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.

Photodynamic Therapy

Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

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Photodynamic therapy of cancer: An update†‡

A review of reported tissue optical properties summarizes the wavelength-dependent behavior of scattering and absorption. Formulae are presented for generating the optical properties of a generic tissue with variable amounts of absorbing chromophores (blood, water, melanin, fat, yellow pigments) and a variable balance between small-scale scatterers and large-scale scatterers in the ultrastructures of cells and tissues.

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Optical properties of biological tissues: a review.

Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.

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Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects.

Sasidharan Swarnalatha Lucky,†,§ Khee Chee Soo,‡ and Yong Zhang*,†,§,∥ †NUS Graduate School for Integrative Sciences & Engineering (NGS), National University of Singapore, Singapore, Singapore 117456 ‡Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore 169610 Department of Biomedical Engineering, Faculty of Engineering, National University of Singapore, Singapore, Singapore 117576 College of Chemistry and Life Sciences, Zhejiang Normal University, Zhejiang, P. R. China 321004

Nanoparticles in photodynamic therapy.

Purpose: The present study investigates the efficacy of compartmental targeting in xenografted tumours treated by meta-tetra (hydroxyphenyl) chlorin (mTHPC) mediated photodynamic therapy (PDT). The therapeutic efficacy was further related to a regional photoinduced distribution of apoptosis and mTHPC biodistribution profile. Methods and Materials: Mice bearing EMT6 tumours were subjected to a single irradiation (10 J/cm2) of red laser light (652 nm) at different intervals after a single (0.3 mg/kg or 0.15 mg/kg) or double intravenous (2 x 0.15 mg/kg) injection(s) of mTHPC. Efficiency of the treatment was evaluated by monitoring tumour regrowth. mTHPC pharmacokinetics were assessed by HPLC analysis of excised organs. Regional distribution of apoptosis in tumour sections was investigated with a newly developed co-labelling immunohistochemistry technique. Results: A fractionated double injection protocol of mTHPC with 24h and 3h drug-light interval (DLI) yielded 100% tumour cure with tumours presenting a massive apoptosis of neoplastic cells along with a distortion of vessels. The best efficiency for a single injection (0.3 mg/kg) was about 54% tumour cures and corresponded to a DLI of 3h. At this DLI tumours showed apoptosis of endothelial cells in residual vessels. Concentrations of mTHPC observed in plasma and tumour for the fractionated injection were not statistically different and were less than the total drug dose in each compartment. Conclusions: The present work suggests that clinical PDT protocols with mTHPC could be greatly improved by fractionation of the drug administration. Time points should be chosen based on the intratumoral spatio-temporal drug distribution.

Compartmental Targeting for mTHPC-Based Photodynamic Treatment In Vivo: Correlation of Efficiency, Pharmacokinetics, and Regional Distribution of Apoptosis

Type II photo-oxidation depends on and consumes oxygen. Several factors, including the concentration of photosensitizer and the radiation fluence rate, determine the rate of oxygen consumption in tissue undergoing Photodynamic Therapy. If the tissue capillary density is sparse, as it is in many human tumors, our calculations indicate that for cells sufficiently distant from the nearest capillary, fluence rates commonly used in PDT (50 - 200 mW/cm2) deplete 3O2 levels below those necessary for 1O2 formation. The calculations suggest that under these conditions reduced fluence rates and radiation dose fractionation should be more effective than continuous radiation at high fluence rates in producing 1O2 throughout the treated tissue volume. These predictions are supported by results obtained in vivo. The data and their interpretation have implications for PDT dosimetry and offer the possibility of improved therapeutic ratio.© (1992) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Analysis of photochemical oxygen consumption effects in photodynamic therapy (Invited Paper)

The shift in optical absorption of hemoglobin upon binding of oxygen provides a basis for near-infrared monitoring of hemoglobin oxygen saturation, which is an important indicator of tissue oxygenation. Tumor oxygenation has long been studied, because hypoxic cells exhibit resistance to ionizing radiation therapy. The ability to measure noninvasively the oxygenation status of tumors and their response to oxygen modifiers is important in research and clinical settings. We have implemented a steady-state diffuse reflectance method of optical spectroscopy in scattering systems based on the theory of Farrell et al. (Med. Phys., 1992). In scattering phantoms containing erythrocytes, the method recovers the hemoglobin absorption spectrum (650 - 820 nm) and accurately monitors hemoglobin oxygen saturation. We have implemented a probe that individually positions several detection fibers normal to the surface of subcutaneous rodent tumors. Near-infrared absorption spectra reconstructed from diffuse reflectance measurements indicate a hemoglobin oxygen saturation of approximately 50% in R3230AC rat mammary adenocarcinomas when the anesthetized animal breathes room air. Administration of carbogen (95% oxygen, 5% carbon dioxide) via a nose cone produces a rapid and readily detectable increase in the saturation to 75% with no increase in tumor blood volume. Several methods of determining hemoglobin oxygen saturation from absorption spectra obtained by diffuse reflectance spectroscopy are compared, including singular value decomposition, which provides the ability to reconstruct the non-hemoglobin absorbing background without a priori knowledge of its structure or absolute magnitude.

Noninvasive near-infrared hemoglobin spectroscopy for in vivo monitoring of tumor oxygenation and response to oxygen modifiers

We have studied the response of human mesothelioma xenografts in nude mice to Photofrin-sensitised photodynamic therapy with 514 nm light. Delays in tumour regrowth following four different 514 nm irradiation regimens were compared with results obtained with the more commonly used 630 nm light. One of these 514 nm regimens, which consisted of 1 h of irradiation at an incident fluence rate of 20 mW cm-2 and a second hour at a fluence rate of 28 mW cm-2, produced tumour volume doubling times that were statistically indistinguishable from results that were observed when tumours were irradiated for 2 h with 630 nm light at an incident fluence rate of 50 mW cm-2. The three other 514 nm light protocols tested were found to be less effective than the 630 nm regimen. The 514 nm treatment protocols were devised on the basis of attempts to equate the photodynamic dose and the dose rate at these two wavelengths, with photodynamic dose defined as the number of photons absorbed by the sensitiser. Photosensitiser extinction coefficients, photon energies and tissue optical properties were considered in these attempts. Our results indicate that, under certain conditions, photodynamic therapy performed with 514 nm light can provide tumour control that is similar to that achieved with 630 nm, with potential for diminished normal tissue damage.

Response of Photofrin-sensitised mesothelioma xenografts to photodynamic therapy with 514 nm light.

An instrument for photodynamic therapy applies treatment light from a dye laser, white light, and ultraviolet fluorescence excitation light from an LED onto a lesion and surrounding areas in a time-multiplexed manner. The reflected white light is analyzed in a spectrometer to determine a correction for the dynamic optical spectral properties of the patient's tissue. Light emitted by fluorescence from the lesion and the surrounding areas is analyzed in another spectrometer, and the results are corrected in a computer, using the correction. An optical switch has been developed for the instrument, using a bistable solenoid and a sled.

Thomas H. Foster

Papers

Compartmental Targeting for mTHPC-Based Photodynamic Treatment In Vivo: Correlation of Efficiency, Pharmacokinetics, and Regional Distribution of Apoptosis

Analysis of photochemical oxygen consumption effects in photodynamic therapy (Invited Paper)

Noninvasive near-infrared hemoglobin spectroscopy for in vivo monitoring of tumor oxygenation and response to oxygen modifiers

Response of Photofrin-sensitised mesothelioma xenografts to photodynamic therapy with 514 nm light.

Photodynamic therapy with spatially resolved dual spectroscopic monitoring