nanoparticles are spherical, highly monodispersed, and stable in aqueous system. The entrapped drug is more fluorescent in aqueous medium than the free drug, permitting use of fluorescence bioimaging studies. Irradiation of the photosensitizing drug entrapped in nanoparticles with light of suitable wavelength results in efficient generation of singlet oxygen, which is made possible by the inherent porosity of the nanoparticles. In vitro studies have demonstrated the active uptake of drug-doped nanoparticles into the cytosol of tumor cells. Significant damage to such impregnated tumor cells was observed upon irradiation with light of wavelength 650 nm. Thus, the potential of using ceramic-based nanoparticles as drug carriers for photodynamic therapy has been demonstrated.

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Abstract. Advances in the use of photosensitizers for detection and treatment of malignant tumors during the previous reviews in this journal have been mainly in the areas of development of potentially useful new photosensitizers (e.g. phthalocyanines and chlorins), further understanding of the mechanisms of photodynamic therapy (PDT), and in dosimetry of light delivery in tissue. Perhaps the most significant advance during the past year has been the initiation of Phase III clinical trials of PDT vs standard therapy in treatment of superficial bladder cancer and obstructive endobronchial tumors. In the final analysis, only such clinical trials can determine the future of this new modality for cancer treatment.

Photodynamic therapy (PDT), following health agency approvals throughout the world for various cancers and other diseases, is slowly being accepted as a standard treatment to be added to the medical practitioner's armamentarium. This includes palliative treatments such as for obstructive esophageal and lung cancers as well as those intended for cure, early stage lung cancer, and actinic keratoses. A particularly new and important application is for the treatment of age-related macular degeneration (AMD), where PDT (Visudyne) has made a major impact on the outcome of this disease, the major cause of blindness in those over the age of 50. In the cancer field, while not yet approved (pending), the use of PDT in treatment of high-grade dysplasia (HGD) in Barrett's esophagus may well change how this disease is currently treated (often esophagectomy). Mechanistically, the recognition of apoptosis as an important mode of cell death following PDT and the critical role of the inflammatory process and immunity has only recently been recognized. This review updates the current and future role of PDT in cancer and other diseases.