1.1 Photodynamic Therapy and Imaging
The purpose of this review is to present the current state of the role of imaging in photodynamic therapy (PDT). In order for the reader to fully appreciate the context of the discussions embodied in this article we begin with an overview of the PDT process, starting with a brief historical perspective followed by detailed discussions of specific applications of imaging in PDT. Each section starts with an overview of the specific topic and, where appropriate, ends with summary and future directions. The review closes with the authors’ perspective of the areas of future emphasis and promise. The basic premise of this review is that a combination of imaging and PDT will provide improved research and therapeutic strategies.

PDT is a photochemistry-based approach that uses a light-activatable chemical, termed a photosensitizer (PS), and light of an appropriate wavelength, to impart cytotoxicity via the generation of reactive molecular species (Figure 1a). In clinical settings, the PS is typically administered intravenously or topically, followed by illumination using a light delivery system suitable for the anatomical site being treated (Figure 1b). The time delay, often referred to as drug-light interval, between PS administration and the start of illumination with currently used PSs varies from 5 minutes to 24 hours or more depending on the specific PS and the target disease. Strictly speaking, this should be referred to as the PS-light interval, as at the concentrations typically used the PS is not a drug, but the drug-light interval terminology seems to be used fairly frequently. Typically, the useful range of wavelengths for therapeutic activation of the PS is 600 to 800 nm, to avoid interference by endogenous chromophores within the body, and yet maintain the energetics necessary for the generation of cytotoxic species (as discussed below) such as singlet oxygen (1O2). However, it is important to note that photosensitizers can also serve as fluorescence imaging agents for which activation with light in the 400nm range is often used and has been extremely useful in diagnostic imaging applications as described extensively in Section 2 of this review. The obvious limitation of short wavelength excitation is the lack of tissue penetration so that the volumes that are probed under these conditions are relatively shallow.






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Figure 1


(A) A schematic representation of PDT where PS is a photoactivatable multifunctional agent, which, upon light activation can serve as both an imaging agent and a therapeutic agent. (B) A schematic representation of the sequence of administration, localization and light activation of the PS for PDT or fluorescence imaging. Typically the PS is delivered systemically and allowed to circulate for an appropriate time interval (the “drug-light interval”), during which the PS accumulates preferentially in the target lesion(s) prior to light activation. In the idealized depiction here the PS is accumulation is shown to be entirely in the target tissue, however, even if this is not the case, light delivery confers a second layer of selectivity so that the cytotoxic effect will be generated only in regions where both drug and light are present. Upon localization of the PS, light activation will result in fluorescence emission which can be implemented for imaging applications, as well as generation cytotoxic species for therapy. In the former case light activation is achieved with a low fluence rate to generate fluorescence emission with little or no cytotoxic effect, while in the latter case a high fluence rate is used to generate a sufficient concentration of cytotoxic species to achieve biological effects.

/pdf/imaging-and-photodynamic-therapy-mechanisms-monitoring-and-76rc7acuq5.pdf

Imaging and photodynamic therapy: mechanisms, monitoring, and optimization.

5-Aminolaevulinic acid (ALA) is a precursor of protoporphyrin IX (Pp IX) in the biosynthetic pathway for haem. Certain types of cells have a large capacity to synthesize Pp IX when exposed to an adequate concentration of exogenous ALA. Since the conversion of Pp IX into haem is relatively slow, such cells tend to accumulate photosensitizing concentrations of Pp IX. Pp IX photosensitization can be induced in cells of the epidermis and its appendages, but not in the dermis. Moreover, since ALA in aqueous solution passes readily through abnormal keratin, but not through normal keratin, the topical application of ALA in aqueous solution to actinic keratoses or superficial basal cell or squamous cell carcinomas induces Pp IX photosensitization that is restricted primarily to the abnormal epithelium. Subsequent exposure to photoactivating light selectively destroys such lesions. In our ongoing clinical trial of ALA-induced Pp IX photodynamic therapy, the response rate for basal cell carcinomas following a single treatment has been 90% complete response and 7.5% partial response for the first 80 lesions treated. The cosmetic results have been excellent, and patient acceptance has been very good.

Photodynamic therapy with endogenous protoporphyrin IX: basic principles and present clinical experience.

Glucose oxidase: an ideal enzyme

The tissue photosensitizer protoporphyrin IX (PpIX) is an immediate precursor of heme in the biosynthetic pathway for heme. In certain types of cells and tissues, the rate of synthesis of PpIX is determined by the rate of synthesis of 5-aminolevulinic acid (ALA), which in turn is regulated via a feedback control mechanism governed by the concentration of free heme. The presence of exogenous ALA bypasses the feedback control, and thus may induce the intracellular accumulation of photosensitizing concentrations of PpIX. However, this occurs only in certain types of cells and tissues. The resulting tissue-specific photosensitization provides a basis for using ALA-induced PpIX for photodynamic therapy. The topical application of ALA to certain malignant and non-malignant lesions of the skin can induce a clinically useful degree of lesion-specific photosensitization. Superficial basal cell carcinomas showed a complete response rate of approximately 79% following a single exposure to light. Recent preclinical studies in experimental animals and human volunteers indicate that ALA can induce a localized tissue-specific photosensitization if administered by intradermal injection. A generalized but still quite tissue-specific photosensitization may be induced if ALA is administered by either subcutaneous or intraperitoneal injection or by mouth. This opens the possibility of using ALA-induced PpIX to treat tumors that are too thick or that lie too deep to be accessible to either topical or locally injected ALA.

Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy.

BACKGROUND
Photodynamic therapy (PDT) for cancer patients has developed into an important new clinical treatment modality in the past 25 years PDT involves administration of a tumor-localizing photosensitizer or photosensitizer prodrug (5-aminolevulinic acid [ALA], a precursor in the heme biosynthetic pathway) and the subsequent activation of the photosensitizer by light Although several photosensitizers other than ALA-derived protoporphyrin IX (PpIX) have been used in clinical PDT, ALA-based PDT has been the most active area of clinical PDT research during the past 5 years Studies have shown that a higher accumulation of ALA-derived PpIX in rapidly proliferating cells may provide a biologic rationale for clinical use of ALA-based PDT and diagnosis However, no review updating the clinical data has appeared so far

METHODS
A review of recently published data on clinical ALA-based PDT and diagnosis was conducted

RESULTS
Several individual studies in which patients with primary nonmelanoma cutaneous tumors received topical ALA-based PDT have reported promising results, including outstanding cosmetic results However, the modality with present protocols does not, in general, appear to be superior to conventional therapies with respect to initial complete response rates and long term recurrence rates, particularly in the treatment of nodular skin tumors Topical ALA-PDT does have the following advantages over conventional treatments: it is noninvasive; it produces excellent cosmetic results; it is well tolerated by patients; it can be used to treat multiple superficial lesions in short treatment sessions; it can be applied to patients who refuse surgery or have pacemakers and bleeding tendency; it can be used to treat lesions in specific locations, such as the oral mucosa or the genital area; it can be used as a palliative treatment; and it can be applied repeatedly without cumulative toxicity Topical ALA-PDT also has potential as a treatment for nonneoplastic skin diseases Systemic administration of ALA does not seem to be severely toxic, but the advantage of using this approach for PDT of superficial lesions of internal hollow organs is still uncertain The ALA-derived porphyrin fluorescence technique would be useful in the diagnosis of superficial lesions of internal hollow organs

CONCLUSIONS
Promising results of ALA-based clinical PDT and diagnosis have been obtained The modality has advantages over conventional treatments However, some improvements need to be made, such as optimization of parameters of ALA-based PDT and diagnosis; increased tumor selectivity of ALA-derived PpIX; better understanding of light distribution in tissue; improvement of light dosimetry procedure; and development of simpler, cheaper, and more efficient light delivery systems Cancer 1997; 79:2282-308 © 1997 American Cancer Society

5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges.

Adams, D. H. (1949). Biochim. Biophy8. Acta, 3, 1. Adams, D. H. & Whittaker, V. P. (1949a). Biochem. J. 44, 62. Adams, D. H. & Whittaker, V. P. (1949b). Biochim. Biophy8. Acta, 3, 358. Ammon, R. (1933). PflJug. Arch. ge8. Phy8iol. 233, 486. Arragon, G. & Sala, E. (1948). Bull. Soc. Chim. biol., Pari8, 30, 44. Huidobro, E. & Atria, P. (1949). J. Pharmacol. 96, 438. Levine, M. G. & Suran, A. A. (1950). Nature, Lond., 166,698. Little, J. M. (1948). Amer. J. Phy8iol. 153, 436. McCance, R. A. (1950). Private communication. McMeekin, T. L. (1939). J. biol. Chem. 128, lxvi. Markham, R. (1942). Biochem. J. 36, 790. Mendel, B. & Mundell, D. B. (1943). Biochem. J. 37, 64. Mendel, B. & Rudney, H. (1943). Biochem. J. 37, 59. Mentha, J., Sprinz, H. & Barnard, R. (1947). J. biol. Chem. 167, 623. Mounter, L. A. & Whittaker, V. P. (1950). Biochem. J. 47, 525. Nachmansohn, D. & Rothenberg, M. A. (1945). J. biol. Chem. 158, 653. Nachmansohn, D. & Rothenberg, M. A. (1947). J. biol. Chem. 168, 223. Ord, M. G. & Thompson, R. H. S. (1950). Biochem. J. 40,346. Rossiter, R. J. (1949). J. Physiol. 110, 136. Sawyer, C. H. (1945). Science, 101, 385. Stedman, E. & Stedman, E. (1935). Biochem. J. 29, 2563. Strelitz, F. (1944). Biochem. J. 38, 86. Sturge, L. M. & Whittaker, V. P. (1950). Biochem. J. 47,518.

/pdf/the-relative-metabolic-inertia-of-tendon-collagen-in-the-rat-1zjy57lx4o.pdf

The relative metabolic inertia of tendon collagen in the rat.

1. The presence of astaxanthin in the shell of Ophidiaster ophidianus is confirmed, and that of #-carotene and cryptoxanthin demonstrated. neop-Carotene B and y-carotene are also probably present. 2. Three new pigments are reported: two are probably keto-carotenoids. 3. The quantitative distribution of carotenoids in the shell of 0. ophidianus is recorded. 4. A possible biosynthetic route from ,-carotene to astaxanthin is discussed.

/pdf/the-metabolism-of-collagen-and-other-proteins-of-the-skin-of-3u02zq949z.pdf

The metabolism of collagen and other proteins of the skin of rabbits.

/pdf/studies-in-congenital-porphyria-2-incorporation-of-15n-in-4it7nj81h3.pdf

Studies in congenital porphyria. 2. Incorporation of 15N in the stercobilin in the normal and in the porphyric.

/pdf/the-metabolism-of-d-aminolaevulic-acid-1-normal-pathways-39grdyn9dj.pdf

The metabolism of δ-aminolaevulic acid. 1. Normal pathways, studied with the aid of 15N

Aminolaevulinic acid and porphyrin biosynthesis.

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