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Wood, and L. Eastman, Appl. Eizenberg, M. Heiblum, M. Nathan, et al. Zhang, Mater. Gunter, D. Dugas, X. Yang, et al.
Bozhkov, Izv. Lee, M. Shur, T. Drummond, and H. Electron Dev. ADS Google Scholar. B, 19 , No. Vinichenko, M. Grekhov, et al. Broom, et al. Both this state and the ground state are spectroscopic singlet states.
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One essential property of a good photosensitizer is a high intersystem crossing ISC yield, i. In the state, the photosensitizer can transfer energy to molecular oxygen , exciting it to its highly reactive singlet state. The details of this energy transfer process are beyond the scope of this article but have been an area of active study.
Energy level diagram for a typical type II photosensitizer and oxygen. The sensitizer in its ground state absorbs a photon of light and is excited to its first singlet state. It spontaneously decays to its excited triplet state via ISC. From , energy is transferred to ground state molecular oxygen , creating reactive singlet oxygen.
Two approaches have been used to study PDT dynamics. First, a microscopic model takes into account diffusion of oxygen and photosensitizer from blood vessels and can determine the singlet oxygen concentration in cells microscopically. Foster et al. If the rate of photochemical oxygen consumption is greater than the rate at which oxygen can be resupplied by the vasculature or ambient medium, an induction of transient hypoxia by PDT can result.
This effect has been modeled theoretically and has been demonstrated in cell spheroids, 17 animals, 19 and human tissues, 20 and continues to be an area of active research. PDT became popular after the invention of the laser, which allowed the production of monochromatic light that could be easily coupled into optical fibers. Early lasers were based on either argon gas lasers and Development of more powerful and cheaper laser sources, e.
The invention of optical fiber allowed light to be directed easily to deliver irradiation to desired regions without the requirement of a straight light path and is another enabler of PDT. Currently, most PDT procedures are performed with optical fibers. By attaching diffuse scattering tips of various geometrical shapes at the exit end of the fiber, point, linear, and planar light sources can be produced.
Light distributions can be modeled using the diffusion approximation to radiative transport.
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In these regions Monte Carlo simulation provides more accurate results but is much slower. Three general strategies have been developed for dosimetry based on the cumulative dose of singlet oxygen, which is presumed to be predictive of tissue damage.
Explicit dosimetry refers to the prediction of singlet oxygen dose on the basis of measurable quantities that contribute to the photodynamic effect. The distributions of photosensitizer and oxygenation can be measured via optical spectroscopy, as described above. In current clinical practice, however, the quantity most straightforward to measure is the light dose. Flat photodiode detectors have been used to measure the incident irradiance at the tissue surface in intraoperative PDT.
Detectors based on optical fibers overcome this problem by collecting light isotropically. Because complete explicit dosimetry requires measurement of three different parameters, it is inherently challenging. Two alternatives have been suggested that require measurement of only a single parameter.
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Implicit dosimetry 31 uses a quantity such as fluorescence photobleaching of the photosensitizer, which is indirectly predictive of the production of singlet oxygen. Strategies for direct and implicit dosimetry are under development and will be discussed in later sections. The most commonly used medical imaging modalities include ultrasound, computer tomography CT , magnetic resonance, magnetic resonance spectroscopy, single photon emission computer tomography, and positron emission tomography PET. The first three modalities produce excellent anatomical images, while the latter three provide functional information e.
Diffuse optical tomography DOT is a viable new biomedical imaging modality.
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In addition, it provides access to a variety of physiological parameters that cannot otherwise be measured easily. Another modality, optical coherence tomography OCT uses coherent light to obtain high resolution images. Most image reconstruction of DOT is based on solving the inverse problem for the diffusion equation.
Interested readers can find more information from some excellent review articles. The concept of absorption and fluorescence spectroscopy as a modality for the diagnosis of disease dates back several decades. In addition to its role in diagnosis, spectroscopy is particularly applicable to PDT in determining the local drug and oxygen concentrations.
Photodynamic therapy can cause changes in the concentration and oxygenation of blood in tissue both directly, through photochemical oxygen consumption, and indirectly, through effects on the vasculature and general physiological responses. The monitoring of these responses may, therefore, be predictive of treatment outcome. This quantity can be related to the oxygen concentration in the blood using the Hill curve. Various photosensitizing drugs have been developed. First, its absorption peak occurs at too short a wavelength to allow deep penetration in tissue.
In preclinical trials, it was observed that verteporfin preferentially targeted neovasculature.
The role of photodynamic therapy (PDT) physics
Verteporfin was approved in the U. When taken up by cells, however, it is converted by a naturally occurring biosynthetic process into the photosensitizer protoporphyrin IX PpIX. Table I summaries several of the more widely used photosensitizers currently available. From the point of view of biological response, PDT is fundamentally different from other cancer therapies. The specific subcellular targets damaged by PDT depend on the photosensitizer's localization within the cell, which varies among photosensitizers and cell lines.
Different types of damage can lead to different mechanisms of cell death. Damage to mitochondria in particular can lead to apoptosis even at relatively low light doses. Photosensitizers that are retained in the vasculature can destroy tumors via vascular damage rather than direct cell killing. Some photosensitizers may act as vascular agents at short times after injection and at high fluence rates, where only the vasculature is sufficiently oxygenated, and produce direct cell kill at low fluence rates and long times after injection.
Much of the research in the early decades of PDT and its related fields proceeded in five almost independent areas, as illustrated in the top row of Fig. The problems associated with light source and light delivery system development, dosimetry, and optical imaging were treated as physics problems, while photosensitizer development and PDT biology were treated as problems of chemistry and biology, respectively.
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In recent years, however, the most promising advances have come out of interdisciplinary collaborations among these areas. The systems and strategies currently in preclinical and clinical trials are examples of such collaborations. Diagram illustrating the progress of PDT development from a set of disparate fields top row to a collaborative effort unifying the contributions of biologists, chemists, physicists, and engineers.
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The second row illustrates the current state of art of research and represents integration of two separate fields. School of Semiconducting Compounds, Jaszowiec, 84 , No. Okamoto, C. Wood, and L. Eastman, Appl.
Eizenberg, M. Heiblum, M.